Cancers

17 pages, 1459 KiB

Open AccessEditor’s ChoiceReview

Radon and Lung Cancer: Current Trends and Future Perspectives

by Mariona Riudavets, Marta Garcia de Herreros, Benjamin Besse and Laura Mezquita

Cancers 2022, 14(13), 3142; https://doi.org/10.3390/cancers14133142 - 27 Jun 2022

Cited by 104 | Viewed by 10076

Lung cancer is a public health problem and the first cause of cancer death worldwide. Radon is a radioactive gas that tends to accumulate inside homes, and it is the second lung cancer risk factor after smoking, and the first one in non-smokers. [...] Read more.

Lung cancer is a public health problem and the first cause of cancer death worldwide. Radon is a radioactive gas that tends to accumulate inside homes, and it is the second lung cancer risk factor after smoking, and the first one in non-smokers. In Europe, there are several radon-prone areas, and although the 2013/59 EURATOM directive is aimed to regulate indoor radon exposition, regulating measures can vary between countries. Radon emits alpha-ionizing radiation that has been linked to a wide variety of cytotoxic and genotoxic effects; however, the link between lung cancer and radon from the genomic point of view remains poorly described. Driver molecular alterations have been recently identified in non-small lung cancer (NSCLC), such as somatic mutations (EGFR, BRAF, HER2, MET) or chromosomal rearrangements (ALK, ROS1, RET, NTRK), mainly in the non-smoking population, where no risk factor has been identified yet. An association between radon exposure and oncogenic NSCLC in non-smokers has been hypothesised. This paper provides a practical, concise and updated review on the implications of indoor radon in lung cancer carcinogenesis, and especially of its potential relation with NSCLC with driver genomic alterations. Full article

(This article belongs to the Special Issue Understanding New Therapeutic Options and Promising Predictive Biomarkers for Lung Cancer Patients. A Selection of Papers from the Third Joint Meeting on Lung Cancer of the FHU OncoAge (Nice, France) and the MD Anderson Cancer Center (Houston, TX, USA))

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14 pages, 1986 KiB

Open AccessEditor’s ChoiceSystematic Review

Proton Pump Inhibitor Use and Risk of Gastric Cancer: Current Evidence from Epidemiological Studies and Critical Appraisal

by Tahmina Nasrin Poly, Ming-Chin Lin, Shabbir Syed-Abdul, Chih-Wei Huang, Hsuan-Chia Yang and Yu-Chuan (Jack) Li

Cancers 2022, 14(13), 3052; https://doi.org/10.3390/cancers14133052 - 21 Jun 2022

Cited by 28 | Viewed by 6390

Abstract

Proton pump inhibitors (PPIs) are used for maintaining or improving gastric problems. Evidence from observational studies indicates that PPI therapy is associated with an increased risk of gastric cancer. However, the evidence for PPIs increasing the risk of gastric cancer is still being [...] Read more.

Proton pump inhibitors (PPIs) are used for maintaining or improving gastric problems. Evidence from observational studies indicates that PPI therapy is associated with an increased risk of gastric cancer. However, the evidence for PPIs increasing the risk of gastric cancer is still being debated. Therefore, we aimed to investigate whether long-term PPI use is associated with an increased risk of gastric cancer. We systematically searched the relevant literature in electronic databases, including PubMed, EMBASE, Scopus, and Web of Science. The search and collection of eligible studies was between 1 January 2000 and 1 July 2021. Two independent authors were responsible for the study selection process, and they considered only observational studies that compared the risk of gastric cancer with PPI treatment. We extracted relevant information from selected studies, and assessed the quality using the Newcastle−Ottawa scale (NOS). Finally, we calculated overall risk ratios (RRs) with 95% confidence intervals (CIs) of gastric cancer in the group receiving PPI therapy and the control group. Thirteen observational studies, comprising 10,557 gastric cancer participants, were included. Compared with patients who did not take PPIs, the pooled RR for developing gastric cancer in patients receiving PPIs was 1.80 (95% CI, 1.46–2.22, p < 0.001). The overall risk of gastric cancer also increased in patients with gastroesophageal reflux disease (GERD), H. pylori treatment, and various adjusted factors. The findings were also consistent across several sensitivity analyses. PPI use is associated with an increased risk of gastric cancer in patients compared with those with no PPI treatment. The findings of this updated study could be used in making clinical decisions between physicians and patients about the initiation and continuation of PPI therapy, especially in patients at high risk of gastric cancer. Additionally, large randomized controlled trials are needed to determine whether PPIs are associated with a higher risk of gastric cancer. Full article

(This article belongs to the Section Cancer Epidemiology and Prevention)

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38 pages, 1873 KiB

Open AccessEditor’s ChoiceReview

Drug Resistance in Colorectal Cancer: From Mechanism to Clinic

by Qianyu Wang, Xiaofei Shen, Gang Chen and Junfeng Du

Cancers 2022, 14(12), 2928; https://doi.org/10.3390/cancers14122928 - 14 Jun 2022

Cited by 98 | Viewed by 8821

Abstract

Colorectal cancer (CRC) is one of the leading causes of death worldwide. The 5-year survival rate is 90% for patients with early CRC, 70% for patients with locally advanced CRC, and 15% for patients with metastatic CRC (mCRC). In fact, most CRC patients [...] Read more.

