Cancers

Article

16 pages, 3171 KiB

Open AccessEditor’s ChoiceArticle

Prognostic and Predictive Role of Body Composition in Metastatic Neuroendocrine Tumor Patients Treated with Everolimus: A Real-World Data Analysis

by Nicoletta Ranallo, Andrea Prochoswski Iamurri, Flavia Foca, Chiara Liverani, Alessandro De Vita, Laura Mercatali, Chiara Calabrese, Chiara Spadazzi, Carlo Fabbri, Davide Cavaliere, Riccardo Galassi, Stefano Severi, Maddalena Sansovini, Andreas Tartaglia, Federica Pieri, Laura Crudi, David Bianchini, Domenico Barone, Giovanni Martinelli, Giovanni Luca Frassineti, Toni Ibrahim, Luana Calabrò, Rossana Berardi and Alberto Bongiovanni Show full author list Hide full author list

Cancers 2022, 14(13), 3231; https://doi.org/10.3390/cancers14133231 - 30 Jun 2022

Cited by 9 | Viewed by 2911

Abstract

Neuroendocrine tumors (NETs) are rare neoplasms frequently characterized by an upregulation of the mammalian rapamycin targeting (mTOR) pathway resulting in uncontrolled cell proliferation. The mTOR pathway is also involved in skeletal muscle protein synthesis and in adipose tissue metabolism. Everolimus inhibits the mTOR [...] Read more.

Neuroendocrine tumors (NETs) are rare neoplasms frequently characterized by an upregulation of the mammalian rapamycin targeting (mTOR) pathway resulting in uncontrolled cell proliferation. The mTOR pathway is also involved in skeletal muscle protein synthesis and in adipose tissue metabolism. Everolimus inhibits the mTOR pathway, resulting in blockade of cell growth and tumor progression. The aim of this study is to investigate the role of body composition indexes in patients with metastatic NETs treated with everolimus. The study population included 30 patients with well-differentiated (G1-G2), metastatic NETs treated with everolimus at the IRCCS Romagnolo Institute for the Study of Tumors (IRST) “Dino Amadori”, Meldola (FC), Italy. The body composition indexes (skeletal muscle index [SMI] and adipose tissue indexes) were assessed by measuring on a computed tomography (CT) scan the cross-sectional area at L3 at baseline and at the first radiological assessment after the start of treatment. The body mass index (BMI) was assessed at baseline. The median progression-free survival (PFS) was 8.9 months (95% confidence interval [CI]: 3.4–13.7 months). The PFS stratified by tertiles was 3.2 months (95% CI: 0.9–10.1 months) in patients with low SMI (tertile 1), 14.2 months (95% CI: 2.3 months-not estimable [NE]) in patients with intermediate SMI (tertile 2), and 9.1 months (95% CI: 2.7 months-NE) in patients with high SMI (tertile 3) (p = 0.039). Similarly, the other body composition indexes also showed a statistically significant difference in the three groups on the basis of tertiles. The median PFS was 3.2 months (95% CI: 0.9–6.7 months) in underweight patients (BMI ≤ 18.49 kg/m²) and 10.1 months (95% CI: 3.7–28.4 months) in normal-weight patients (p = 0.011). There were no significant differences in terms of overall survival. The study showed a correlation between PFS and the body composition indexes in patients with NETs treated with everolimus, underlining the role of adipose and muscle tissue in these patients. Full article

(This article belongs to the Special Issue Updates on Diagnostic and Therapeutic Management of Neuroendocrine Neoplasms)

► Show Figures

Figure 1

17 pages, 3161 KiB

Open AccessEditor’s ChoiceArticle

Targeting Immunosuppressive Tumor-Associated Macrophages Using Innate T Cells for Enhanced Antitumor Reactivity

by Yan-Ruide Li, James Brown, Yanqi Yu, Derek Lee, Kuangyi Zhou, Zachary Spencer Dunn, Ryan Hon, Matthew Wilson, Adam Kramer, Yichen Zhu, Ying Fang and Lili Yang

Cancers 2022, 14(11), 2749; https://doi.org/10.3390/cancers14112749 - 1 Jun 2022

Cited by 46 | Viewed by 6383

Abstract

The field of T cell-based and chimeric antigen receptor (CAR)-engineered T (CAR-T) cell-based antitumor immunotherapy has seen substantial developments in the past decade; however, considerable issues, such as graft-versus-host disease (GvHD) and tumor-associated immunosuppression, have proven to be substantial roadblocks to widespread adoption [...] Read more.

The field of T cell-based and chimeric antigen receptor (CAR)-engineered T (CAR-T) cell-based antitumor immunotherapy has seen substantial developments in the past decade; however, considerable issues, such as graft-versus-host disease (GvHD) and tumor-associated immunosuppression, have proven to be substantial roadblocks to widespread adoption and implementation. Recent developments in innate immune cell-based CAR therapy have opened several doors for the expansion of this therapy, especially as it relates to allogeneic cell sources and solid tumor infiltration. This study establishes in vitro killing assays to examine the TAM-targeting efficacy of MAIT, iNKT, and γδT cells. This study also assesses the antitumor ability of CAR-engineered innate T cells, evaluating their potential adoption for clinical therapies. The in vitro trials presented in this study demonstrate the considerable TAM-killing abilities of all three innate T cell types, and confirm the enhanced antitumor abilities of CAR-engineered innate T cells. The tumor- and TAM-targeting capacity of these innate T cells suggest their potential for antitumor therapy that supplements cytotoxicity with remediation of tumor microenvironment (TME)-immunosuppression. Full article

(This article belongs to the Special Issue Engineering the Tumor Immune Microenvironment)

► Show Figures

Figure 1

19 pages, 2247 KiB

Open AccessEditor’s ChoiceArticle

Gallic Acid: A Natural Phenolic Compound Exerting Antitumoral Activities in Colorectal Cancer via Interaction with G-Quadruplexes

by Victoria Sanchez-Martin, María del Carmen Plaza-Calonge, Ana Soriano-Lerma, Matilde Ortiz-Gonzalez, Angel Linde-Rodriguez, Virginia Perez-Carrasco, Inmaculada Ramirez-Macias, Marta Cuadros, Jose Gutierrez-Fernandez, Javier Murciano-Calles, Juan Carlos Rodríguez-Manzaneque, Miguel Soriano and Jose Antonio Garcia-Salcedo

Cancers 2022, 14(11), 2648; https://doi.org/10.3390/cancers14112648 - 26 May 2022

Cited by 29 | Viewed by 3634

Abstract

Natural phenolic compounds have gained momentum for the prevention and treatment of cancer, but their antitumoral mechanism of action is not yet well understood. In the present study, we screened the antitumoral potential of several phenolic compounds in a cellular model of colorectal [...] Read more.

Natural phenolic compounds have gained momentum for the prevention and treatment of cancer, but their antitumoral mechanism of action is not yet well understood. In the present study, we screened the antitumoral potential of several phenolic compounds in a cellular model of colorectal cancer (CRC). We selected gallic acid (GA) as a candidate in terms of potency and selectivity and extensively evaluated its biological activity. We report on the role of GA as a ligand of DNA G-quadruplexes (G4s), explaining several of its antitumoral effects, including the transcriptional inhibition of ribosomal and CMYC genes. In addition, GA shared with other established G4 ligands some effects such as cell cycle arrest, nucleolar stress, and induction of DNA damage. We further confirmed the antitumoral and G4-stabilizing properties of GA using a xenograft model of CRC. Finally, we succinctly demonstrate that GA could be explored as a therapeutic agent in a patient cohort with CRC. Our work reveals that GA, a natural bioactive compound present in the diet, affects gene expression by interaction with G4s both in vitro and in vivo and paves the way towards G4s targeting with phenolic compounds. Full article

► Show Figures

Figure 1

12 pages, 1890 KiB

Open AccessEditor’s ChoiceArticle

Sex Differences in the Prevalence of Head and Neck Cancers: A 10-Year Follow-Up Study of 10 Million Healthy People

by Jun-Ook Park, Inn-Chul Nam, Choung-Soo Kim, Sung-Joon Park, Dong-Hyun Lee, Hyun-Bum Kim, Kyung-Do Han and Young-Hoon Joo

Cancers 2022, 14(10), 2521; https://doi.org/10.3390/cancers14102521 - 20 May 2022

Cited by 67 | Viewed by 4866

Abstract

Background: Descriptive epidemiologists have repeatedly reported that males are more susceptible to head and neck cancers. However, most published data are those of cross-sectional studies, and no population-based cohort study has yet been published. The aim of this study was to compare the [...] Read more.

Background: Descriptive epidemiologists have repeatedly reported that males are more susceptible to head and neck cancers. However, most published data are those of cross-sectional studies, and no population-based cohort study has yet been published. The aim of this study was to compare the prevalence of head and neck cancers in healthy males with females. Methods: A retrospective cohort study using the Korean National Health Insurance Service database on 9,598,085 individuals who underwent regular health checkups from 1 January to 31 December 2009. We sought head and neck cancers developed during the 10-year follow-up. Results: A total of 10,732 (incidence rate (IR) per 1000 person-years 0.25) individuals were newly diagnosed with head and neck cancer among the 9,598,085 individuals during the 10-year follow-up. The IR was 0.19 in males (8500 affected) and 0.06 in females (2232 affected). Notably, the male–female ratio increased with age below 70 years but decreased thereafter. The male–female difference was most apparent for laryngeal cancer; the male IR was 11-fold higher in the 40 s and 20-fold higher in the 60 s, followed by hypopharyngeal cancer (6.8- and 24.2-fold). Males smoked more and drank more alcohol than females (p < 0.0001 *, p < 0.0001 *). When never-smokers/-drinkers (only) were compared, males remained at a 2.9-fold higher risk of head and neck cancer than females. The hazard ratios for head and neck cancers in males tended to increase in the lower part of the upper aerodigestive tract: larynx (13.9) > hypopharynx (10.9) > oropharynx (4.4) > nasopharynx (2.9) > sinonasal region (1.8) > oral (1.6). Only the salivary gland cancer incidence did not differ between the sexes; the gland is not in the upper aerodigestive tract. Conclusion: Males are much more susceptible to head and neck cancers than females regardless of whether they drink alcohol or smoke tobacco. Sex differences in the incidence of head and neck cancer are most evident in the 60 s in the lower part of the upper aerodigestive tract, such as the larynx and hypopharynx. Full article

(This article belongs to the Topic Big Data in Healthcare, Bioinformatics and Precision Medicine)

► Show Figures

Figure 1

12 pages, 902 KiB

Open AccessEditor’s ChoiceArticle

Impact of HER2 Status on Pathological Response after Neoadjuvant Chemotherapy in Early Triple-Negative Breast Cancer

by Camille Domergue, Elodie Martin, Camille Lemarié, Pascal Jézéquel, Jean-Sebastien Frenel, Paule Augereau, Mario Campone and Anne Patsouris

Cancers 2022, 14(10), 2509; https://doi.org/10.3390/cancers14102509 - 19 May 2022

Cited by 42 | Viewed by 3223

Abstract

Purpose: Investigates the link between HER2 status and histological response after neoadjuvant chemotherapy in patients with early TNBC. Methods: We retrieved clinical and anatomopathological data retrospectively from 449 patients treated for the first time with standard neoadjuvant chemotherapy for early unilateral BC between [...] Read more.

Purpose: Investigates the link between HER2 status and histological response after neoadjuvant chemotherapy in patients with early TNBC. Methods: We retrieved clinical and anatomopathological data retrospectively from 449 patients treated for the first time with standard neoadjuvant chemotherapy for early unilateral BC between 2005 and 2020. The primary endpoint was pathological complete response (pCR, i.e., ypT0 ypN0), according to HER2 status. Secondary endpoints included invasive disease-free survival (I-DFS) and overall survival (OS). Results: 437 patients were included, and 121 (27.7%) patients had HER2-low tumours. The pCR rate was not significantly different between the HER2-low group vs. the HER2-0 group (35.7% versus 41.8%, p = 0.284) in either univariate analysis or multivariate analysis adjusted for TNM classification and grade (odds ratio [OR] = 0.70, confidence interval [CI] 95% 0.45–1.08). With a median follow-up of 72.9 months, no significant survival differences were observed between patients with HER2-low tumours vs. patients with HER2-0 tumours in terms of I-DFS (p = 0.487) and OS (p = 0.329). Conclusions: In our cohort, HER2 status was not significantly associated with pCR in a manner consistent with data published recently on TNBC. However, the prognostic impact of HER2-low expression among TNBC patients warrants further evaluation. Full article

(This article belongs to the Section Cancer Biomarkers)

► Show Figures

Figure 1

12 pages, 1601 KiB

Open AccessEditor’s ChoiceArticle

Worldwide Burden, Risk Factors, and Temporal Trends of Ovarian Cancer: A Global Study

by Junjie Huang, Wing Chung Chan, Chun Ho Ngai, Veeleah Lok, Lin Zhang, Don Eliseo Lucero-Prisno III, Wanghong Xu, Zhi-Jie Zheng, Edmar Elcarte, Mellissa Withers, Martin C. S. Wong and on behalf of NCD Global Health Research Group of Association of Pacific Rim Universities (APRU)

Cancers 2022, 14(9), 2230; https://doi.org/10.3390/cancers14092230 - 29 Apr 2022

Cited by 180 | Viewed by 16505

Abstract

This study aimed to investigate the most updated worldwide incidence and mortality, risk factors, and epidemiologic trend of ovarian cancer in different countries, regions, and age groups. The Global Cancer Observatory database was used for incidence and mortality rates of ovarian cancer in [...] Read more.

This study aimed to investigate the most updated worldwide incidence and mortality, risk factors, and epidemiologic trend of ovarian cancer in different countries, regions, and age groups. The Global Cancer Observatory database was used for incidence and mortality rates of ovarian cancer in 2020. Data from Cancer Incidence in Five Continents and the WHO mortality database was accessed for trend analysis. Age-standardized rates (ASRs, per 100,000 persons) were calculated for incidence and mortality. The 10-year annual average percent change (AAPC) was estimated by Joinpoint regression analysis. There was an overall decreasing trend of ovarian cancer, yet its burden has been increasing in lower-income countries and among younger females in some countries. Intensive lifestyle modifications are warranted, especially for the populations at high risk for ovarian cancer, including smoking cessation, alcohol use reduction, physical activity, weight control, and treatment of metabolic diseases. Full article

(This article belongs to the Special Issue Gynaecological Cancer and Surgery: Current Practice, Novel Technologies and Future Developments)

► Show Figures

Figure 1

24 pages, 3780 KiB

Open AccessEditor’s ChoiceArticle

Spatial Characterization of Tumor-Infiltrating Lymphocytes and Breast Cancer Progression

by Danielle J. Fassler, Luke A. Torre-Healy, Rajarsi Gupta, Alina M. Hamilton, Soma Kobayashi, Sarah C. Van Alsten, Yuwei Zhang, Tahsin Kurc, Richard A. Moffitt, Melissa A. Troester, Katherine A. Hoadley and Joel Saltz

Cancers 2022, 14(9), 2148; https://doi.org/10.3390/cancers14092148 - 26 Apr 2022

Cited by 34 | Viewed by 7450

Abstract

Tumor-infiltrating lymphocytes (TILs) have been established as a robust prognostic biomarker in breast cancer, with emerging utility in predicting treatment response in the adjuvant and neoadjuvant settings. In this study, the role of TILs in predicting overall survival and progression-free interval was evaluated [...] Read more.