Colorectal cancer (CRC) is one of the leading causes of death worldwide. The 5-year survival rate is 90% for patients with early CRC, 70% for patients with locally advanced CRC, and 15% for patients with metastatic CRC (mCRC). In fact, most CRC patients are at an advanced stage at the time of diagnosis. Although chemotherapy, molecularly targeted therapy and immunotherapy have significantly improved patient survival, some patients are initially insensitive to these drugs or initially sensitive but quickly become insensitive, and the emergence of such primary and secondary drug resistance is a significant clinical challenge. The most direct cause of resistance is the aberrant anti-tumor drug metabolism, transportation or target. With more in-depth research, it is found that cell death pathways, carcinogenic signals, compensation feedback loop signal pathways and tumor immune microenvironment also play essential roles in the drug resistance mechanism. Here, we assess the current major mechanisms of CRC resistance and describe potential therapeutic interventions. Full article

(This article belongs to the Collection Drug Resistance and Novel Therapies in Cancers)

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16 pages, 1771 KiB

Open AccessEditor’s ChoiceReview

Bias and Class Imbalance in Oncologic Data—Towards Inclusive and Transferrable AI in Large Scale Oncology Data Sets

by Erdal Tasci, Ying Zhuge, Kevin Camphausen and Andra V. Krauze

Cancers 2022, 14(12), 2897; https://doi.org/10.3390/cancers14122897 - 12 Jun 2022

Cited by 63 | Viewed by 16687

Abstract

Recent technological developments have led to an increase in the size and types of data in the medical field derived from multiple platforms such as proteomic, genomic, imaging, and clinical data. Many machine learning models have been developed to support precision/personalized medicine initiatives [...] Read more.

Recent technological developments have led to an increase in the size and types of data in the medical field derived from multiple platforms such as proteomic, genomic, imaging, and clinical data. Many machine learning models have been developed to support precision/personalized medicine initiatives such as computer-aided detection, diagnosis, prognosis, and treatment planning by using large-scale medical data. Bias and class imbalance represent two of the most pressing challenges for machine learning-based problems, particularly in medical (e.g., oncologic) data sets, due to the limitations in patient numbers, cost, privacy, and security of data sharing, and the complexity of generated data. Depending on the data set and the research question, the methods applied to address class imbalance problems can provide more effective, successful, and meaningful results. This review discusses the essential strategies for addressing and mitigating the class imbalance problems for different medical data types in the oncologic domain. Full article

(This article belongs to the Special Issue Bioinformatics, Big Data and Cancer)

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26 pages, 2015 KiB

Open AccessEditor’s ChoiceReview

Clinical Viability of Boron Neutron Capture Therapy for Personalized Radiation Treatment

by Dominika Skwierawska, José Antonio López-Valverde, Marcin Balcerzyk and Antonio Leal

Cancers 2022, 14(12), 2865; https://doi.org/10.3390/cancers14122865 - 10 Jun 2022

Cited by 31 | Viewed by 6680

Abstract

Boron Neutron Capture Therapy (BNCT) is a promising binary disease-targeted therapy, as neutrons preferentially kill cells labeled with boron (¹⁰B), which makes it a precision medicine treatment modality that provides a therapeutic effect exclusively on patient-specific tumor spread. Contrary to what [...] Read more.

Boron Neutron Capture Therapy (BNCT) is a promising binary disease-targeted therapy, as neutrons preferentially kill cells labeled with boron (¹⁰B), which makes it a precision medicine treatment modality that provides a therapeutic effect exclusively on patient-specific tumor spread. Contrary to what is usual in radiotherapy, BNCT proposes cell-tailored treatment planning rather than to the tumor mass. The success of BNCT depends mainly on the sufficient spatial biodistribution of ¹⁰B located around or within neoplastic cells to produce a high-dose gradient between the tumor and healthy tissue. However, it is not yet possible to precisely determine the concentration of ¹⁰B in a specific tissue in real-time using non-invasive methods. Critical issues remain to be resolved if BNCT is to become a valuable, minimally invasive, and efficient treatment. In addition, functional imaging technologies, such as PET, can be applied to determine biological information that can be used for the combined-modality radiotherapy protocol for each specific patient. Regardless, not only imaging methods but also proteomics and gene expression methods will facilitate BNCT becoming a modality of personalized medicine. This work provides an overview of the fundamental principles, recent advances, and future directions of BNCT as cell-targeted cancer therapy for personalized radiation treatment. Full article

(This article belongs to the Special Issue Personalized Radiation Therapy for Oncology)

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24 pages, 967 KiB

Open AccessEditor’s ChoiceReview

New Therapeutic Strategies for Adult Acute Myeloid Leukemia

by Hiroto Ishii and Shingo Yano

Cancers 2022, 14(11), 2806; https://doi.org/10.3390/cancers14112806 - 5 Jun 2022

Cited by 24 | Viewed by 7760

Abstract

Acute myeloid leukemia (AML) is a genetically heterogeneous hematological malignancy. Chromosomal and genetic analyses are important for the diagnosis and prognosis of AML. Some patients experience relapse or have refractory disease, despite conventional cytotoxic chemotherapies and allogeneic transplantation, and a variety of new [...] Read more.

Acute myeloid leukemia (AML) is a genetically heterogeneous hematological malignancy. Chromosomal and genetic analyses are important for the diagnosis and prognosis of AML. Some patients experience relapse or have refractory disease, despite conventional cytotoxic chemotherapies and allogeneic transplantation, and a variety of new agents and treatment strategies have emerged. After over 20 years during which no new drugs became available for the treatment of AML, the CD33-targeting antibody–drug conjugate gemtuzumab ozogamicin was developed. This is currently used in combination with standard chemotherapy or as a single agent. CPX-351, a liposomal formulation containing daunorubicin and cytarabine, has become one of the standard treatments for secondary AML in the elderly. FMS-like tyrosine kinase 3 (FLT3) inhibitors and isocitrate dehydrogenase 1/2 (IDH 1/2) inhibitors are mainly used for AML patients with actionable mutations. In addition to hypomethylating agents and venetoclax, a B-cell lymphoma-2 inhibitor is used in frail patients with newly diagnosed AML. Recently, tumor protein p53 inhibitors, cyclin-dependent kinase inhibitors, and NEDD8 E1-activating enzyme inhibitors have been gaining attention, and a suitable strategy for the use of these drugs is required. Antibody drugs targeting cell-surface markers and immunotherapies, such as antibody–drug conjugates and chimeric antigen receptor T-cell therapy, have also been developed for AML. Full article

(This article belongs to the Special Issue New Therapeutic Strategies for Acute Myeloid Leukemia)

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15 pages, 1164 KiB

Open AccessEditor’s ChoiceReview

The Kynurenine Pathway and Cancer: Why Keep It Simple When You Can Make It Complicated

by Roumaïssa Gouasmi, Carole Ferraro-Peyret, Stéphane Nancey, Isabelle Coste, Toufic Renno, Cédric Chaveroux, Nicolas Aznar and Stéphane Ansieau

Cancers 2022, 14(11), 2793; https://doi.org/10.3390/cancers14112793 - 4 Jun 2022

Cited by 47 | Viewed by 7269

Abstract

The kynurenine pathway has been highlighted as a gatekeeper of immune-privileged sites through its ability to generate from tryptophan a set of immunosuppressive metabolic intermediates. It additionally constitutes an important source of cellular NAD⁺ for the organism. Hijacking of its immunosuppressive functions, [...] Read more.

The kynurenine pathway has been highlighted as a gatekeeper of immune-privileged sites through its ability to generate from tryptophan a set of immunosuppressive metabolic intermediates. It additionally constitutes an important source of cellular NAD⁺ for the organism. Hijacking of its immunosuppressive functions, as recurrently observed in multiple cancers, facilitates immune evasion and promotes tumor development. Based on these observations, researchers have focused on characterizing indoleamine 2,3-dioxygenase (IDO1), the main enzyme catalyzing the first and limiting step of the pathway, and on developing therapies targeting it. Unfortunately, clinical trials studying IDO1 inhibitors have thus far not met expectations, highlighting the need to unravel this complex signaling pathway further. Recent advances demonstrate that these metabolites additionally promote tumor growth, metastatic dissemination and chemoresistance by a combination of paracrine and autocrine effects. Production of NAD⁺ also contributes to cancer progression by providing cancer cells with enhanced plasticity, invasive properties and chemoresistance. A comprehensive survey of this complexity is challenging but necessary to achieve medical success. Full article