Tumor-infiltrating lymphocytes (TILs) have been established as a robust prognostic biomarker in breast cancer, with emerging utility in predicting treatment response in the adjuvant and neoadjuvant settings. In this study, the role of TILs in predicting overall survival and progression-free interval was evaluated in two independent cohorts of breast cancer from the Cancer Genome Atlas (TCGA BRCA) and the Carolina Breast Cancer Study (UNC CBCS). We utilized machine learning and computer vision algorithms to characterize TIL infiltrates in digital whole-slide images (WSIs) of breast cancer stained with hematoxylin and eosin (H&E). Multiple parameters were used to characterize the global abundance and spatial features of TIL infiltrates. Univariate and multivariate analyses show that large aggregates of peritumoral and intratumoral TILs (forests) were associated with longer survival, whereas the absence of intratumoral TILs (deserts) is associated with increased risk of recurrence. Patients with two or more high-risk spatial features were associated with significantly shorter progression-free interval (PFI). This study demonstrates the practical utility of Pathomics in evaluating the clinical significance of the abundance and spatial patterns of distribution of TIL infiltrates as important biomarkers in breast cancer. Full article

(This article belongs to the Special Issue Tumor Infiltrating Lymphocytes (TIL) in Solid Tumors: Emerging Insights)

► Show Figures

Figure 1

23 pages, 38669 KiB

Open AccessEditor’s ChoiceArticle

Efficient Small Extracellular Vesicles (EV) Isolation Method and Evaluation of EV-Associated DNA Role in Cell–Cell Communication in Cancer

by Venkatesh Kumar Chetty, Jamal Ghanam, Srishti Anchan, Katarina Reinhardt, Alexandra Brenzel, Márton Gelléri, Christoph Cremer, Elena Grueso-Navarro, Markus Schneider, Nils von Neuhoff, Dirk Reinhardt, Jadwiga Jablonska, Irina Nazarenko and Basant Kumar Thakur

Cancers 2022, 14(9), 2068; https://doi.org/10.3390/cancers14092068 - 20 Apr 2022

Cited by 14 | Viewed by 6920

Abstract

Small extracellular vesicles (sEVs) play essential roles in intercellular signaling both in normal and pathophysiological conditions. Comprehensive studies of dsDNA associated with sEVs are hampered by a lack of methods, allowing efficient separation of sEVs from free-circulating DNA and apoptotic bodies. In this [...] Read more.

Small extracellular vesicles (sEVs) play essential roles in intercellular signaling both in normal and pathophysiological conditions. Comprehensive studies of dsDNA associated with sEVs are hampered by a lack of methods, allowing efficient separation of sEVs from free-circulating DNA and apoptotic bodies. In this work, using controlled culture conditions, we enriched the reproducible separation of sEVs from free-circulated components by combining tangential flow filtration, size-exclusion chromatography, and ultrafiltration (TSU). EV-enriched fractions (F2 and F3) obtained using TSU also contained more dsDNA derived from the host genome and mitochondria, predominantly localized inside the vesicles. Three-dimensional reconstruction of high-resolution imaging showed that the recipient cell membrane barrier restricts a portion of EV-DNA. Simultaneously, the remaining EV-DNA overcomes it and enters the cytoplasm and nucleus. In the cytoplasm, EV-DNA associates with dsDNA-inflammatory sensors (cGAS/STING) and endosomal proteins (Rab5/Rab7). Relevant to cancer, we found that EV-DNA isolated from leukemia cell lines communicates with mesenchymal stromal cells (MSCs), a critical component in the BM microenvironment. Furthermore, we illustrated the arrangement of sEVs and EV-DNA at a single vesicle level using super-resolution microscopy. Altogether, employing TSU isolation, we demonstrated EV-DNA distribution and a tool to evaluate the exact EV-DNA role of cell–cell communication in cancer. Full article

(This article belongs to the Special Issue Biogenesis and Function of Extracellular Vesicles in Cancers)

► Show Figures

Figure 1

18 pages, 2344 KiB

Open AccessEditor’s ChoiceArticle

T-Cells Expressing a Highly Potent PRAME-Specific T-Cell Receptor in Combination with a Chimeric PD1-41BB Co-Stimulatory Receptor Show a Favorable Preclinical Safety Profile and Strong Anti-Tumor Reactivity

by Nadja Sailer, Ina Fetzer, Melanie Salvermoser, Monika Braun, Doris Brechtefeld, Christian Krendl, Christiane Geiger, Kathrin Mutze, Elfriede Noessner, Dolores J. Schendel, Maja Bürdek, Susanne Wilde and Daniel Sommermeyer

Cancers 2022, 14(8), 1998; https://doi.org/10.3390/cancers14081998 - 14 Apr 2022

Cited by 20 | Viewed by 9847

Abstract

The hostile tumor microenvironment (TME) is a major challenge for the treatment of solid tumors with T-cell receptor (TCR)-modified T-cells (TCR-Ts), as it negatively influences T-cell efficacy, fitness, and persistence. These negative influences are caused, among others, by the inhibitory checkpoint PD-1/PD-L1 axis. [...] Read more.

The hostile tumor microenvironment (TME) is a major challenge for the treatment of solid tumors with T-cell receptor (TCR)-modified T-cells (TCR-Ts), as it negatively influences T-cell efficacy, fitness, and persistence. These negative influences are caused, among others, by the inhibitory checkpoint PD-1/PD-L1 axis. The Preferentially Expressed Antigen in Melanoma (PRAME) is a highly relevant cancer/testis antigen for TCR-T immunotherapy due to broad expression in multiple solid cancer indications. A TCR with high specificity and sensitivity for PRAME was isolated from non-tolerized T-cell repertoires and introduced into T-cells alongside a chimeric PD1-41BB receptor, consisting of the natural extracellular domain of PD-1 and the intracellular signaling domain of 4-1BB, turning an inhibitory pathway into a T-cell co-stimulatory pathway. The addition of PD1-41BB to CD8+ T-cells expressing the transgenic PRAME-TCR enhanced IFN-γ secretion, improved cytotoxic capacity, and prevented exhaustion upon repetitive re-challenge with tumor cells in vitro without altering the in vitro safety profile. Furthermore, a single dose of TCR-Ts co-expressing PD1-41BB was sufficient to clear a hard-to-treat melanoma xenograft in a mouse model, whereas TCR-Ts without PD1-41BB could not eradicate the PD-L1-positive tumors. This cutting-edge strategy supports development efforts to provide more effective TCR-T immunotherapies for the treatment of solid tumors. Full article

(This article belongs to the Special Issue Engineering the Tumor Immune Microenvironment)

► Show Figures

Figure 1

13 pages, 6512 KiB

Open AccessEditor’s ChoiceArticle

Sarcopenia Predicts Major Complications after Resection for Primary Hepatocellular Carcinoma in Compensated Cirrhosis

by Giovanni Marasco, Elton Dajti, Matteo Serenari, Luigina Vanessa Alemanni, Federico Ravaioli, Matteo Ravaioli, Amanda Vestito, Giulio Vara, Davide Festi, Rita Golfieri, Matteo Cescon, Matteo Renzulli and Antonio Colecchia

Cancers 2022, 14(8), 1935; https://doi.org/10.3390/cancers14081935 - 12 Apr 2022

Cited by 21 | Viewed by 2626

Abstract

The burden of post-operative complications of patients undergoing liver resection for hepatocellular carcinoma (HCC) is a cause of morbidity and mortality. Recently, sarcopenia has been reported to influence the outcome of patients with cirrhosis. We aimed to assess factors associated with sarcopenia and [...] Read more.

The burden of post-operative complications of patients undergoing liver resection for hepatocellular carcinoma (HCC) is a cause of morbidity and mortality. Recently, sarcopenia has been reported to influence the outcome of patients with cirrhosis. We aimed to assess factors associated with sarcopenia and its prognostic role in liver surgery candidates. We included all patients with compensated advanced chronic liver disease (cACLD) undergoing liver resection for primary HCC consecutively referred to the University of Bologna from 2014 to 2019 with an available preoperative abdominal CT-scan performed within the previous three months. A total of 159 patients were included. The median age was 68 years, and 80.5% of the patients were male. Sarcopenia was present in 82 patients (51.6%). Age and body mass index (BMI) were associated with the presence of sarcopenia at multivariate analysis. Thirteen (8.2%) patients developed major complications and 14 (8.9%) presented PHLF grade B-C. The model for end-stage liver disease score was associated with the development of major complications, whereas cACLD presence, thrombocytopenia, portal hypertension (PH), Child-Pugh score and Albumin-Bilirubin score were found to be predictors of clinically significative PHLF. The rate of major complications was 11.8% in sarcopenic patients with cACLD compared with no complications (0%) in patients without sarcopenia and cACLD (p = 0.032). The rate of major complications was significantly higher in patients with (16.3%) vs. patients without (0%) sarcopenia (p = 0.012) in patients with PH. In conclusion, sarcopenia, which is associated with age and BMI, may improve the risk stratification of post-hepatectomy major complications in patients with cACLD and PH. Full article

(This article belongs to the Section Cancer Therapy)

► Show Figures

Figure 1

20 pages, 32847 KiB

Open AccessEditor’s ChoiceArticle

Anticancer Effects and Molecular Mechanisms of Apigenin in Cervical Cancer Cells

by Ya-Hui Chen, Jyun-Xue Wu, Shun-Fa Yang, Chueh-Ko Yang, Tze-Ho Chen and Yi-Hsuan Hsiao

Cancers 2022, 14(7), 1824; https://doi.org/10.3390/cancers14071824 - 4 Apr 2022

Cited by 43 | Viewed by 5787

Abstract

Cervical cancer is the fourth most frequent malignancy in women. Apigenin is a natural plant-derived flavonoid present in common fruit, vegetables, and herbs, and has been found to possess antioxidant and anti-inflammatory properties as a health-promoting agent. It also exhibits important anticancer effects [...] Read more.

Cervical cancer is the fourth most frequent malignancy in women. Apigenin is a natural plant-derived flavonoid present in common fruit, vegetables, and herbs, and has been found to possess antioxidant and anti-inflammatory properties as a health-promoting agent. It also exhibits important anticancer effects in various cancers, but its effects are not widely accepted by clinical practitioners. The present study investigated the anticancer effects and molecular mechanisms of apigenin in cervical cancer in vitro and in vivo. HeLa and C33A cells were treated with different concentrations of apigenin. The effects of apigenin on cell viability, cell cycle distribution, migration potential, phosphorylation of PI3K/AKT, the integrin β1-FAK signaling pathway, and epithelial-to-mesenchymal transition (EMT)-related protein levels were investigated. Mechanisms identified from the in vitro study were further validated in a cervical tumor xenograft mouse model. Apigenin effectively inhibited the growth of cervical cancer cells and cervical tumors in xenograft mice. Furthermore, the apigenin down-regulated FAK signaling (FAK, paxillin, and integrin β1) and PI3K/AKT signaling (PI3K, AKT, and mTOR), inactivated or activated various signaling targets, such as Bcl-2, Bax, p21^cip1, CDK1, CDC25c, cyclin B1, fibronectin, N-cadherin, vimentin, laminin, and E-cadherin, promoted mitochondrial-mediated apoptosis, induced G2/M-phase cell cycle arrest, and reduced EMT to inhibit HeLa and C33A cancer cell migration, producing anticancer effects in cervical cancer. Thus, apigenin may act as a chemotherapeutic agent for cervical cancer treatment. Full article

(This article belongs to the Special Issue Biological Basis of Anti-tumor Therapies)

► Show Figures

Figure 1

13 pages, 5003 KiB

Open AccessEditor’s ChoiceArticle

Expression of CD47 and SIRPα Macrophage Immune-Checkpoint Pathway in Non-Small-Cell Lung Cancer

by Alexandra Giatromanolaki, Achilleas Mitrakas, Ioannis Anestopoulos, Andreas Kontosis, Ioannis M. Koukourakis, Aglaia Pappa, Mihalis I. Panayiotidis and Michael I. Koukourakis

Cancers 2022, 14(7), 1801; https://doi.org/10.3390/cancers14071801 - 1 Apr 2022

Cited by 24 | Viewed by 4505

Abstract

Background: Cancer cells escape macrophage phagocytosis by expressing the CD47 integrin-associated protein that binds to the SIRPα ligand (signal regulatory protein alpha) expressed by macrophages. Immunotherapy targeting this pathway is under clinical development. Methods: We investigated the expression of CD47/SIRPα molecules in a [...] Read more.

Background: Cancer cells escape macrophage phagocytosis by expressing the CD47 integrin-associated protein that binds to the SIRPα ligand (signal regulatory protein alpha) expressed by macrophages. Immunotherapy targeting this pathway is under clinical development. Methods: We investigated the expression of CD47/SIRPα molecules in a series of 98 NSCLCs, in parallel with the infiltration of tumor stroma by CD68+ macrophages, tumor-infiltrating lymphocytes (TILs), and PD-L1/PD-1 molecules. Results: Extensive membranous CD47 expression by cancer cells characterized 29/98 cases. SIRPα and CD68 were expressed, to a varying extent, by tumor-associated macrophages (Μφ, TAMs). A high CD68Mφ-score in inner tumor areas was linked with improved overall survival (p = 0.005); and this was independent of the stage (p = 0.02, hazard ratio 0.4). In contrast, high SIRPα expression by CD68+ TAMs (SIRPα/CD68-ratio) was linked with CD47 expression by cancer cells, low TIL-score, and poor prognosis (p = 0.02). A direct association of CD47 expression by cancer cells and the % FOXP3+ TILs (p = 0.01, r = 0.25) was also noted. Conclusions: TAMs play an important role in the prognosis of operable NSCLC. As SIRPα+ macrophages adversely affect prognosis, it is suggested that the CD47/SIRPα axis is a sound target for adjuvant immunotherapy policies, aiming to improve the cure rates in operable NSCLC. Full article

(This article belongs to the Special Issue Immune Checkpoint Inhibitors in Cancer Therapy—How Can We Improve Clinical Benefits?)

► Show Figures

Figure 1

17 pages, 3863 KiB

Open AccessEditor’s ChoiceArticle

Estrogens and Progestins Cooperatively Shift Breast Cancer Cell Metabolism

by Ashley V. Ward, Shawna B. Matthews, Lynsey M. Fettig, Duncan Riley, Jessica Finlay-Schultz, Kiran V. Paul, Matthew Jackman, Peter Kabos, Paul S. MacLean and Carol A. Sartorius

Cancers 2022, 14(7), 1776; https://doi.org/10.3390/cancers14071776 - 31 Mar 2022

Cited by 10 | Viewed by 4086

Abstract

Metabolic reprogramming remains largely understudied in relation to hormones in estrogen receptor (ER) and progesterone receptor (PR) positive breast cancer. In this study, we investigated how estrogens, progestins, or the combination, impact metabolism in three ER and PR positive breast cancer cell lines. [...] Read more.