(This article belongs to the Special Issue Targeting Amino Acid Signaling and Metabolism in Cancer)

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10 pages, 1606 KiB

Open AccessEditor’s ChoiceReview

Interconnected Adaptive Responses: A Way Out for Cancer Cells to Avoid Cellular Demise

by Gabriella D’Orazi and Mara Cirone

Cancers 2022, 14(11), 2780; https://doi.org/10.3390/cancers14112780 - 3 Jun 2022

Cited by 12 | Viewed by 2567

Abstract

Different from normal cells, cancer cells must hyperactivate a variety of integrated responses in order to survive their basal stress or its exacerbation caused by exposure to anti-cancer agents. As cancer cells become particularly dependent on these adaptive responses, namely UPR, DDR autophagy, [...] Read more.

Different from normal cells, cancer cells must hyperactivate a variety of integrated responses in order to survive their basal stress or its exacerbation caused by exposure to anti-cancer agents. As cancer cells become particularly dependent on these adaptive responses, namely UPR, DDR autophagy, anti-oxidant and heat shock responses, this turns out to be an Achille’s heel, which allows them to be selectively killed while sparing normal unstressed cells. Better knowledge of the cross-talk between these adaptive processes and their impact on the immune system is needed to design more effective anti-cancer therapies, as reviewed in this paper. Full article

(This article belongs to the Special Issue Advances in Immuno-Oncology Research)

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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 47 | Viewed by 6447

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)

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21 pages, 2578 KiB

Open AccessEditor’s ChoiceReview

Surgical Treatment of Bone Sarcoma

by Felix Bläsius, Heide Delbrück, Frank Hildebrand and Ulf Krister Hofmann

Cancers 2022, 14(11), 2694; https://doi.org/10.3390/cancers14112694 - 29 May 2022

Cited by 38 | Viewed by 13217

Abstract

Bone sarcomas are rare primary malignant mesenchymal bone tumors. The three main entities are osteosarcoma, chondrosarcoma, and Ewing sarcoma. While prognosis has improved for affected patients over the past decades, bone sarcomas are still critical conditions that require an interdisciplinary diagnostic and therapeutic [...] Read more.

Bone sarcomas are rare primary malignant mesenchymal bone tumors. The three main entities are osteosarcoma, chondrosarcoma, and Ewing sarcoma. While prognosis has improved for affected patients over the past decades, bone sarcomas are still critical conditions that require an interdisciplinary diagnostic and therapeutic approach. While radiotherapy plays a role especially in Ewing sarcoma and chemotherapy in Ewing sarcoma and osteosarcoma, surgery remains the main pillar of treatment in all three entities. After complete tumor resection, the created bone defects need to be reconstructed. Possible strategies are implantation of allografts or autografts including vascularized bone grafts (e.g., of the fibula). Around the knee joint, rotationplasty can be performed or, as an alternative, the implantation of (expandable) megaprostheses can be performed. Challenges still associated with the implantation of foreign materials are aseptic loosening and infection. Future improvements may come with advances in 3D printing of individualized resection blades/implants, thus also securing safe tumor resection margins while at the same time shortening the required surgical time. Faster osseointegration and lower infection rates may possibly be achieved through more elaborate implant surface structures. Full article

(This article belongs to the Special Issue Soft and Hard Tissue Sarcoma—Current and Future Concepts in Diagnosis and Treatment)

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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 3688

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

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27 pages, 401 KiB

Open AccessEditor’s ChoiceReview

Breast Cancer—Epidemiology, Classification, Pathogenesis and Treatment (Review of Literature)

by Beata Smolarz, Anna Zadrożna Nowak and Hanna Romanowicz

Cancers 2022, 14(10), 2569; https://doi.org/10.3390/cancers14102569 - 23 May 2022

Cited by 320 | Viewed by 53882

Abstract

Breast cancer is the most-commonly diagnosed malignant tumor in women in the world, as well as the first cause of death from malignant tumors. The incidence of breast cancer is constantly increasing in all regions of the world. For this reason, despite the [...] Read more.

Breast cancer is the most-commonly diagnosed malignant tumor in women in the world, as well as the first cause of death from malignant tumors. The incidence of breast cancer is constantly increasing in all regions of the world. For this reason, despite the progress in its detection and treatment, which translates into improved mortality rates, it seems necessary to look for new therapeutic methods, and predictive and prognostic factors. Treatment strategies vary depending on the molecular subtype. Breast cancer treatment is multidisciplinary; it includes approaches to locoregional therapy (surgery and radiation therapy) and systemic therapy. Systemic therapies include hormone therapy for hormone-positive disease, chemotherapy, anti-HER2 therapy for HER2-positive disease, and quite recently, immunotherapy. Triple negative breast cancer is responsible for more than 15–20% of all breast cancers. It is of particular research interest as it presents a therapeutic challenge, mainly due to its low response to treatment and its highly invasive nature. Future therapeutic concepts for breast cancer aim to individualize therapy and de-escalate and escalate treatment based on cancer biology and early response to therapy. The article presents a review of the literature on breast carcinoma—a disease affecting women in the world. Full article

14 pages, 814 KiB

Open AccessEditor’s ChoiceReview

Immune Checkpoint Inhibitors as a Neoadjuvant/Adjuvant Treatment of Muscle-Invasive Bladder Cancer: A Systematic Review

by Biagio Barone, Armando Calogero, Luca Scafuri, Matteo Ferro, Giuseppe Lucarelli, Erika Di Zazzo, Enrico Sicignano, Alfonso Falcone, Lorenzo Romano, Luigi De Luca, Francesco Oliva, Benito Fabio Mirto, Federico Capone, Ciro Imbimbo and Felice Crocetto

Cancers 2022, 14(10), 2545; https://doi.org/10.3390/cancers14102545 - 21 May 2022

Cited by 49 | Viewed by 5203

Abstract

Bladder cancer is the ninth most common cancer worldwide. Over 75% of non-muscle invasive cancer patients require conservative local treatment, while the remaining 25% of patients undergo radical cystectomy or radiotherapy. Immune checkpoint inhibitors represent a novel class of immunotherapy drugs that restore [...] Read more.

Bladder cancer is the ninth most common cancer worldwide. Over 75% of non-muscle invasive cancer patients require conservative local treatment, while the remaining 25% of patients undergo radical cystectomy or radiotherapy. Immune checkpoint inhibitors represent a novel class of immunotherapy drugs that restore natural antitumoral immune activity via the blockage of inhibitory receptors and ligands expressed on antigen-presenting cells, T lymphocytes and tumour cells. The use of immune checkpoint inhibitors in bladder cancer has been expanded from the neoadjuvant setting, i.e., after radical cystectomy, to the adjuvant setting, i.e., before the operative time or chemotherapy, in order to improve the overall survival and to reduce the morbidity and mortality of both the disease and its treatment. However, some patients do not respond to checkpoint inhibitors. As result, the capability for identifying patients that are eligible for this immunotherapy represent one of the efforts of ongoing studies. The aim of this systematic review is to summarize the most recent evidence regarding the use of immune checkpoint inhibitors, in a neoadjuvant and adjuvant setting, in the treatment of muscle-invasive bladder cancer. Full article

(This article belongs to the Special Issue Advances in Immunotherapy for Genitourinary Malignancies)

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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 69 | Viewed by 4945

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)

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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 43 | Viewed by 3258

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)

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20 pages, 2934 KiB

Open AccessEditor’s ChoiceReview

Role of Cytokines and Chemokines in Angiogenesis in a Tumor Context

by Mannon GEINDREAU, Mélanie BRUCHARD and Frédérique VEGRAN

Cancers 2022, 14(10), 2446; https://doi.org/10.3390/cancers14102446 - 16 May 2022

Cited by 79 | Viewed by 6011

Abstract

During carcinogenesis, tumors set various mechanisms to help support their development. Angiogenesis is a crucial process for cancer development as it drives the creation of blood vessels within the tumor. These newly formed blood vessels insure the supply of oxygen and nutrients to [...] Read more.

During carcinogenesis, tumors set various mechanisms to help support their development. Angiogenesis is a crucial process for cancer development as it drives the creation of blood vessels within the tumor. These newly formed blood vessels insure the supply of oxygen and nutrients to the tumor, helping its growth. The main factors that regulate angiogenesis are the five members of the vascular endothelial growth factor (VEGF) family. Angiogenesis is a hallmark of cancer and has been the target of new therapies this past few years. However, angiogenesis is a complex phenomenon with many redundancy pathways that ensure its maintenance. In this review, we will first describe the consecutive steps forming angiogenesis, as well as its classical regulators. We will then discuss how the cytokines and chemokines present in the tumor microenvironment can induce or block angiogenesis. Finally, we will focus on the therapeutic arsenal targeting angiogenesis in cancer and the challenges they have to overcome. Full article

(This article belongs to the Special Issue Inflammatory Cytokines and Chemokines in Cancer: Regulation, Function and Translational Significance)

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21 pages, 4524 KiB

Open AccessEditor’s ChoiceSystematic Review

Current Trend of Artificial Intelligence Patents in Digital Pathology: A Systematic Evaluation of the Patent Landscape

by Muhammad Joan Ailia, Nishant Thakur, Jamshid Abdul-Ghafar, Chan Kwon Jung, Kwangil Yim and Yosep Chong

Cancers 2022, 14(10), 2400; https://doi.org/10.3390/cancers14102400 - 13 May 2022

Cited by 33 | Viewed by 7540

Abstract

The integration of digital pathology (DP) with artificial intelligence (AI) enables faster, more accurate, and thorough diagnoses, leading to more precise personalized treatment. As technology is advancing rapidly, it is critical to understand the current state of AI applications in DP. Therefore, a [...] Read more.