Metabolic reprogramming remains largely understudied in relation to hormones in estrogen receptor (ER) and progesterone receptor (PR) positive breast cancer. In this study, we investigated how estrogens, progestins, or the combination, impact metabolism in three ER and PR positive breast cancer cell lines. We measured metabolites in the treated cells using ultra-performance liquid chromatography coupled with mass spectrometry (UPLC-MS). Top metabolic processes upregulated with each treatment involved glucose metabolism, including Warburg effect/glycolysis, gluconeogenesis, and the pentose phosphate pathway. RNA-sequencing and pathway analysis on two of the cell lines treated with the same hormones, found estrogens target oncogenes, such as MYC and PI3K/AKT/mTOR that control tumor metabolism, while progestins increased genes associated with fatty acid metabolism, and the estrogen/progestin combination additionally increased glycolysis. Phenotypic analysis of cell energy metabolism found that glycolysis was the primary hormonal target, particularly for the progestin and estrogen-progestin combination. Transmission electron microscopy found that, compared to vehicle, estrogens elongated mitochondria, which was reversed by co-treatment with progestins. Progestins promoted lipid storage both alone and in combination with estrogen. These findings highlight the shift in breast cancer cell metabolism to a more glycolytic and lipogenic phenotype in response to combination hormone treatment, which may contribute to a more metabolically adaptive state for cell survival. Full article

(This article belongs to the Special Issue Tumor and Metabolism)

► Show Figures

Figure 1

16 pages, 1702 KiB

Open AccessEditor’s ChoiceArticle

Next Generation Plasma Proteomics Identifies High-Precision Biomarker Candidates for Ovarian Cancer

by Ulf Gyllensten, Julia Hedlund-Lindberg, Johanna Svensson, Johanna Manninen, Torbjörn Öst, Jon Ramsell, Matilda Åslin, Emma Ivansson, Marta Lomnytska, Maria Lycke, Tomas Axelsson, Ulrika Liljedahl, Jessica Nordlund, Per-Henrik Edqvist, Tobias Sjöblom, Mathias Uhlén, Karin Stålberg, Karin Sundfeldt, Mikael Åberg and Stefan Enroth

Cancers 2022, 14(7), 1757; https://doi.org/10.3390/cancers14071757 - 30 Mar 2022

Cited by 23 | Viewed by 7310

Abstract

Background: Ovarian cancer is the eighth most common cancer among women and has a 5-year survival of only 30–50%. The survival is close to 90% for patients in stage I but only 20% for patients in stage IV. The presently available biomarkers have [...] Read more.

Background: Ovarian cancer is the eighth most common cancer among women and has a 5-year survival of only 30–50%. The survival is close to 90% for patients in stage I but only 20% for patients in stage IV. The presently available biomarkers have insufficient sensitivity and specificity for early detection and there is an urgent need to identify novel biomarkers. Methods: We employed the Explore PEA technology for high-precision analysis of 1463 plasma proteins and conducted a discovery and replication study using two clinical cohorts of previously untreated patients with benign or malignant ovarian tumours (N = 111 and N = 37). Results: The discovery analysis identified 32 proteins that had significantly higher levels in malignant cases as compared to benign diagnoses, and for 28 of these, the association was replicated in the second cohort. Multivariate modelling identified three highly accurate models based on 4 to 7 proteins each for separating benign tumours from early-stage and/or late-stage ovarian cancers, all with AUCs above 0.96 in the replication cohort. We also developed a model for separating the early-stage from the late-stage achieving an AUC of 0.81 in the replication cohort. These models were based on eleven proteins in total (ALPP, CXCL8, DPY30, IL6, IL12, KRT19, PAEP, TSPAN1, SIGLEC5, VTCN1, and WFDC2), notably without MUCIN-16. The majority of the associated proteins have been connected to ovarian cancer but not identified as potential biomarkers. Conclusions: The results show the ability of using high-precision proteomics for the identification of novel plasma protein biomarker candidates for the early detection of ovarian cancer. Full article

(This article belongs to the Special Issue Ovarian Cancer Biomarkers, Diagnostic and Therapeutic Technologies)

► Show Figures

Figure 1

16 pages, 1272 KiB

Open AccessEditor’s ChoiceArticle

CT-Based Radiomics Analysis to Predict Histopathological Outcomes Following Liver Resection in Colorectal Liver Metastases

by Vincenza Granata, Roberta Fusco, Sergio Venanzio Setola, Federica De Muzio, Federica Dell’ Aversana, Carmen Cutolo, Lorenzo Faggioni, Vittorio Miele, Francesco Izzo and Antonella Petrillo

Cancers 2022, 14(7), 1648; https://doi.org/10.3390/cancers14071648 - 24 Mar 2022

Cited by 42 | Viewed by 6099

Abstract

Purpose: We aimed to assess the efficacy of radiomic features extracted by computed tomography (CT) in predicting histopathological outcomes following liver resection in colorectal liver metastases patients, evaluating recurrence, mutational status, histopathological characteristics (mucinous), and surgical resection margin. Methods: This retrospectively approved study [...] Read more.

Purpose: We aimed to assess the efficacy of radiomic features extracted by computed tomography (CT) in predicting histopathological outcomes following liver resection in colorectal liver metastases patients, evaluating recurrence, mutational status, histopathological characteristics (mucinous), and surgical resection margin. Methods: This retrospectively approved study included a training set and an external validation set. The internal training set included 49 patients with a median age of 60 years and 119 liver colorectal metastases. The validation cohort consisted of 28 patients with single liver colorectal metastasis and a median age of 61 years. Radiomic features were extracted using PyRadiomics on CT portal phase. Nonparametric Kruskal–Wallis tests, intraclass correlation, receiver operating characteristic (ROC) analyses, linear regression modeling, and pattern recognition methods (support vector machine (SVM), k-nearest neighbors (KNN), artificial neural network (NNET), and decision tree (DT)) were considered. Results: The median value of intraclass correlation coefficients for the features was 0.92 (range 0.87–0.96). The best performance in discriminating expansive versus infiltrative front of tumor growth was wavelet_HHL_glcm_Imc2, with an accuracy of 79%, a sensitivity of 84%, and a specificity of 67%. The best performance in discriminating expansive versus tumor budding was wavelet_LLL_firstorder_Mean, with an accuracy of 86%, a sensitivity of 91%, and a specificity of 65%. The best performance in differentiating the mucinous type of tumor was original_firstorder_RobustMeanAbsoluteDeviation, with an accuracy of 88%, a sensitivity of 42%, and a specificity of 100%. The best performance in identifying tumor recurrence was the wavelet_HLH_glcm_Idmn, with an accuracy of 85%, a sensitivity of 81%, and a specificity of 88%. The best linear regression model was obtained with the identification of recurrence considering the linear combination of the 16 significant textural metrics (accuracy of 97%, sensitivity of 94%, and specificity of 98%). The best performance for each outcome was reached using KNN as a classifier with an accuracy greater than 86% in the training and validation sets for each classification problem; the best results were obtained with the identification of tumor front growth considering the seven significant textural features (accuracy of 97%, sensitivity of 90%, and specificity of 100%). Conclusions: This study confirmed the capacity of radiomics data to identify several prognostic features that may affect the treatment choice in patients with liver metastases, in order to obtain a more personalized approach. Full article

(This article belongs to the Special Issue Radiology and Imaging of Cancer)

► Show Figures

Figure 1

20 pages, 3124 KiB

Open AccessEditor’s ChoiceArticle

MitoQ Inhibits Human Breast Cancer Cell Migration, Invasion and Clonogenicity

by Tania Capeloa, Joanna Krzystyniak, Donatienne d’Hose, Amanda Canas Rodriguez, Valery L. Payen, Luca X. Zampieri, Justine A. Van de Velde, Zohra Benyahia, Erica Pranzini, Thibaut Vazeille, Maude Fransolet, Caroline Bouzin, Davide Brusa, Carine Michiels, Bernard Gallez, Michael P. Murphy, Paolo E. Porporato and Pierre Sonveaux

Cancers 2022, 14(6), 1516; https://doi.org/10.3390/cancers14061516 - 16 Mar 2022

Cited by 22 | Viewed by 6480

Abstract

To successfully generate distant metastases, metastatic progenitor cells must simultaneously possess mesenchymal characteristics, resist to anoïkis, migrate and invade directionally, resist to redox and shear stresses in the systemic circulation, and possess stem cell characteristics. These cells primarily originate from metabolically hostile areas [...] Read more.

To successfully generate distant metastases, metastatic progenitor cells must simultaneously possess mesenchymal characteristics, resist to anoïkis, migrate and invade directionally, resist to redox and shear stresses in the systemic circulation, and possess stem cell characteristics. These cells primarily originate from metabolically hostile areas of the primary tumor, where oxygen and nutrient deprivation, together with metabolic waste accumulation, exert a strong selection pressure promoting evasion. Here, we followed the hypothesis according to which metastasis as a whole implies the existence of metabolic sensors. Among others, mitochondria are singled out as a major source of superoxide that supports the metastatic phenotype. Molecularly, stressed cancer cells increase mitochondrial superoxide production, which activates the transforming growth factor-β pathway through src directly within mitochondria, ultimately activating focal adhesion kinase Pyk2. The existence of mitochondria-targeted antioxidants constitutes an opportunity to interfere with the metastatic process. Here, using aggressive triple-negative and HER2-positive human breast cancer cell lines as models, we report that MitoQ inhibits all the metastatic traits that we tested in vitro. Compared to other mitochondria-targeted antioxidants, MitoQ already successfully passed Phase I safety clinical trials, which provides an important incentive for future preclinical and clinical evaluations of this drug for the prevention of breast cancer metastasis. Full article

(This article belongs to the Topic Targeting Tumor Metabolism for Cancer Therapy)

► Show Figures

Figure 1

17 pages, 2808 KiB

Open AccessEditor’s ChoiceArticle

A Randomised, Comparative, Effectiveness Trial Evaluating Low- versus High-Level Supervision of an Exercise Intervention for Women with Breast Cancer: The SAFE Trial

by Rosalind R. Spence, Carolina X. Sandler, Benjamin Singh, Jodie Tanner, Christopher Pyke, Elizabeth Eakin, Dimitrios Vagenas and Sandra C. Hayes

Cancers 2022, 14(6), 1528; https://doi.org/10.3390/cancers14061528 - 16 Mar 2022

Cited by 9 | Viewed by 3714

Abstract

The aim of this comparative, effectiveness trial was to evaluate the safety, feasibility and effect of an exercise intervention delivered via low-level versus high-level supervision. The target population were women who were diagnosed with ≥stage II breast cancer, had ≥ one comorbidity and/or [...] Read more.

The aim of this comparative, effectiveness trial was to evaluate the safety, feasibility and effect of an exercise intervention delivered via low-level versus high-level supervision. The target population were women who were diagnosed with ≥stage II breast cancer, had ≥ one comorbidity and/or persistent treatment-related side-effects, and were insufficiently physically active. Sixty women (50 ± 9 years) were randomized to the low-supervision group (n = 30) or high-supervision group (n = 30). The low-supervision group participated in a 12-week, individually-tailored exercise intervention supported by five supervised sessions with an exercise professional. The high-supervision group participated in the same exercise intervention but received 20 supervised sessions across the 12-week period. The target weekly dosage of 600 metabolic equivalent minutes of exercise per week (MET-mins/wk) and the session content, such as safety and behaviour change topics, were standardized between the groups. The primary outcomes were intervention safety, defined as the number, type, and severity of exercise-related adverse events (e.g., musculoskeletal injury or exacerbated treatment-related side effects), and feasibility, which was defined as compliance to target exercise dosage. The effect of the intervention on quality of life, physical activity, self-efficacy, fitness, and strength was also assessed (pre- and post-intervention, and at 12-week follow-up). The intervention was safe, with no exercise-related adverse events of grade 3 or above in either group. Both groups reported high compliance to the target exercise dosage (median MET-mins/wk: High = 817; Low = 663), suggesting the exercise intervention was feasible, irrespective of supervision level. Improvements in quality of life, physical activity and fitness were observed post-intervention and maintained at follow-up for both groups (p < 0.05). Only the high-supervision group showed clinically-relevant improvements in strength and self-efficacy at post-intervention (p < 0.05). Individually-targeted exercise delivered under high- or low-levels of supervision is safe, feasible and beneficial for women with stage II+ breast cancer. Future research needs to assess whether the greater gains observed in the group who received higher supervision may contribute to longer term maintenance of physical activity levels and overall health benefits. Australian and New Zealand Clinical Trials Registry: ACTRN12616000547448. Full article

(This article belongs to the Special Issue Physical Activity and Cancer Care)

► Show Figures

Figure 1

15 pages, 1299 KiB

Open AccessEditor’s ChoiceArticle

Tumor Infiltration Levels of CD3, Foxp3 (+) Lymphocytes and CD68 Macrophages at Diagnosis Predict 5-Year Disease-Specific Survival in Patients with Oropharynx Squamous Cell Carcinoma

by Borghild Ljokjel, Hilde Haave, Stein Lybak, Olav Karsten Vintermyr, Lars Helgeland and Hans Jørgen Aarstad

Cancers 2022, 14(6), 1508; https://doi.org/10.3390/cancers14061508 - 15 Mar 2022

Cited by 15 | Viewed by 2980

Abstract

Head and neck cancer (HNC) is the sixth most common cancer worldwide. Oropharyngeal (OP) cancers are of special interest because of possible underlying HPV infection which is tied to prognosis. Influxes of inflammatory cells into tumors may vary with prognoses. We wanted to [...] Read more.

Head and neck cancer (HNC) is the sixth most common cancer worldwide. Oropharyngeal (OP) cancers are of special interest because of possible underlying HPV infection which is tied to prognosis. Influxes of inflammatory cells into tumors may vary with prognoses. We wanted to study whether the number of tumor-infiltrating lymphocytes (TIL) and tumor-associated macrophages (TAM) in tumors correlated to HPV status and predicted 5-year disease-specific survival (DSS). Formalin-fixed paraffin-embedded (FFPE) biopsies cut sections from 170 patients treated for OP cancer were stained by immunohistochemistry and evaluated for the number of CD68 (+) TAMs, CD3 (+), and Foxp3 (+) (T regulatory) TILs. From FFPE slides HPV by PCR and p16 by immunohistochemistry were established. From FFPE Hematoxylin-Eosin slides, levels of tumor nuclear polymorphism, tumor invasion, desmoplasia, and inflammation were determined as previously published. Levels of TIL CD3 (+) and TIL Foxp3 (+) were increased among the HPV (+) compared to the HPV (−) patients. High levels of TIL Foxp3 (+) and CD68 (+) macrophages predicted better 5-year DSS. TIL Foxp3 (+) levels predicted independent of age, gender, TNM stage, and HPV infection as well as level of stromal desmoplasia, tumor invasion, and nuclear polymorphism, but more pronounced among tumor HPV (+) than HPV (−) patients. Full article

(This article belongs to the Topic Anti-Tumor Immune Responses)

► Show Figures

Figure 1

13 pages, 1406 KiB

Open AccessEditor’s ChoiceArticle

MitoQ Prevents Human Breast Cancer Recurrence and Lung Metastasis in Mice

by Tania Capeloa, Joanna Krzystyniak, Amanda Canas Rodriguez, Valéry L. Payen, Luca X. Zampieri, Erica Pranzini, Françoise Derouane, Thibaut Vazeille, Caroline Bouzin, François P. Duhoux, Michael P. Murphy, Paolo E. Porporato and Pierre Sonveaux

Cancers 2022, 14(6), 1488; https://doi.org/10.3390/cancers14061488 - 15 Mar 2022

Cited by 17 | Viewed by 11505

Abstract

In oncology, the occurrence of distant metastases often marks the transition from curative to palliative care. Such outcome is highly predictable for breast cancer patients, even if tumors are detected early, and there is no specific treatment to prevent metastasis. Previous observations indicated [...] Read more.

In oncology, the occurrence of distant metastases often marks the transition from curative to palliative care. Such outcome is highly predictable for breast cancer patients, even if tumors are detected early, and there is no specific treatment to prevent metastasis. Previous observations indicated that cancer cell mitochondria are bioenergetic sensors of the tumor microenvironment that produce superoxide to promote evasion. Here, we tested whether mitochondria-targeted antioxidant MitoQ is capable to prevent metastasis in the MDA-MB-231 model of triple-negative human breast cancer in mice and in the MMTV-PyMT model of spontaneously metastatic mouse breast cancer. At clinically relevant doses, we report that MitoQ not only prevented metastatic take and dissemination, but also local recurrence after surgery. We further provide in vitro evidence that MitoQ does not interfere with conventional chemotherapies used to treat breast cancer patients. Since MitoQ already successfully passed Phase I safety clinical trials, our preclinical data collectively provide a strong incentive to test this drug for the prevention of cancer dissemination and relapse in clinical trials with breast cancer patients. Full article

(This article belongs to the Topic Targeting Tumor Metabolism for Cancer Therapy)

► Show Figures

Figure 1

13 pages, 3562 KiB

Open AccessEditor’s ChoiceArticle

The Matrisome Is Associated with Metabolic Reprograming in Stem-like Phenotypes of Gastric Cancer

by Ji-Yong Sung and Jae-Ho Cheong

Cancers 2022, 14(6), 1438; https://doi.org/10.3390/cancers14061438 - 10 Mar 2022

Cited by 16 | Viewed by 3441

Abstract

The extracellular matrix (ECM) is an important regulator of all cellular functions, and the matrisome represents a major component of the tumor microenvironment. The matrisome is an essential component comprising genes encoding ECM glycoproteins, collagens, and proteoglycans; however, its role in cancer progression [...] Read more.

The extracellular matrix (ECM) is an important regulator of all cellular functions, and the matrisome represents a major component of the tumor microenvironment. The matrisome is an essential component comprising genes encoding ECM glycoproteins, collagens, and proteoglycans; however, its role in cancer progression and the development of stem-like molecular subtypes in gastric cancer is unknown. We analyzed gastric cancer data from five molecular subtypes (n = 497) and found that metabolic reprograming differs based on the state of the matrisome. Approximately 95% of stem-like cancer type samples of gastric cancer were in the high-matrisome category, and energy metabolism was considerably increased in the high-matrisome group. Particularly, high glycosaminoglycan biosynthesis-chondroitin sulfate metabolic reprograming was associated with an unfavorable prognosis. Glycosaminoglycan biosynthesis-chondroitin sulfate metabolic reprograming may occur according to the matrisome status and contribute to the development of stem-like phenotypes. Our analysis suggests the possibility of precision medicine for anticancer therapies. Full article

(This article belongs to the Special Issue Matrix Glycans as Multifunctional Pathogenesis Factors and Therapeutic Targets in Cancer)

► Show Figures

Figure 1

14 pages, 2090 KiB

Open AccessEditor’s ChoiceArticle

Rintatolimod (Ampligen^®) Enhances Numbers of Peripheral B Cells and Is Associated with Longer Survival in Patients with Locally Advanced and Metastasized Pancreatic Cancer Pre-Treated with FOLFIRINOX: A Single-Center Named Patient Program

by Hassana el Haddaoui, Rianne Brood, Diba Latifi, Astrid A. Oostvogels, Yarne Klaver, Miranda Moskie, Dana A. Mustafa, Reno Debets and Casper H. J. van Eijck

Cancers 2022, 14(6), 1377; https://doi.org/10.3390/cancers14061377 - 8 Mar 2022

Cited by 10 | Viewed by 6974

Abstract

Background: Treatment with the TLR-3 agonist rintatolimod may improve pancreatic cancer patients’ survival via immunomodulation, but the effect is unproven. Methods: In this single-center named patient program, patients with locally advanced pancreatic cancer (LAPC) or metastatic disease were treated with rintatolimod (six weeks [...] Read more.

Background: Treatment with the TLR-3 agonist rintatolimod may improve pancreatic cancer patients’ survival via immunomodulation, but the effect is unproven. Methods: In this single-center named patient program, patients with locally advanced pancreatic cancer (LAPC) or metastatic disease were treated with rintatolimod (six weeks total, twice per week, with a maximum of 400 mg per infusion). The primary endpoints were the systemic immune-inflammation index (SIII), the neutrophil to lymphocyte ratio (NLR), and the absolute counts of 18 different populations of circulating immune cells as measured by flow cytometry. Secondary endpoints were progression-free survival (PFS) and overall survival (OS). Subgroup analyses were performed in long-term survivors (>1-year overall survival after starting rintatolimod) and compared to short-term survivors (≤1 year). Results: Between January 2017 and February 2019, twenty-seven patients with stable LAPC or metastatic disease were pre-treated with FOLFIRINOX and treated with rintatolimod. Rintatolimod treatment was well-tolerated. The SIII and NLR values were significantly lower in the 11 long-term survivors, versus 16 short-term survivors. The numbers of B-cells were significantly increased in long-term survivors. Numbers of T cells and myeloid cells were not significantly increased after treatment with rintatolimod. Median PFS was 13 months with rintatolimod, versus 8.6 months in a subset of matched controls (n = 27, hazard ratio = 0.52, 95% CI = 0.28–0.90, p = 0.007). The median OS was 19 months with rintatolimod, versus 12.5 months in the matched control (hazard ratio = 0.51, 95% CI = 0.28–0.90, p = 0.016). Conclusions: Treatment with rintatolimod showed a favorable effect on the numbers of peripheral B cells in patients with pancreatic cancer and improved survival in pancreatic cancer, but additional evidence is required. Full article

(This article belongs to the Special Issue Combination and Innovative Therapies for Pancreatic Cancer)

► Show Figures

Figure 1

20 pages, 5118 KiB

Open AccessEditor’s ChoiceArticle

Assessing the Acceptability of Home-Based HPV Self-Sampling: A Qualitative Study on Cervical Cancer Screening Conducted in Reunion Island Prior to the RESISTE Trial

by Dolorès Pourette, Amber Cripps, Margaux Guerrien, Caroline Desprès, Eric Opigez, Marc Bardou and Alexandre Dumont

Cancers 2022, 14(6), 1380; https://doi.org/10.3390/cancers14061380 - 8 Mar 2022

Cited by 8 | Viewed by 3310

Abstract

Cervical cancer incidence and mortality rates are 2 to 3 times higher in the overseas department of Reunion compared with mainland France. RESISTE’s cluster-randomized controlled trial aims to test the effectiveness of home-based self-sampling (HBSS) through a high-risk oncogenic papillomavirus test sent out [...] Read more.

Cervical cancer incidence and mortality rates are 2 to 3 times higher in the overseas department of Reunion compared with mainland France. RESISTE’s cluster-randomized controlled trial aims to test the effectiveness of home-based self-sampling (HBSS) through a high-risk oncogenic papillomavirus test sent out by post to women who have not been screened in the past 3 years, despite having been invited to do so through a reminder letter. Prior to the trial, qualitative research was carried out to understand screening barriers and assess anticipated acceptability. Semi-structured interviews were conducted with 35 women and 20 healthcare providers. Providers consider HBSS a viable method in reaching women who tend not to visit a doctor regularly, or who are reluctant to undergo a smear pap, as well as those who are geographically isolated. They considered, however, that women would require support, and that outreach was necessary to ensure more socially isolated women participate. The majority of the women surveyed were in favour of HBSS. However, two-thirds voiced concerns regarding the test’s efficiency and their ability to perform the test correctly, without harming themselves. Based on these findings, recommendations were formulated to reassure women on usage and quality, and to help reach socially isolated women. Full article

(This article belongs to the Special Issue Successes and Barriers of HPV Vaccination and Cervical Screening on Cervical Cancer Elimination)

► Show Figures

Figure 1

21 pages, 7075 KiB

Open AccessEditor’s ChoiceArticle

Discovery of a New CaMKII-Targeted Synthetic Lethal Therapy against Glioblastoma Stem-like Cells

by Jang Mi Han, Yu Jin Kim and Hye Jin Jung

Cancers 2022, 14(5), 1315; https://doi.org/10.3390/cancers14051315 - 4 Mar 2022

Cited by 15 | Viewed by 5677

Abstract

Glioblastoma stem-like cells (GSCs) drive tumor initiation, cancer invasion, immune evasion, and therapeutic resistance and are thus a key therapeutic target for improving treatment for glioblastoma multiforme (GBM). We previously identified calcium/calmodulin-dependent protein kinase II (CaMKII) as an emerging molecular target for eliminating [...] Read more.

Glioblastoma stem-like cells (GSCs) drive tumor initiation, cancer invasion, immune evasion, and therapeutic resistance and are thus a key therapeutic target for improving treatment for glioblastoma multiforme (GBM). We previously identified calcium/calmodulin-dependent protein kinase II (CaMKII) as an emerging molecular target for eliminating GSCs. In this study, we aim to explore a new CaMKII-targeted synthetic lethal therapy for GSCs. Through high-throughput drug combination screening using CaMKII inhibitors and a bioactive compound library in GSCs, neurokinin 1 receptor (NK1R) inhibitors such as SR 140333 and aprepitant are found to be potential anticancer agents that exhibit chemical synthetic lethal interactions with CaMKII inhibitors, including hydrazinobenzoylcurcumin (HBC), berbamine, and KN93. Combined treatment with NK1R and CaMKII inhibitors markedly suppresses the viability and neurosphere formation of U87MG- and U373MG-derived GSCs. In addition, the combination of HBC and NK1R inhibitors significantly inhibits U87MG GSC tumor growth in a chick embryo chorioallantoic membrane (CAM) model. Furthermore, the synthetic lethal interaction is validated using RNA interference of CaMKIIγ and NK1R. Notably, the synthetic lethal effects in GSCs are associated with the activation of caspase-mediated apoptosis by inducing p53 expression and reactive oxygen species generation, as well as the suppression of stemness marker expression by reducing nuclear factor-kappa B (NF-κB) activity. This follows the downregulation of phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT) signaling and a decrease in intracellular calcium concentration. Moreover, NK1R affects CaMKIIγ activation. These findings demonstrate that NK1R is a potential synthetic lethal partner of CaMKII that is involved in eradicating GSCs, and they suggest a new CaMKII-targeted combination therapy for treating GBM. Full article

(This article belongs to the Special Issue Recent Advances in Drug Therapy for Glioblastoma)

► Show Figures

Figure 1

25 pages, 23552 KiB

Open AccessEditor’s ChoiceArticle

Comprehensive Metabolic Profiling of MYC-Amplified Medulloblastoma Tumors Reveals Key Dependencies on Amino Acid, Tricarboxylic Acid and Hexosamine Pathways

by Khoa Pham, Allison R. Hanaford, Brad A. Poore, Micah J. Maxwell, Heather Sweeney, Akhila Parthasarathy, Jesse Alt, Rana Rais, Barbara S. Slusher, Charles G. Eberhart and Eric H. Raabe

Cancers 2022, 14(5), 1311; https://doi.org/10.3390/cancers14051311 - 3 Mar 2022

Cited by 15 | Viewed by 5325

Abstract

Reprograming of cellular metabolism is a hallmark of cancer. Altering metabolism allows cancer cells to overcome unfavorable microenvironment conditions and to proliferate and invade. Medulloblastoma is the most common malignant brain tumor of children. Genomic amplification of MYC defines a subset of poor-prognosis [...] Read more.

Reprograming of cellular metabolism is a hallmark of cancer. Altering metabolism allows cancer cells to overcome unfavorable microenvironment conditions and to proliferate and invade. Medulloblastoma is the most common malignant brain tumor of children. Genomic amplification of MYC defines a subset of poor-prognosis medulloblastoma. We performed comprehensive metabolic studies of human MYC-amplified medulloblastoma by comparing the metabolic profiles of tumor cells in three different conditions—in vitro, in flank xenografts and in orthotopic xenografts in the cerebellum. Principal component analysis showed that the metabolic profiles of brain and flank high-MYC medulloblastoma tumors clustered closely together and separated away from normal brain and in vitro MYC-amplified cells. Compared to normal brain, MYC-amplified medulloblastoma orthotopic xenograft tumors showed upregulation of the TCA cycle as well as the synthesis of nucleotides, hexosamines, amino acids and glutathione. There was significantly higher glucose uptake and usage in orthotopic xenograft tumors compared to flank xenograft tumors and cells in culture. In orthotopic tumors, glucose was the main carbon source for the de novo synthesis of glutamate, glutamine and glutathione through the TCA cycle. In vivo, the glutaminase II pathway was the main pathway utilizing glutamine. Glutathione was the most abundant upregulated metabolite in orthotopic tumors compared to normal brain. Glutamine-derived glutathione was synthesized through the glutamine transaminase K (GTK) enzyme in vivo. In conclusion, high MYC medulloblastoma cells have different metabolic profiles in vitro compared to in vivo, and key vulnerabilities may be missed by not performing in vivo metabolic analyses. Full article

(This article belongs to the Special Issue Updates on Molecular Targeted Therapies for CNS Tumors)

► Show Figures

Graphical abstract

15 pages, 5789 KiB

Open AccessEditor’s ChoiceArticle

Cannabidiol Inhibits Tumorigenesis in Cisplatin-Resistant Non-Small Cell Lung Cancer via TRPV2

by Swati Misri, Kirti Kaul, Sanjay Mishra, Manish Charan, Ajeet Kumar Verma, Martin P. Barr, Dinesh K. Ahirwar and Ramesh K. Ganju

Cancers 2022, 14(5), 1181; https://doi.org/10.3390/cancers14051181 - 24 Feb 2022

Cited by 37 | Viewed by 5145

Abstract

Chemotherapy forms the backbone of current treatments for many patients with advanced non-small-cell lung cancer (NSCLC). However, the survival rate is low in these patients due to the development of drug resistance, including cisplatin resistance. In this study, we developed a novel strategy [...] Read more.