The integration of digital pathology (DP) with artificial intelligence (AI) enables faster, more accurate, and thorough diagnoses, leading to more precise personalized treatment. As technology is advancing rapidly, it is critical to understand the current state of AI applications in DP. Therefore, a patent analysis of AI in DP is required to assess the application and publication trends, major assignees, and leaders in the field. We searched five major patent databases, namely, those of the USPTO, EPO, KIPO, JPO, and CNIPA, from 1974 to 2021, using keywords such as DP, AI, machine learning, and deep learning. We discovered 6284 patents, 523 of which were used for trend analyses on time series, international distribution, top assignees; word cloud analysis; and subject category analyses. Patent filing and publication have increased exponentially over the past five years. The United States has published the most patents, followed by China and South Korea (248, 117, and 48, respectively). The top assignees were Paige.AI, Inc. (New York City, NY, USA) and Siemens, Inc. (Munich, Germany) The primary areas were whole-slide imaging, segmentation, classification, and detection. Based on these findings, we expect a surge in DP and AI patent applications focusing on the digitalization of pathological images and AI technologies that support the vital role of pathologists. Full article

(This article belongs to the Special Issue Artificial Intelligence and Advanced Medical Imaging in Cancer Diagnosis and Precision Care)

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29 pages, 1779 KiB

Open AccessEditor’s ChoiceReview

Engineering Induced Pluripotent Stem Cells for Cancer Immunotherapy

by Yang Zhou, Miao Li, Kuangyi Zhou, James Brown, Tasha Tsao, Xinjian Cen, Tiffany Husman, Aarushi Bajpai, Zachary Spencer Dunn and Lili Yang

Cancers 2022, 14(9), 2266; https://doi.org/10.3390/cancers14092266 - 1 May 2022

Cited by 47 | Viewed by 12938

Abstract

Cell-based immunotherapy, such as chimeric antigen receptor (CAR) T cell therapy, has revolutionized the treatment of hematological malignancies, especially in patients who are refractory to other therapies. However, there are critical obstacles that hinder the widespread clinical applications of current autologous therapies, such [...] Read more.

Cell-based immunotherapy, such as chimeric antigen receptor (CAR) T cell therapy, has revolutionized the treatment of hematological malignancies, especially in patients who are refractory to other therapies. However, there are critical obstacles that hinder the widespread clinical applications of current autologous therapies, such as high cost, challenging large-scale manufacturing, and inaccessibility to the therapy for lymphopenia patients. Therefore, it is in great demand to generate the universal off-the-shelf cell products with significant scalability. Human induced pluripotent stem cells (iPSCs) provide an “unlimited supply” for cell therapy because of their unique self-renewal properties and the capacity to be genetically engineered. iPSCs can be differentiated into different immune cells, such as T cells, natural killer (NK) cells, invariant natural killer T (iNKT) cells, gamma delta T (γδ T), mucosal-associated invariant T (MAIT) cells, and macrophages (Mφs). In this review, we describe iPSC-based allogeneic cell therapy, the different culture methods of generating iPSC-derived immune cells (e.g., iPSC-T, iPSC-NK, iPSC-iNKT, iPSC-γδT, iPSC-MAIT and iPSC-Mφ), as well as the recent advances in iPSC-T and iPSC-NK cell therapies, particularly in combinations with CAR-engineering. We also discuss the current challenges and the future perspectives in this field towards the foreseeable applications of iPSC-based immune therapy. Full article

(This article belongs to the Special Issue Cell Therapy for Cancers)

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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 192 | Viewed by 16841

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)

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30 pages, 1812 KiB

Open AccessEditor’s ChoiceReview

Biomarkers of Response and Resistance to Immunotherapy in Microsatellite Stable Colorectal Cancer: Toward a New Personalized Medicine

by Nicolas Huyghe, Elena Benidovskaya, Philippe Stevens and Marc Van den Eynde

Cancers 2022, 14(9), 2241; https://doi.org/10.3390/cancers14092241 - 29 Apr 2022

Cited by 36 | Viewed by 6583

Abstract

Immune Checkpoint Inhibitors (ICIs) are well recognized as a major immune treatment modality for multiple types of solid cancers. However, for colorectal cancer (CRC), ICIs are only approved for the treatment of Mismatch-Repair-Deficient and Microsatellite Instability-High (dMMR/MSI-H) tumors. For the vast majority of [...] Read more.