Chemotherapy forms the backbone of current treatments for many patients with advanced non-small-cell lung cancer (NSCLC). However, the survival rate is low in these patients due to the development of drug resistance, including cisplatin resistance. In this study, we developed a novel strategy to combat the growth of cisplatin-resistant (CR) NSCLC cells. We have shown that treatment with the plant-derived, non-psychotropic small molecular weight molecule, cannabidiol (CBD), significantly induced apoptosis of CR NSCLC cells. In addition, CBD treatment significantly reduced tumor progression and metastasis in a mouse xenograft model and suppressed cancer stem cell properties. Further mechanistic studies demonstrated the ability of CBD to inhibit the growth of CR cell lines by reducing NRF-2 and enhancing the generation of reactive oxygen species (ROS). Moreover, we show that CBD acts through Transient Receptor Potential Vanilloid-2 (TRPV2) to induce apoptosis, where TRPV2 is expressed on human lung adenocarcinoma tumors. High expression of TRPV2 correlates with better overall survival of lung cancer patients. Our findings identify CBD as a novel therapeutic agent targeting TRPV2 to inhibit the growth and metastasis of this aggressive cisplatin-resistant phenotype in NSCLC. Full article

(This article belongs to the Special Issue Advances in Lung Cancer Therapy)

► Show Figures

Figure 1

15 pages, 12400 KiB

Open AccessEditor’s ChoiceArticle

A Deep Learning Model for Cervical Cancer Screening on Liquid-Based Cytology Specimens in Whole Slide Images

by Fahdi Kanavati, Naoki Hirose, Takahiro Ishii, Ayaka Fukuda, Shin Ichihara and Masayuki Tsuneki

Cancers 2022, 14(5), 1159; https://doi.org/10.3390/cancers14051159 - 24 Feb 2022

Cited by 45 | Viewed by 9832

Abstract

Liquid-based cytology (LBC) for cervical cancer screening is now more common than the conventional smears, which when digitised from glass slides into whole-slide images (WSIs), opens up the possibility of artificial intelligence (AI)-based automated image analysis. Since conventional screening processes by cytoscreeners and [...] Read more.

Liquid-based cytology (LBC) for cervical cancer screening is now more common than the conventional smears, which when digitised from glass slides into whole-slide images (WSIs), opens up the possibility of artificial intelligence (AI)-based automated image analysis. Since conventional screening processes by cytoscreeners and cytopathologists using microscopes is limited in terms of human resources, it is important to develop new computational techniques that can automatically and rapidly diagnose a large amount of specimens without delay, which would be of great benefit for clinical laboratories and hospitals. The goal of this study was to investigate the use of a deep learning model for the classification of WSIs of LBC specimens into neoplastic and non-neoplastic. To do so, we used a dataset of 1605 cervical WSIs. We evaluated the model on three test sets with a combined total of 1468 WSIs, achieving ROC AUCs for WSI diagnosis in the range of 0.89–0.96, demonstrating the promising potential use of such models for aiding screening processes. Full article

(This article belongs to the Collection Artificial Intelligence in Oncology)

► Show Figures

Figure 1

22 pages, 1555 KiB

Open AccessEditor’s ChoiceArticle

Immune Checkpoint Inhibitors—Associated Cardiotoxicity

by Chenghui Li, Sajjad A. Bhatti and Jun Ying

Cancers 2022, 14(5), 1145; https://doi.org/10.3390/cancers14051145 - 23 Feb 2022

Cited by 40 | Viewed by 5607

Abstract

Large population-based studies examining differences in ICI-associated cardiotoxicity across cancer types and agents are limited. Data of 5518 cancer patients who received at least one cycle of ICIs were extracted from a large network of health care organizations. ICI treatment groups were classified [...] Read more.

Large population-based studies examining differences in ICI-associated cardiotoxicity across cancer types and agents are limited. Data of 5518 cancer patients who received at least one cycle of ICIs were extracted from a large network of health care organizations. ICI treatment groups were classified by the first ICI agent(s) (ipilimumab, nivolumab, pembrolizumab, cemiplimab, avelumab, atezolizumab, or durvalumab) or its class (PD-1 inhibitors, PD-L1 inhibitors, CTLA4-inhibitors, or their combination (ipilimumab + nivolumab)). Time to first cardiac adverse event (CAE) (arrhythmia, acute myocardial infarction, myocarditis, cardiomyopathy, or pericarditis) developed within one year after ICI initiation was analyzed using a competing-risks regression model adjusting for ICI treatment groups, patient demographic and clinical characteristics, and cancer sites. By month 12, 12.5% developed cardiotoxicity. The most common cardiotoxicity was arrhythmia (9.3%) and 2.1% developed myocarditis. After adjusting for patient characteristics and cancer sites, patients who initiated on monotherapy with ipilimumab (adjusted Hazard Ratio (aHR): 2.00; 95% CI: 1.49–2.70; p < 0.001) or pembrolizumab (aHR: 1.21; 95% CI: 1.01–1.46; p = 0.040) had a higher risk of developing CAEs within one year compared to nivolumab monotherapy. Ipilimumab and pembrolizumab use may increase the risk of cardiotoxicity compared to other agents. Avelumab also estimated a highly elevated risk (aHR: 1.92; 95% CI: 0.85–4.34; p = 0.117) compared to nivolumab and other PD-L1 agents, although the estimate did not reach statistical significance, warranting future studies. Full article

► Show Figures

Figure 1

20 pages, 8036 KiB

Open AccessEditor’s ChoiceArticle

Patient-Derived Ovarian Cancer Spheroids Rely on PI3K-AKT Signaling Addiction for Cancer Stemness and Chemoresistance

by Deepak Parashar, Anjali Geethadevi, Sonam Mittal, Lindsey A. McAlarnen, Jasmine George, Ishaque P. Kadamberi, Prachi Gupta, Denise S. Uyar, Elizabeth E. Hopp, Holli Drendel, Erin A. Bishop, William H. Bradley, Kathleen M. Bone, Janet S. Rader, Sunila Pradeep and Pradeep Chaluvally-Raghavan

Cancers 2022, 14(4), 958; https://doi.org/10.3390/cancers14040958 - 15 Feb 2022

Cited by 18 | Viewed by 4220

Abstract

Ovarian cancer is the most lethal gynecological malignancy among women worldwide and is characterized by aggressiveness, cancer stemness, and frequent relapse due to resistance to platinum-based therapy. Ovarian cancer cells metastasize through ascites fluid as 3D spheroids which are more resistant to apoptosis [...] Read more.

Ovarian cancer is the most lethal gynecological malignancy among women worldwide and is characterized by aggressiveness, cancer stemness, and frequent relapse due to resistance to platinum-based therapy. Ovarian cancer cells metastasize through ascites fluid as 3D spheroids which are more resistant to apoptosis and chemotherapeutic agents. However, the precise mechanism as an oncogenic addiction that makes 3D spheroids resistant to apoptosis and chemotherapeutic agents is not understood. To study the signaling addiction mechanism that occurs during cancer progression in patients, we developed an endometrioid subtype ovarian cancer cell line named ‘MCW-OV-SL-3’ from the ovary of a 70-year-old patient with stage 1A endometrioid adenocarcinoma of the ovary. We found that the cell line MCW-OV-SL-3 exhibits interstitial duplication of 1q (q21–q42), where this duplication resulted in high expression of the PIK3C2B gene and aberrant activation of PI3K-AKT-ERK signaling. Using short tandem repeat (STR) analysis, we demonstrated that the cell line exhibits a unique genetic identity compared to existing ovarian cancer cell lines. Notably, the MCW-OV-SL-3 cell line was able to form 3D spheroids spontaneously, which is an inherent property of tumor cells when plated on cell culture dishes. Importantly, the tumor spheroids derived from the MCW-OV-SL-3 cell line expressed high levels of c-Kit, PROM1, ZEB1, SNAI, VIM, and Twist1 compared to 2D monolayer cells. We also observed that the hyperactivation of ERK and PI3K/AKT signaling in these cancer cells resulted in resistance to cisplatin. In summary, the MCW-OV-SL3 endometrioid cell line is an excellent model to study the mechanism of cancer stemness and chemoresistance in endometrioid ovarian cancer. Full article

(This article belongs to the Topic Advances in Ovarian Cancer Research: From Biology to Therapeutics)

► Show Figures

Figure 1

16 pages, 2548 KiB

Open AccessEditor’s ChoiceArticle

Risk Stratification Using a Novel Nomogram for 2190 EGFR-Mutant NSCLC Patients Receiving the First or Second Generation EGFR-TKI

by John Wen-Cheng Chang, Chen-Yang Huang, Yueh-Fu Fang, Ching-Fu Chang, Cheng-Ta Yang, Chih-Hsi Scott Kuo, Ping-Chih Hsu and Chiao-En Wu

Cancers 2022, 14(4), 977; https://doi.org/10.3390/cancers14040977 - 15 Feb 2022

Cited by 19 | Viewed by 2989

Abstract

Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) are the standard treatment for EGFR mutation-positive (EGFRm+) non-small cell lung cancer (NSCLC). This study aimed to create a novel nomogram to help physicians suggest the optimal treatment for patients with EGFRm+ NSCLC. Records of [...] Read more.

Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) are the standard treatment for EGFR mutation-positive (EGFRm+) non-small cell lung cancer (NSCLC). This study aimed to create a novel nomogram to help physicians suggest the optimal treatment for patients with EGFRm+ NSCLC. Records of 2190 patients with EGFRm+ NSCLC cancer who were treated with EGFR-TKIs (including gefitinib, erlotinib, and afatinib) at the branches of a hospital group between 2011 and 2018 were retrospectively reviewed. Their clinicopathological characteristics, clinical tumor response, progression-free survival (PFS), and overall survival (OS) data were collected. Univariate and multivariate analyses were performed to identify potential prognostic factors to create a nomogram for risk stratification. Univariate analysis identified 14 prognostic factors, and multivariate analysis confirmed the pretreatment independent factors, including Eastern Cooperative Oncology Group performance status, morphology, mutation, stage, EGFR-TKIs (gefitinib, erlotinib, or afatinib), and metastasis to liver, brain, bone, pleura, adrenal gland, and distant lymph nodes. Based on these factors, a novel nomogram was created and used to stratify the patients into five different risk groups for PFS and OS using recursive partitioning analysis. This risk stratification can provide additional information to clinicians and patients when determining the optimal therapeutic options for EGFRm+ NSCLC. Full article

► Show Figures

Figure 1

12 pages, 1623 KiB

Open AccessEditor’s ChoiceArticle

Interleukin-6 Is a Circulating Prognostic Biomarker for Hepatocellular Carcinoma Patients Treated with Combined Immunotherapy

by Yuta Myojin, Takahiro Kodama, Ryotaro Sakamori, Kazuki Maesaka, Takayuki Matsumae, Yoshiyuki Sawai, Yasuharu Imai, Kazuyoshi Ohkawa, Masanori Miyazaki, Satoshi Tanaka, Eiji Mita, Seiichi Tawara, Takayuki Yakushijin, Yasutoshi Nozaki, Hideki Hagiwara, Yuki Tahata, Ryoko Yamada, Hayato Hikita, Tomohide Tatsumi and Tetsuo Takehara

Cancers 2022, 14(4), 883; https://doi.org/10.3390/cancers14040883 - 10 Feb 2022

Cited by 68 | Viewed by 4799

Abstract

Atezolizumab/bevacizumab (Atezo/Bev) combination therapy has become a front-line therapy for advanced hepatocellular carcinoma (HCC), but approximately 20% of patients are nonresponders. We investigated circulating biomarkers to predict therapeutic outcomes. We performed simultaneous measurement of 34 proteins using a multiplex bead-based immunoassay in baseline [...] Read more.

Atezolizumab/bevacizumab (Atezo/Bev) combination therapy has become a front-line therapy for advanced hepatocellular carcinoma (HCC), but approximately 20% of patients are nonresponders. We investigated circulating biomarkers to predict therapeutic outcomes. We performed simultaneous measurement of 34 proteins using a multiplex bead-based immunoassay in baseline plasma from 34 patients who underwent Atezo/Bev therapy as first- or second-line treatment. Logistic regression analysis showed that plasma IL-6 and interferon alpha (IFNα) levels were significant predictors of non-responders (odds ratio of 13.33 and FDR p = 0.021 for IL-6 and IFNα). The progression-free survival (PFS) and overall survival (OS) of patients with high IL-6 levels were significantly shorter than those of patients with low IL-6 levels. Next, we measured baseline plasma IL-6 levels in 64 HCC patients who underwent Atezo/Bev therapy by ELISA. The IL-6-high group showed higher female ratio, AST levels, tumor markers, Child–Pugh score, and vascular invasion ratio. The PFS and OS of the IL-6-high group were significantly shorter than those of the IL-6-low group. Multivariate Cox proportional hazards analysis showed that IL-6 level and age were independent risk factors for disease progression (hazard ratio of 2.785 and p = 0.015 for IL-6, and hazard ratio 0.306 and p = 0.03 for age). In conclusion, circulating IL-6 levels are a novel prognostic biomarker for advanced HCC patients who undergo combined immunotherapy. Full article

(This article belongs to the Special Issue Hepatobiliary and Pancreatic Neoplasms: Biomarkers and Targeted Therapy)

► Show Figures

Figure 1

15 pages, 11700 KiB

Open AccessFeature PaperEditor’s ChoiceArticle

HPRT1 Promotes Chemoresistance in Oral Squamous Cell Carcinoma via Activating MMP1/PI3K/Akt Signaling Pathway

by Tong Wu, Zan Jiao, Yixuan Li, Xuan Su, Fan Yao, Jin Peng, Weichao Chen and Ankui Yang

Cancers 2022, 14(4), 855; https://doi.org/10.3390/cancers14040855 - 9 Feb 2022

Cited by 32 | Viewed by 3897

Abstract

Hypoxanthine phosphoribosyl transferase 1 (HPRT1) is traditionally believed to be a housekeeping gene. However, recent reports have indicated that HPRT1 overexpression is associated with a poor prognosis in various types of cancers. Using The Cancer Genome Atlas (TCGA), HPRT1 was found to be [...] Read more.

Hypoxanthine phosphoribosyl transferase 1 (HPRT1) is traditionally believed to be a housekeeping gene. However, recent reports have indicated that HPRT1 overexpression is associated with a poor prognosis in various types of cancers. Using The Cancer Genome Atlas (TCGA), HPRT1 was found to be highly expressed in various cancer types, especially in head and neck squamous cell carcinoma (HNSCC). Therefore, we measured HPRT1 expression in human cancer tissues and adjacent non-carcinoma tissues (ANT) and explored the relationship between HPRT1 expression and clinical pathological factors and prognosis in patients with oral squamous cell carcinoma (OSCC), a common type of HNSCC. We built OSCC cells with stable knockdown and overexpression of HPRT1 to observe its influence on chemoresistance and malignancy in vitro and vivo. We found that highly expressed HPRT1 was associated with a poor prognosis and could promote resistance to cisplatin (CDDP) in OSCC cells in both in vitro and in vivo. An RNA sequence assay was carried out to explore the mechanism of function of HPRT1, we found that HPRT1 could positively regulate the expression of MMP1 and the activation of the PI3K/AKT pathway, to regulate the resistance to CDDP of OSCC. In conclusion, HPRT1 can no longer be simply believed to be a housekeeping gene. HPRT1 overexpression indicates a worse prognosis and can improve CDDP resistance for patients with OSCC by promoting the MMP1/PI3K/Akt axis. HPRT1 may be a potential prognostic biomarker and therapeutic target in OSCC. Full article

(This article belongs to the Special Issue The Biomarkers and Detection of Head and Neck Cancer)

► Show Figures

Figure 1

16 pages, 1818 KiB

Open AccessEditor’s ChoiceArticle

Identification of Prognostic Markers of Gynecologic Cancers Utilizing Patient-Derived Xenograft Mouse Models

by Ha-Yeon Shin, Eun-ju Lee, Wookyeom Yang, Hyo Sun Kim, Dawn Chung, Hanbyoul Cho and Jae-Hoon Kim

Cancers 2022, 14(3), 829; https://doi.org/10.3390/cancers14030829 - 6 Feb 2022

Cited by 15 | Viewed by 3595

Abstract

Patient-derived xenografts (PDXs) are important in vivo models for the development of precision medicine. However, challenges exist regarding genetic alterations and relapse after primary treatment. Thus, PDX models are required as a new approach for preclinical and clinical studies. We established PDX models [...] Read more.

Patient-derived xenografts (PDXs) are important in vivo models for the development of precision medicine. However, challenges exist regarding genetic alterations and relapse after primary treatment. Thus, PDX models are required as a new approach for preclinical and clinical studies. We established PDX models of gynecologic cancers and analyzed their clinical information. We subcutaneously transplanted 207 tumor tissues from patients with gynecologic cancer into nude mice from 2014 to 2019. The successful engraftment rate of ovarian, cervical, and uterine cancer was 47%, 64%, and 56%, respectively. The subsequent passages (P2 and P3) showed higher success and faster growth rates than the first passage (P1). Using gynecologic cancer PDX models, the tumor grade is a common clinical factor affecting PDX establishment. We found that the PDX success rate correlated with the patient’s prognosis, and also that ovarian cancer patients with a poor prognosis had a faster PDX growth rate (p < 0.0001). Next, the gene sets associated with inflammation and immune responses were shown in high-ranking successful PDX engraftment through gene set enrichment analysis and RNA sequencing. Up-regulated genes in successful engraftment were found to correlate with ovarian clear cell cancer patient outcomes via Gene Expression Omnibus dataset analysis. Full article

(This article belongs to the Collection The Biomarkers for the Diagnosis and Prognosis in Cancer)

► Show Figures

Figure 1

17 pages, 3623 KiB

Open AccessEditor’s ChoiceArticle

Characterization of Cellular and Acellular Analytes from Pre-Cystectomy Liquid Biopsies in Patients Newly Diagnosed with Primary Bladder Cancer

by Stephanie N. Shishido, Salmaan Sayeed, George Courcoubetis, Hooman Djaladat, Gus Miranda, Kenneth J. Pienta, Jorge Nieva, Donna E. Hansel, Mihir Desai, Inderbir S. Gill, Peter Kuhn and Jeremy Mason

Cancers 2022, 14(3), 758; https://doi.org/10.3390/cancers14030758 - 1 Feb 2022

Cited by 16 | Viewed by 4995

Abstract

Urinary bladder cancer (BCa) is the 10th most frequent cancer in the world, most commonly found among the elderly population, and becomes highly lethal once cells have spread from the primary tumor to surrounding tissues and distant organs. Cystectomy, alone or with other [...] Read more.

Urinary bladder cancer (BCa) is the 10th most frequent cancer in the world, most commonly found among the elderly population, and becomes highly lethal once cells have spread from the primary tumor to surrounding tissues and distant organs. Cystectomy, alone or with other treatments, is used to treat most BCa patients, as it offers the best chance of cure. However, even with curative intent, 29% of patients experience relapse of the cancer, 50% of which occur within the first year of surgery. This study aims to use the liquid biopsy to noninvasively detect disease and discover prognostic markers for disease progression. Using the third generation high-definition single cell assay (HDSCA3.0), 50 bladder cancer patient samples and 50 normal donor (ND) samples were analyzed for circulating rare events in the peripheral blood (PB), including circulating tumor cells (CTCs) and large extracellular vesicles (LEVs). Here, we show that (i) CTCs and LEVs are detected in the PB of BCa patients prior to cystectomy, (ii) there is a high heterogeneity of CTCs, and (iii) liquid biopsy analytes correlate with clinical data elements. We observed a significant difference in the incidence of rare cells and LEVs between BCa and ND samples (median of 74.61 cells/mL and 30.91 LEVs/mL vs. 34.46 cells/mL and 3.34 LEVs/mL, respectively). Furthermore, using classification models for the liquid biopsy data, we achieved a sensitivity of 78% and specificity of 92% for the identification of BCa patient samples. Taken together, these data support the clinical utility of the liquid biopsy in detecting BCa, as well as the potential for predicting cancer recurrence and survival post-cystectomy to better inform treatment decisions in BCa care. Full article

(This article belongs to the Special Issue Targetable Pathways in Advanced Bladder Cancer)

► Show Figures

Graphical abstract

13 pages, 1638 KiB

Open AccessEditor’s ChoiceArticle

Sex Differences in the Effect of Vitamin D on Fatigue in Palliative Cancer Care—A Post Hoc Analysis of the Randomized, Controlled Trial ‘Palliative-D’

by Caritha Klasson, Maria Helde Frankling, Anna Warnqvist, Carina Sandberg, Marie Nordström, Carina Lundh-Hagelin and Linda Björkhem-Bergman

Cancers 2022, 14(3), 746; https://doi.org/10.3390/cancers14030746 - 31 Jan 2022

Cited by 4 | Viewed by 5019

Abstract

In the randomized, placebo-controlled, double-blind trial ‘Palliative-D’, vitamin D treatment of 4000 IE/day for 12 weeks reduced opioid use and fatigue in vitamin-D-deficient cancer patients. In screening data from this trial, lower levels of vitamin D were associated with more fatigue in men [...] Read more.

In the randomized, placebo-controlled, double-blind trial ‘Palliative-D’, vitamin D treatment of 4000 IE/day for 12 weeks reduced opioid use and fatigue in vitamin-D-deficient cancer patients. In screening data from this trial, lower levels of vitamin D were associated with more fatigue in men but not in women. The aim of the present study was to investigate possible sex differences in the effect of vitamin D in patients with advanced cancer, with a specific focus on fatigue. A post hoc analysis of sex differences in patients completing the Palliative-D study (n = 150) was performed. Fatigue assessed with the Edmonton Symptom Assessment Scale (ESAS) was reduced in vitamin-D-treated men; −1.50 ESAS points (95%CI −2.57 to −0.43; p = 0.007) but not in women; −0.75 (95%CI −1.85 to 0.36; p = 0.18). Fatigue measured with EORTC QLQ-C15-PAL had a borderline significant effect in men (−0.33 (95%CI −0.67 to 0.03; p = 0.05)) but not in women (p = 0.55). The effect on fatigue measured with ESAS in men remained the same after adjustment for opioid doses (p = 0.01). In conclusion, the positive effect of the correction of vitamin D deficiency on fatigue may be more pronounced in men than in women. However, studies focused on analyzing sex differences in this context must be performed before firm conclusions can be drawn. Full article

(This article belongs to the Special Issue Palliative and Supportive Care in Oncology: An Update)

► Show Figures

Figure 1

18 pages, 6998 KiB

Open AccessEditor’s ChoiceArticle

Early-Stage Lung Adenocarcinoma MDM2 Genomic Amplification Predicts Clinical Outcome and Response to Targeted Therapy

by Abhilasha Sinha, Yong Zou, Ayushi S. Patel, Seungyeul Yoo, Feng Jiang, Takashi Sato, Ranran Kong, Hideo Watanabe, Jun Zhu, Pierre P. Massion, Alain C. Borczuk and Charles A. Powell

Cancers 2022, 14(3), 708; https://doi.org/10.3390/cancers14030708 - 29 Jan 2022

Cited by 15 | Viewed by 5004

Abstract

Lung cancer is the most common cause of cancer-related deaths in both men and women, accounting for one-quarter of total cancer-related mortality globally. Lung adenocarcinoma is the major subtype of non-small cell lung cancer (NSCLC) and accounts for around 40% of lung cancer [...] Read more.

Lung cancer is the most common cause of cancer-related deaths in both men and women, accounting for one-quarter of total cancer-related mortality globally. Lung adenocarcinoma is the major subtype of non-small cell lung cancer (NSCLC) and accounts for around 40% of lung cancer cases. Lung adenocarcinoma is a highly heterogeneous disease and patients often display variable histopathological morphology, genetic alterations, and genomic aberrations. Recent advances in transcriptomic and genetic profiling of lung adenocarcinoma by investigators, including our group, has provided better stratification of this heterogeneous disease, which can facilitate devising better treatment strategies suitable for targeted patient cohorts. In a recent study we have shown gene expression profiling identified novel clustering of early stage LUAD patients and correlated with tumor invasiveness and patient survival. In this study, we focused on copy number alterations in LUAD patients. SNP array data identified amplification at chromosome 12q15 on MDM2 locus and protein overexpression in a subclass of LUAD patients with an invasive subtype of the disease. High copy number amplification and protein expression in this subclass correlated with poor overall survival. We hypothesized that MDM2 copy number and overexpression predict response to MDM2-targeted therapy. In vitro functional data on a panel of LUAD cells showed that MDM2-targeted therapy effectively suppresses cell proliferation, migration, and invasion in cells with MDM2 amplification/overexpression but not in cells without MDM2 amplification, independent of p53 status. To determine the key signaling mechanisms, we used RNA sequencing (RNA seq) to examine the response to therapy in MDM2-amplified/overexpressing p53 mutant and wild-type LUAD cells. RNA seq data shows that in MDM2-amplified/overexpression with p53 wild-type condition, the E2F → PEG10 → MMPs pathway is operative, while in p53 mutant genetic background, MDM2-targeted therapy abrogates tumor progression in LUAD cells by suppressing epithelial to mesenchymal transition (EMT) signaling. Our study provides a potentially clinically relevant strategy of selecting LUAD patients for MDM2-targeted therapy that may provide for increased response rates and, thus, better survival. Full article

(This article belongs to the Special Issue Tumor Heterogeneity)

► Show Figures

Figure 1

19 pages, 4641 KiB

Open AccessEditor’s ChoiceArticle

Slip versus Slop: A Head-to-Head Comparison of UV-Protective Clothing to Sunscreen

by Elizabeth G. Berry, Joshua Bezecny, Michael Acton, Taylor P. Sulmonetti, David M. Anderson, Haskell W. Beckham, Rebecca A. Durr, Takahiro Chiba, Jennifer Beem, Douglas E. Brash, Rajan Kulkarni, Pamela B. Cassidy and Sancy A. Leachman

Cancers 2022, 14(3), 542; https://doi.org/10.3390/cancers14030542 - 21 Jan 2022

Cited by 28 | Viewed by 10701

Abstract

Ultraviolet radiation (UVR) exposure is the most important modifiable risk factor for skin cancer development. Although sunscreen and sun-protective clothing are essential tools to minimize UVR exposure, few studies have compared the two modalities head-to-head. This study evaluates the UV-protective capacity of four [...] Read more.

Ultraviolet radiation (UVR) exposure is the most important modifiable risk factor for skin cancer development. Although sunscreen and sun-protective clothing are essential tools to minimize UVR exposure, few studies have compared the two modalities head-to-head. This study evaluates the UV-protective capacity of four modern, sun-protective textiles and two broad-spectrum, organic sunscreens (SPF 30 and 50). Sun Protection Factor (SPF), Ultraviolet Protection Factor (UPF), Critical Wavelength (CW), and % UVA- and % UVB-blocking were measured for each fabric. UPF, CW, % UVA- and % UVB-blocking were measured for each sunscreen at 2 mg/cm² (recommended areal density) and 1 mg/cm² (simulating real-world consumer application). The four textiles provided superior UVR protection when compared to the two sunscreens tested. All fabrics blocked erythemogenic UVR better than the sunscreens, as measured by SPF, UPF, and % UVB-blocking. Each fabric was superior to the sunscreens in blocking full-spectrum UVR, as measured by CW and % UVA-blocking. Our data demonstrate the limitations of sunscreen and UV-protective clothing labeling and suggest the combination of SPF or UPF with % UVA-blocking may provide more suitable measures for broad-spectrum protection. While sunscreen remains an important photoprotective modality (especially for sites where clothing is impractical), these data suggest that clothing should be considered the cornerstone of UV protection. Full article

(This article belongs to the Special Issue Melanoma: Prevention and Molecular Epidemiology)

► Show Figures

Figure 1

18 pages, 2848 KiB

Open AccessEditor’s ChoiceArticle

Platelet Count and Survival after Cancer

by Vasily Giannakeas, Joanne Kotsopoulos, Jennifer D. Brooks, Matthew C. Cheung, Laura Rosella, Lorraine Lipscombe, Mohammad R. Akbari, Peter C. Austin and Steven A. Narod

Cancers 2022, 14(3), 549; https://doi.org/10.3390/cancers14030549 - 21 Jan 2022

Cited by 36 | Viewed by 7581

Abstract

Thrombocytosis is associated with cancer progression and death for many cancer types. It is unclear if platelet count is also associated with cancer survival. We conducted a cohort study of 112,231 adults in Ontario with a diagnosis of cancer between January 2007 and [...] Read more.

Thrombocytosis is associated with cancer progression and death for many cancer types. It is unclear if platelet count is also associated with cancer survival. We conducted a cohort study of 112,231 adults in Ontario with a diagnosis of cancer between January 2007 and December 2016. We included patients who had a complete blood count (CBC) completed in the 30 days prior to their cancer diagnosis. Subjects were assigned to one of three categories according to platelet count: low (≤25th percentile), medium (>25 to <75th percentile), and high (≥75th percentile). Study subjects were followed from the date of their cancer diagnosis for cancer-specific death. Of the 112,231 eligible cancer patients in the cohort study, 40,329 (35.9%) died from their cancer in the follow-up period. Relative to those with a medium platelet count, the rate of cancer-specific death was higher among individuals with a high platelet count (HR 1.52; 95%CI 1.48–1.55) and was lower among individuals with a low platelet count (HR 0.91; 95%CI 0.88–0.93). A high platelet count was associated with poor survival for many cancer types. Platelet count could potentially be used as a risk stratification measure for cancer patients. Full article

► Show Figures

Figure 1

21 pages, 3019 KiB

Open AccessEditor’s ChoiceArticle

CXCR2 Mediates Distinct Neutrophil Behavior in Brain Metastatic Breast Tumor

by Simrit Safarulla, Ankit Madan, Fei Xing and Arvind Chandrasekaran

Cancers 2022, 14(3), 515; https://doi.org/10.3390/cancers14030515 - 20 Jan 2022

Cited by 23 | Viewed by 5897

Abstract

Brain metastasis is one of the main causes of mortality among breast cancer patients, but the origins and the mechanisms that drive this process remain poorly understood. Here, we report that the upregulation of certain CXCR2-associated ligands in the brain metastatic variants of [...] Read more.