Immune Checkpoint Inhibitors (ICIs) are well recognized as a major immune treatment modality for multiple types of solid cancers. However, for colorectal cancer (CRC), ICIs are only approved for the treatment of Mismatch-Repair-Deficient and Microsatellite Instability-High (dMMR/MSI-H) tumors. For the vast majority of CRC, that are not dMMR/MSI-H, ICIs alone provide limited to no clinical benefit. This discrepancy of response between CRC and other solid cancers suggests that CRC may be inherently resistant to ICIs alone. In translational research, efforts are underway to thoroughly characterize the immune microenvironment of CRC to better understand the mechanisms behind this resistance and to find new biomarkers of response. In the clinic, trials are being set up to study biomarkers along with treatments targeting newly discovered immune checkpoint molecules or treatments combining ICIs with other existing therapies to improve response in MSS CRC. In this review, we will focus on the characteristics of response and resistance to ICIs in CRC, and discuss promising biomarkers studied in recent clinical trials combining ICIs with other therapies. Full article

(This article belongs to the Special Issue Response, Toxicity and Resistance to Immune Checkpoint Inhibitor Cancer Therapy: Biological Mechanisms and Promising Solutions to Improve Future Outcomes)

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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 7538

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)

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29 pages, 1944 KiB

Open AccessEditor’s ChoiceReview

Targeting Ribosome Biogenesis in Cancer: Lessons Learned and Way Forward

by Asimina Zisi, Jiri Bartek and Mikael S. Lindström

Cancers 2022, 14(9), 2126; https://doi.org/10.3390/cancers14092126 - 24 Apr 2022

Cited by 52 | Viewed by 8616

Abstract

Rapid growth and unrestrained proliferation is a hallmark of many cancers. To accomplish this, cancer cells re-wire and increase their biosynthetic and metabolic activities, including ribosome biogenesis (RiBi), a complex, highly energy-consuming process. Several chemotherapeutic agents used in the clinic impair this process [...] Read more.

Rapid growth and unrestrained proliferation is a hallmark of many cancers. To accomplish this, cancer cells re-wire and increase their biosynthetic and metabolic activities, including ribosome biogenesis (RiBi), a complex, highly energy-consuming process. Several chemotherapeutic agents used in the clinic impair this process by interfering with the transcription of ribosomal RNA (rRNA) in the nucleolus through the blockade of RNA polymerase I or by limiting the nucleotide building blocks of RNA, thereby ultimately preventing the synthesis of new ribosomes. Perturbations in RiBi activate nucleolar stress response pathways, including those controlled by p53. While compounds such as actinomycin D and oxaliplatin effectively disrupt RiBi, there is an ongoing effort to improve the specificity further and find new potent RiBi-targeting compounds with improved pharmacological characteristics. A few recently identified inhibitors have also become popular as research tools, facilitating our advances in understanding RiBi. Here we provide a comprehensive overview of the various compounds targeting RiBi, their mechanism of action, and potential use in cancer therapy. We discuss screening strategies, drug repurposing, and common problems with compound specificity and mechanisms of action. Finally, emerging paths to discovery and avenues for the development of potential biomarkers predictive of therapeutic outcomes across cancer subtypes are also presented. Full article

(This article belongs to the Special Issue Protein Synthesis in Cancer Cells: Mechanisms and Novel Targeted Therapies)

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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 7013

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)

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33 pages, 5085 KiB

Open AccessEditor’s ChoiceReview

Current and Developing Liquid Biopsy Techniques for Breast Cancer

by Hsing-Ju Wu and Pei-Yi Chu

Cancers 2022, 14(9), 2052; https://doi.org/10.3390/cancers14092052 - 19 Apr 2022

Cited by 36 | Viewed by 8546

Abstract

Breast cancer is the most commonly diagnosed cancer and leading cause of cancer mortality among woman worldwide. The techniques of diagnosis, prognosis, and therapy monitoring of breast cancer are critical. Current diagnostic techniques are mammography and tissue biopsy; however, they have limitations. With [...] Read more.