Brain metastasis is one of the main causes of mortality among breast cancer patients, but the origins and the mechanisms that drive this process remain poorly understood. Here, we report that the upregulation of certain CXCR2-associated ligands in the brain metastatic variants of the breast cancer cells (BrM) dynamically activate the corresponding CXCR2 receptors on the neutrophils, thereby resulting in the modulation of certain key functional neutrophil responses towards the BrM. Using established neutrophil-tumor biomimetic co-culture models, we show that the upregulation of CXCR2 increases the recruitment of Tumor-Associated Neutrophils (TANs) towards the BrM, to enable location-favored formation of Neutrophil Extracellular Traps (NETs). Inhibition of CXCR2 using small molecule antagonist AZD5069 reversed this behavior, limiting the neutrophil responses to the BrM and retarding the reciprocal tumor development. We further demonstrate that abrogation of NETs formation using Neutrophil Elastase Inhibitor (NEI) significantly decreases the influx of neutrophils towards BrM but not to their parental tumor, suggesting that CXCR2 activation could be used by the brain metastatic tumors as a mechanism to program the tumor-infiltrating TANs into a pro-NETotic state, so as to assume a unique spatial distribution that assists in the subsequent migration and invasion of the metastatic tumor cells. This new perspective indicates that CXCR2 is a critical target for suppressing neutrophilic inflammation in brain metastasis. Full article

(This article belongs to the Special Issue Neutrophils in Cancer: Role and Therapeutic Strategies)

► Show Figures

Figure 1

16 pages, 14033 KiB

Open AccessEditor’s ChoiceArticle

Biglycan Promotes Cancer Stem Cell Properties, NFκB Signaling and Metastatic Potential in Breast Cancer Cells

by Kanakaraju Manupati, Ritama Paul, Mingang Hao, Michael Haas, Zhaoqun Christine Bian, Tammy M. Holm, Jun-Lin Guan and Syn Kok Yeo

Cancers 2022, 14(2), 455; https://doi.org/10.3390/cancers14020455 - 17 Jan 2022

Cited by 15 | Viewed by 4048

Abstract

It is a major challenge to treat metastasis due to the presence of heterogenous BCSCs. Therefore, it is important to identify new molecular targets and their underlying molecular mechanisms in various BCSCs to improve treatment of breast cancer metastasis. Here, we performed RNA [...] Read more.

It is a major challenge to treat metastasis due to the presence of heterogenous BCSCs. Therefore, it is important to identify new molecular targets and their underlying molecular mechanisms in various BCSCs to improve treatment of breast cancer metastasis. Here, we performed RNA sequencing on two distinct co-existing BCSC populations, ALDH⁺ and CD29^hi CD61⁺ from PyMT mammary tumor cells and detected upregulation of biglycan (BGN) in these BCSCs. Genetic depletion of BGN reduced BCSC proportions and tumorsphere formation. Furthermore, BCSC associated aggressive traits such as migration and invasion were significantly reduced by depletion of BGN. Glycolytic and mitochondrial metabolic assays also revealed that BCSCs exhibited decreased metabolism upon loss of BGN. BCSCs showed decreased activation of the NFκB transcription factor, p65, and phospho-IκB levels upon BGN ablation, indicating regulation of NFκB pathway by BGN. To further support our data, we also characterized CD24⁻/CD44⁺ BCSCs from human luminal MCF-7 breast cancer cells. These CD24⁻/CD44⁺ BCSCs similarly exhibited reduced tumorigenic phenotypes, metabolism and attenuation of NFκB pathway after knockdown of BGN. Finally, loss of BGN in ALDH⁺ and CD29^hi CD61⁺ BCSCs showed decreased metastatic potential, suggesting BGN serves as an important therapeutic target in BCSCs for treating metastasis of breast cancer. Full article

(This article belongs to the Special Issue Signalling Pathways of Cancer Stem Cells)

► Show Figures

Figure 1

14 pages, 1672 KiB

Open AccessEditor’s ChoiceArticle

Comprehensive Approach to Distinguish Patients with Solid Tumors from Healthy Controls by Combining Androgen Receptor Mutation p.H875Y with Cell-Free DNA Methylation and Circulating miRNAs

by Elena Tomeva, Olivier J. Switzeny, Clemens Heitzinger, Berit Hippe and Alexander G. Haslberger

Cancers 2022, 14(2), 462; https://doi.org/10.3390/cancers14020462 - 17 Jan 2022

Cited by 23 | Viewed by 7701

Abstract

Liquid biopsy-based tests emerge progressively as an important tool for cancer diagnostics and management. Currently, researchers focus on a single biomarker type and one tumor entity. This study aimed to create a multi-analyte liquid biopsy test for the simultaneous detection of several solid [...] Read more.

Liquid biopsy-based tests emerge progressively as an important tool for cancer diagnostics and management. Currently, researchers focus on a single biomarker type and one tumor entity. This study aimed to create a multi-analyte liquid biopsy test for the simultaneous detection of several solid cancers. For this purpose, we analyzed cell-free DNA (cfDNA) mutations and methylation, as well as circulating miRNAs (miRNAs) in plasma samples from 97 patients with cancer (20 bladder, 9 brain, 30 breast, 28 colorectal, 29 lung, 19 ovarian, 12 pancreas, 27 prostate, 23 stomach) and 15 healthy controls via real-time qPCR. Androgen receptor p.H875Y mutation (AR) was detected for the first time in bladder, lung, stomach, ovarian, brain, and pancreas cancer, all together in 51.3% of all cancer samples and in none of the healthy controls. A discriminant function model, comprising cfDNA mutations (COSM10758, COSM18561), cfDNA methylation markers (MLH1, MDR1, GATA5, SFN) and miRNAs (miR-17-5p, miR-20a-5p, miR-21-5p, miR-26a-5p, miR-27a-3p, miR-29c-3p, miR-92a-3p, miR-101-3p, miR-133a-3p, miR-148b-3p, miR-155-5p, miR-195-5p) could further classify healthy and tumor samples with 95.4% accuracy, 97.9% sensitivity, 80% specificity. This multi-analyte liquid biopsy-based test may help improve the simultaneous detection of several cancer types and underlines the importance of combining genetic and epigenetic biomarkers. Full article

(This article belongs to the Special Issue Liquid Nucleic Acid-Based Biomarkers in Solid Tumors)

► Show Figures

Graphical abstract

16 pages, 1973 KiB

Open AccessEditor’s ChoiceArticle

Machine Learning Using Real-World and Translational Data to Improve Treatment Selection for NSCLC Patients Treated with Immunotherapy

by Arsela Prelaj, Mattia Boeri, Alessandro Robuschi, Roberto Ferrara, Claudia Proto, Giuseppe Lo Russo, Giulia Galli, Alessandro De Toma, Marta Brambilla, Mario Occhipinti, Sara Manglaviti, Teresa Beninato, Achille Bottiglieri, Giacomo Massa, Emma Zattarin, Rosaria Gallucci, Edoardo Gregorio Galli, Monica Ganzinelli, Gabriella Sozzi, Filippo G. M. de Braud, Marina Chiara Garassino, Marcello Restelli, Alessandra Laura Giulia Pedrocchi and Francesco Trovo' Show full author list Hide full author list

Cancers 2022, 14(2), 435; https://doi.org/10.3390/cancers14020435 - 16 Jan 2022

Cited by 23 | Viewed by 4543

Abstract

(1) Background: In advanced non-small cell lung cancer (aNSCLC), programmed death ligand 1 (PD-L1) remains the only biomarker for candidate patients to immunotherapy (IO). This study aimed at using artificial intelligence (AI) and machine learning (ML) tools to improve response and efficacy predictions [...] Read more.

(1) Background: In advanced non-small cell lung cancer (aNSCLC), programmed death ligand 1 (PD-L1) remains the only biomarker for candidate patients to immunotherapy (IO). This study aimed at using artificial intelligence (AI) and machine learning (ML) tools to improve response and efficacy predictions in aNSCLC patients treated with IO. (2) Methods: Real world data and the blood microRNA signature classifier (MSC) were used. Patients were divided into responders (R) and non-responders (NR) to determine if the overall survival of the patients was likely to be shorter or longer than 24 months from baseline IO. (3) Results: One-hundred sixty-four out of 200 patients (i.e., only those ones with PD-L1 data available) were considered in the model, 73 (44.5%) were R and 91 (55.5%) NR. Overall, the best model was the linear regression (RL) and included 5 features. The model predicting R/NR of patients achieved accuracy ACC = 0.756, F1 score F1 = 0.722, and area under the ROC curve AUC = 0.82. LR was also the best-performing model in predicting patients with long survival (24 months OS), achieving ACC = 0.839, F1 = 0.908, and AUC = 0.87. (4) Conclusions: The results suggest that the integration of multifactorial data provided by ML techniques is a useful tool to select NSCLC patients as candidates for IO. Full article

(This article belongs to the Special Issue Cancer: Advances in T Cell-Based Clinical Immunotherapies)

► Show Figures

Figure 1

27 pages, 3431 KiB

Open AccessEditor’s ChoiceArticle

The Anti-Proliferative Effect of PI3K/mTOR and ERK Inhibition in Monolayer and Three-Dimensional Ovarian Cancer Cell Models

by Elizabeth Dunn, Kenny Chitcholtan, Peter Sykes and Ashley Garrill

Cancers 2022, 14(2), 395; https://doi.org/10.3390/cancers14020395 - 13 Jan 2022

Cited by 12 | Viewed by 3575

Abstract

Most ovarian cancer patients are diagnosed with advanced stage disease, which becomes unresponsive to chemotherapeutic treatments. The PI3K/AKT/mTOR and the RAS/RAF/MEK/ERK kinase signaling pathways are attractive targets for potential therapeutic inhibitors, due to the high frequency of mutations to PTEN, PIK3CA, KRAS and [...] Read more.

Most ovarian cancer patients are diagnosed with advanced stage disease, which becomes unresponsive to chemotherapeutic treatments. The PI3K/AKT/mTOR and the RAS/RAF/MEK/ERK kinase signaling pathways are attractive targets for potential therapeutic inhibitors, due to the high frequency of mutations to PTEN, PIK3CA, KRAS and BRAF in several ovarian cancer subtypes. However, monotherapies targeting one of these pathways have shown modest effects in clinical trials. This limited efficacy of the agents could be due to upregulation and increased signaling via the adjacent alternative pathway. In this study, the efficacy of combined PI3K/mTOR (BEZ235) and ERK inhibition (SCH772984) was investigated in four human ovarian cancer cell lines, grown as monolayer and three-dimensional cell aggregates. The inhibitor combination reduced cellular proliferation in a synergistic manner in OV-90 and OVCAR8 monolayers and in OV-90, OVCAR5 and SKOV3 aggregates. Sensitivity to the inhibitors was reduced in three-dimensional cell aggregates in comparison to monolayers. OV-90 cells cultured in large spheroids were sensitive to the inhibitors and displayed a robust synergistic antiproliferative response to the inhibitor combination. In contrast, OVCAR8 spheroids were resistant to the inhibitors. These findings suggest that combined PI3K/mTOR and ERK inhibition could be a useful strategy for overcoming treatment resistance in ovarian cancer and warrants further preclinical investigation. Additionally, in some cell lines the use of different three-dimensional models can influence cell line sensitivity to PI3K/mTOR and RAS/RAF/MEK/ERK pathway inhibitors. Full article

(This article belongs to the Special Issue Three-Dimensional Culture Systems in Cancer Research)

► Show Figures

Figure 1

20 pages, 4654 KiB

Open AccessEditor’s ChoiceArticle

Metabolomic Phenotyping of Gliomas: What Can We Get with Simplified Protocol for Intact Tissue Analysis?

by Paulina Zofia Goryńska, Kamila Chmara, Bogumiła Kupcewicz, Krzysztof Goryński, Karol Jaroch, Dariusz Paczkowski, Jacek Furtak, Marek Harat and Barbara Bojko

Cancers 2022, 14(2), 312; https://doi.org/10.3390/cancers14020312 - 9 Jan 2022

Cited by 11 | Viewed by 3151

Abstract

Glioblastoma multiforme is one of the most malignant neoplasms among humans in their third and fourth decades of life, which is evidenced by short patient survival times and rapid tumor-cell proliferation after radiation and chemotherapy. At present, the diagnosis of gliomas and decisions [...] Read more.

Glioblastoma multiforme is one of the most malignant neoplasms among humans in their third and fourth decades of life, which is evidenced by short patient survival times and rapid tumor-cell proliferation after radiation and chemotherapy. At present, the diagnosis of gliomas and decisions related to therapeutic strategies are based on genetic testing and histological analysis of the tumor, with molecular biomarkers still being sought to complement the diagnostic panel. This work aims to enable the metabolomic characterization of cancer tissue and the discovery of potential biomarkers via high-resolution mass spectrometry coupled to liquid chromatography and a solvent-free sampling protocol that uses a microprobe to extract metabolites directly from intact tumors. The metabolomic analyses were performed independently from genetic and histological testing and at a later time. Despite the small cohort analyzed in this study, the results indicated that the proposed method is able to identify metabolites associated with different malignancy grades of glioma, as well as IDH and 1p19q codeletion mutations. A comparison of the constellation of identified metabolites and the results of standard tests indicated the validity of using the characterization of one comprehensive tumor phenotype as a reflection of all diagnostically meaningful information. Due to its simplicity, the proposed analytical approach was verified as being compatible with a surgical environment and applicable for large-scale studies. Full article

(This article belongs to the Collection Diagnostic and Therapeutic Challenges in Patients with Primary or Secondary Brain Tumor)

► Show Figures

Figure 1

20 pages, 4267 KiB

Open AccessEditor’s ChoiceArticle

PRMT1 Regulates EGFR and Wnt Signaling Pathways and Is a Promising Target for Combinatorial Treatment of Breast Cancer

by Samyuktha Suresh, Solène Huard, Amélie Brisson, Fariba Némati, Rayan Dakroub, Coralie Poulard, Mengliang Ye, Elise Martel, Cécile Reyes, David C. Silvestre, Didier Meseure, André Nicolas, David Gentien, Hussein Fayyad-Kazan, Muriel Le Romancer, Didier Decaudin, Sergio Roman-Roman and Thierry Dubois

Cancers 2022, 14(2), 306; https://doi.org/10.3390/cancers14020306 - 8 Jan 2022

Cited by 24 | Viewed by 4616

Abstract

Identifying new therapeutic strategies for triple-negative breast cancer (TNBC) patients is a priority as these patients are highly prone to relapse after chemotherapy. Here, we found that protein arginine methyltransferase 1 (PRMT1) is highly expressed in all breast cancer subtypes. PRMT1 depletion decreases [...] Read more.

Identifying new therapeutic strategies for triple-negative breast cancer (TNBC) patients is a priority as these patients are highly prone to relapse after chemotherapy. Here, we found that protein arginine methyltransferase 1 (PRMT1) is highly expressed in all breast cancer subtypes. PRMT1 depletion decreases cell survival by inducing DNA damage and apoptosis in various breast cancer cell lines. Transcriptomic analysis and chromatin immunoprecipitation revealed that PRMT1 regulates the epidermal growth factor receptor (EGFR) and the Wnt signaling pathways, reported to be activated in TNBC. PRMT1 enzymatic activity is also required to stimulate the canonical Wnt pathway. Type I PRMT inhibitors decrease breast cancer cell proliferation and show anti-tumor activity in a TNBC xenograft model. These inhibitors display synergistic interactions with some chemotherapies used to treat TNBC patients as well as erlotinib, an EGFR inhibitor. Therefore, targeting PRMT1 in combination with these chemotherapies may improve existing treatments for TNBC patients. Full article

(This article belongs to the Section Cancer Therapy)

► Show Figures

Figure 1

21 pages, 2241 KiB

Open AccessEditor’s ChoiceArticle

ATX-101, a Peptide Targeting PCNA, Has Antitumor Efficacy Alone or in Combination with Radiotherapy in Murine Models of Human Glioblastoma

by Giovanni Luca Gravina, Alessandro Colapietro, Andrea Mancini, Alessandra Rossetti, Stefano Martellucci, Luca Ventura, Martina Di Franco, Francesco Marampon, Vincenzo Mattei, Leda Assunta Biordi, Marit Otterlei and Claudio Festuccia

Cancers 2022, 14(2), 289; https://doi.org/10.3390/cancers14020289 - 7 Jan 2022

Cited by 23 | Viewed by 3774

Abstract

Cell proliferation requires the orchestrated actions of a myriad of proteins regulating DNA replication, DNA repair and damage tolerance, and cell cycle. Proliferating cell nuclear antigen (PCNA) is a master regulator which interacts with multiple proteins functioning in these processes, and this makes [...] Read more.

Cell proliferation requires the orchestrated actions of a myriad of proteins regulating DNA replication, DNA repair and damage tolerance, and cell cycle. Proliferating cell nuclear antigen (PCNA) is a master regulator which interacts with multiple proteins functioning in these processes, and this makes PCNA an attractive target in anticancer therapies. Here, we show that a cell-penetrating peptide containing the AlkB homolog 2 PCNA-interacting motif (APIM), ATX-101, has antitumor activity in a panel of human glioblastoma multiforme (GBM) cell lines and patient-derived glioma-initiating cells (GICs). Their sensitivity to ATX-101 was not related to cellular levels of PCNA, or p53, PTEN, or MGMT status. However, ATX-101 reduced Akt/mTOR and DNA-PKcs signaling, and a correlation between high Akt activation and sensitivity for ATX-101 was found. ATX-101 increased the levels of γH2AX, DNA fragmentation, and apoptosis when combined with radiotherapy (RT). In line with the in vitro results, ATX-101 strongly reduced tumor growth in two subcutaneous xenografts and two orthotopic GBM models, both as a single agent and in combination with RT. The ability of ATX-101 to sensitize cells to RT is promising for further development of this compound for use in GBM. Full article

► Show Figures

Figure 1

22 pages, 7485 KiB

Open AccessEditor’s ChoiceArticle

Onco-miR-21 Promotes Stat3-Dependent Gastric Cancer Progression

by Janson Tse, Thomas Pierce, Annalisa L. E. Carli, Mariah G. Alorro, Stefan Thiem, Eric G. Marcusson, Matthias Ernst and Michael Buchert

Cancers 2022, 14(2), 264; https://doi.org/10.3390/cancers14020264 - 6 Jan 2022

Cited by 25 | Viewed by 3238

Abstract

MicroRNA-21 (miR-21) is a small, non-coding RNA overexpressed in gastric cancer and many other solid malignancies, where it exhibits both pro-and anti-tumourigenic properties. However, the pathways regulating miR-21 and the consequences of its inhibition in gastric cancer remain incompletely understood. By exploiting the [...] Read more.

MicroRNA-21 (miR-21) is a small, non-coding RNA overexpressed in gastric cancer and many other solid malignancies, where it exhibits both pro-and anti-tumourigenic properties. However, the pathways regulating miR-21 and the consequences of its inhibition in gastric cancer remain incompletely understood. By exploiting the spontaneous Stat3-dependent formation of inflammation-associated gastric tumors in Gp130^F^/F mice, we functionally established miR-21 as a Stat3-controlled driver of tumor growth and progression. We reconciled our discoveries by identifying several conserved Stat3 binding motifs upstream of the miR-21 gene promoter, and showed that the systemic administration of a miR-21-specific antisense oligonucleotide antagomir reduced the established gastric tumor burden in Gp130^F^/F mice. We molecularly delineated the therapeutic benefits of miR-21 inhibition with the functional restoration of PTEN in vitro and in vivo, alongside an attenuated epithelial-to-mesenchymal transition and the extracellular matrix remodeling phenotype of tumors. We corroborated our preclinical findings by correlating high STAT3 and miR-21 expression with the reduced survival probability of gastric cancer patients. Collectively, our results provide a molecular framework by which miR-21 mediates inflammation-associated gastric cancer progression, and establish miR-21 as a robust therapeutic target for solid malignancies characterized by excessive Stat3 activity. Full article

(This article belongs to the Special Issue Multicellular Effects of STAT3 in the Tumour Microenvironment)

► Show Figures

Figure 1

17 pages, 4020 KiB

Open AccessEditor’s ChoiceArticle

Upregulation of CD36, a Fatty Acid Translocase, Promotes Colorectal Cancer Metastasis by Increasing MMP28 and Decreasing E-Cadherin Expression

by James Drury, Piotr G. Rychahou, Courtney O. Kelson, Mariah E. Geisen, Yuanyuan Wu, Daheng He, Chi Wang, Eun Y. Lee, B. Mark Evers and Yekaterina Y. Zaytseva

Cancers 2022, 14(1), 252; https://doi.org/10.3390/cancers14010252 - 5 Jan 2022

Cited by 39 | Viewed by 6664

Abstract

Altered fatty acid metabolism continues to be an attractive target for therapeutic intervention in cancer. We previously found that colorectal cancer (CRC) cells with a higher metastatic potential express a higher level of fatty acid translocase (CD36). However, the role of CD36 in [...] Read more.

Altered fatty acid metabolism continues to be an attractive target for therapeutic intervention in cancer. We previously found that colorectal cancer (CRC) cells with a higher metastatic potential express a higher level of fatty acid translocase (CD36). However, the role of CD36 in CRC metastasis has not been studied. Here, we demonstrate that high expression of CD36 promotes invasion of CRC cells. Consistently, CD36 promoted lung metastasis in the tail vein model and GI metastasis in the cecum injection model. RNA-Seq analysis of CRC cells with altered expression of CD36 revealed an association between high expression of CD36 and upregulation of MMP28, a novel member of the metallopeptidase family of proteins. Using shRNA-mediated knockdown and overexpression of CD36, we confirmed that CD36 regulates MMP28 expression in CRC cells. siRNA-mediated knockdown of MMP28 decreases invasion of CRC cells, suggesting that MMP28 regulates the metastatic properties of cells downstream of CD36. Importantly, high expression of MMP28 leads to a significant decrease in active E-cadherin and an increase in the products of E-cadherin cleavage, CTF1 and CTF2. In summary, upregulation of CD36 expression promotes the metastatic properties of CRC via upregulation of MMP28 and an increase in E-cadherin cleavage, suggesting that targeting the CD36–MMP28 axis may be an effective therapeutic strategy for CRC metastasis. Full article

(This article belongs to the Special Issue Insight into Fatty Acid Metabolism in Colorectal Cancer)

► Show Figures

Figure 1

13 pages, 2379 KiB

Open AccessEditor’s ChoiceArticle

Delta-Radiomics Predicts Response to First-Line Oxaliplatin-Based Chemotherapy in Colorectal Cancer Patients with Liver Metastases

by Valentina Giannini, Laura Pusceddu, Arianna Defeudis, Giulia Nicoletti, Giovanni Cappello, Simone Mazzetti, Andrea Sartore-Bianchi, Salvatore Siena, Angelo Vanzulli, Francesco Rizzetto, Elisabetta Fenocchio, Luca Lazzari, Alberto Bardelli, Silvia Marsoni and Daniele Regge

Cancers 2022, 14(1), 241; https://doi.org/10.3390/cancers14010241 - 4 Jan 2022

Cited by 30 | Viewed by 7195

Abstract

The purpose of this paper is to develop and validate a delta-radiomics score to predict the response of individual colorectal cancer liver metastases (lmCRC) to first-line FOLFOX chemotherapy. Three hundred one lmCRC were manually segmented on both CT performed at baseline and after [...] Read more.

The purpose of this paper is to develop and validate a delta-radiomics score to predict the response of individual colorectal cancer liver metastases (lmCRC) to first-line FOLFOX chemotherapy. Three hundred one lmCRC were manually segmented on both CT performed at baseline and after the first cycle of first-line FOLFOX, and 107 radiomics features were computed by subtracting textural features of CT at baseline from those at timepoint 1 (TP1). LmCRC were classified as nonresponders (R−) if they showed progression of disease (PD), according to RECIST1.1, before 8 months, and as responders (R+), otherwise. After feature selection, we developed a decision tree statistical model trained using all lmCRC coming from one hospital. The final output was a delta-radiomics signature subsequently validated on an external dataset. Sensitivity, specificity, positive (PPV), and negative (NPV) predictive values in correctly classifying individual lesions were assessed on both datasets. Per-lesion sensitivity, specificity, PPV, and NPV were 99%, 94%, 95%, 99%, 85%, 92%, 90%, and 87%, respectively, in the training and validation datasets. The delta-radiomics signature was able to reliably predict R− lmCRC, which were wrongly classified by lesion RECIST as R+ at TP1, (93%, averaging training and validation set, versus 67% of RECIST). The delta-radiomics signature developed in this study can reliably predict the response of individual lmCRC to oxaliplatin-based chemotherapy. Lesions forecasted as poor or nonresponders by the signature could be further investigated, potentially paving the way to lesion-specific therapies. Full article

(This article belongs to the Collection Artificial Intelligence in Oncology)

► Show Figures

Figure 1

15 pages, 3727 KiB

Open AccessEditor’s ChoiceArticle

Phototheranostics of Cervical Neoplasms with Chlorin e6 Photosensitizer

by Aida Gilyadova, Anton Ishchenko, Artem Shiryaev, Polina Alekseeva, Kanamat Efendiev, Radmila Karpova, Maxim Loshchenov, Victor Loschenov and Igor Reshetov

Cancers 2022, 14(1), 211; https://doi.org/10.3390/cancers14010211 - 2 Jan 2022

Cited by 20 | Viewed by 4442

Abstract

(1) Purpose: Improving the treatment effectiveness of intraepithelial neoplasia of the cervix associated with human papillomavirus infection, based on the application of the method of photodynamic therapy with simultaneous laser excitation of fluorescence to clarify the boundaries of cervical neoplasms. (2) Methods: Examination [...] Read more.

(1) Purpose: Improving the treatment effectiveness of intraepithelial neoplasia of the cervix associated with human papillomavirus infection, based on the application of the method of photodynamic therapy with simultaneous laser excitation of fluorescence to clarify the boundaries of cervical neoplasms. (2) Methods: Examination and treatment of 52 patients aged 22 to 53 years with morphologically and cytologically confirmed mild to severe intraepithelial cervix neoplasia, preinvasive, micro-invasive, and squamous cell cervix carcinoma. All patients were carriers of human papillomavirus infection. The patients underwent photodynamic therapy with simultaneous laser excitation of fluorescence. The combined use of video and spectral fluorescence diagnostics for cervical neoplasms made it possible to control the photodynamic therapy process at all stages of the procedure. Evaluation of the photodynamic therapy of intraepithelial cervical neoplasms was carried out with colposcopic examination, cytological conclusion, and morphological verification of the biopsy material after the photodynamic therapy course. The success of human papillomavirus therapy was assessed based on the results of the polymerase chain reaction. (3) Results. The possibility of simultaneous spectral fluorescence diagnostics and photodynamic therapy using a laser source with a wavelength of 660 nm has been established, making it possible to assess the fluorescence index in real-time and control the photobleaching of photosensitizers in the irradiated area. The treatment of all 52 patients was successful after the first photodynamic therapy procedure. According to the PCR test of the discharge from the cervical canal, the previously identified HPV types were not observed in 48 patients. Previously identified HPV types were absent after repeated PDT in four patients (CIN III (n = 2), CIS (n = 2)). In 80.8% of patients, regression of the lesion was noted. (4) Conclusions. The high efficiency of photodynamic therapy with intravenous photosensitizer administration of chlorin e6 has been demonstrated both in relation to eradication therapy of human papillomavirus and in relation to the treatment of intraepithelial lesions of the cervix. Full article

(This article belongs to the Special Issue Innovative Cancer Treatments and Photodynamic Therapy)

► Show Figures

Figure 1

18 pages, 3590 KiB

Open AccessEditor’s ChoiceArticle

Combining an Autophagy Inhibitor, MPT0L145, with Abemaciclib Is a New Therapeutic Strategy in GBM Treatment

by Tsung-Han Hsieh, Muh-Lii Liang, Jia-Huei Zheng, Yu-Chen Lin, Yu-Chen Yang, Thanh-Hoa Vo, Jing-Ping Liou, Yun Yen and Chun-Han Chen

Cancers 2021, 13(23), 6117; https://doi.org/10.3390/cancers13236117 - 4 Dec 2021

Cited by 5 | Viewed by 3940

Abstract

Glioblastoma multiforme (GBM) is the most malignant brain tumor in the world, only 25% of GBM patients were alive one year after diagnosis. Although Temozolamide combined with radiation therapy more effectively prolonged the survival rate than radiation alone, the overall survival rate is [...] Read more.

Glioblastoma multiforme (GBM) is the most malignant brain tumor in the world, only 25% of GBM patients were alive one year after diagnosis. Although Temozolamide combined with radiation therapy more effectively prolonged the survival rate than radiation alone, the overall survival rate is still dismal. Therefore, a new therapeutic strategy is urgently needed. CDK4/6 inhibitors are newly FDA-approved agents to treat HR-positive, HER2-negative advanced, and metastatic breast cancers, and preclinical results showed that CDK4/6 inhibitors significantly reduced cell proliferation and tumor growth. However, several studies have suggested that CDK4/6 inhibitor-induced non-genetic changes caused treatment failure, including autophagy activation. Therefore, this study aimed to combine an autophagy inhibitor, MPT0L145, with abemaciclib to improve therapeutic efficiency. The use of abemaciclib effectively inhibited cell proliferation via suppression of RB phosphorylation and induced autophagy activation in GBM cancer cells. MPT0L145 treatment alone not only blocked autophagy activation, but also induced generation of ROS and DNA damage in a concentration-dependent manner. Importantly, MPT0L145 had a comparable penetration ability to TMZ in our blood brain barrier permeability assay. Combined MPT0L145 with abemaciclib significantly reduced cell proliferation, suppressed RB phosphorylation, and increased ROS production. In conclusion, the data suggested that blocking autophagy by MPT0L145 synergistically sensitized GBM cancer cells to abemaciclib and represents a potential therapeutic strategy for treating GBM in the future. Full article

(This article belongs to the Special Issue Brain Tumors: Molecular and Cell Biology for Target Therapy)

► Show Figures

Figure 1

Journal Menu

Journal Browser

Editor’s Choice Articles

Article

Further Information

Guidelines

MDPI Initiatives

Follow MDPI