Breast cancer is the most commonly diagnosed cancer and leading cause of cancer mortality among woman worldwide. The techniques of diagnosis, prognosis, and therapy monitoring of breast cancer are critical. Current diagnostic techniques are mammography and tissue biopsy; however, they have limitations. With the development of novel techniques, such as personalized medicine and genetic profiling, liquid biopsy is emerging as the less invasive tool for diagnosing and monitoring breast cancer. Liquid biopsy is performed by sampling biofluids and extracting tumor components, such as circulating tumor cells (CTCs), circulating tumor DNA (ctDNA), cell-free mRNA (cfRNA) and microRNA (miRNA), proteins, and extracellular vehicles (EVs). In this review, we summarize and focus on the recent discoveries of tumor components and biomarkers applied in liquid biopsy and novel development of detection techniques, such as surface-enhanced Raman spectroscopy (SERS) and microfluidic devices. Full article

(This article belongs to the Special Issue Clinical Perspective and Translational Oncology of Liquid Biopsy)

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15 pages, 303 KiB

Open AccessFeature PaperEditor’s ChoiceReview

Current Landscape of Immune Checkpoint Inhibitor Therapy for Hepatocellular Carcinoma

by Nikolaos Machairas, Diamantis I. Tsilimigras and Timothy M. Pawlik

Cancers 2022, 14(8), 2018; https://doi.org/10.3390/cancers14082018 - 16 Apr 2022

Cited by 22 | Viewed by 6425

Abstract

Hepatocellular carcinoma (HCC) is the most frequent primary liver tumor. As a result of advanced disease being often present at diagnosis, only a small percentage of patients are amenable to curative-intent treatment options such as surgical resection and liver transplantation. Systemic therapy consisting [...] Read more.

Hepatocellular carcinoma (HCC) is the most frequent primary liver tumor. As a result of advanced disease being often present at diagnosis, only a small percentage of patients are amenable to curative-intent treatment options such as surgical resection and liver transplantation. Systemic therapy consisting of tyrosine kinase inhibitors such as sorafenib had been used for over a decade with limited efficacy. More recently, treatment with immune checkpoint inhibitors has revolutionized the treatment landscape of various malignant tumors. With this shifting paradigm, recent data have demonstrated encouraging outcomes among patients with HCC. In particular, several trials have investigated the safety and efficacy of various immune checkpoint inhibitors (ICI) either as monotherapy or in the form of combined treatments. We sought to provide an overview of recent clinical trials among patients with advanced HCC as well as to highlight predictors of response and immune-related adverse events and to review the evidence on perioperative administration of ICI in patients with resectable HCC. Full article

(This article belongs to the Special Issue Immune Checkpoint and Novel Perspectives in the Management of Hepatocellular Carcinoma)

25 pages, 1591 KiB

Open AccessEditor’s ChoiceReview

Dissecting Tumor-Immune Microenvironment in Breast Cancer at a Spatial and Multiplex Resolution

by Evangelos Tzoras, Ioannis Zerdes, Nikos Tsiknakis, Georgios C. Manikis, Artur Mezheyeuski, Jonas Bergh, Alexios Matikas and Theodoros Foukakis

Cancers 2022, 14(8), 1999; https://doi.org/10.3390/cancers14081999 - 14 Apr 2022

Cited by 17 | Viewed by 6481

Abstract

The tumor immune microenvironment (TIME) is an important player in breast cancer pathophysiology. Surrogates for antitumor immune response have been explored as predictive biomarkers to immunotherapy, though with several limitations. Immunohistochemistry for programmed death ligand 1 suffers from analytical problems, immune signatures are [...] Read more.

The tumor immune microenvironment (TIME) is an important player in breast cancer pathophysiology. Surrogates for antitumor immune response have been explored as predictive biomarkers to immunotherapy, though with several limitations. Immunohistochemistry for programmed death ligand 1 suffers from analytical problems, immune signatures are devoid of spatial information and histopathological evaluation of tumor infiltrating lymphocytes exhibits interobserver variability. Towards improved understanding of the complex interactions in TIME, several emerging multiplex in situ methods are being developed and gaining much attention for protein detection. They enable the simultaneous evaluation of multiple targets in situ, detection of cell densities/subpopulations as well as estimations of functional states of immune infiltrate. Furthermore, they can characterize spatial organization of TIME—by cell-to-cell interaction analyses and the evaluation of distribution within different regions of interest and tissue compartments—while digital imaging and image analysis software allow for reproducibility of the various assays. In this review, we aim to provide an overview of the different multiplex in situ methods used in cancer research with special focus on breast cancer TIME at the neoadjuvant, adjuvant and metastatic setting. Spatial heterogeneity of TIME and importance of longitudinal evaluation of TIME changes under the pressure of therapy and metastatic progression are also addressed. Full article

(This article belongs to the Special Issue Multiplexed Imaging for Cancer Diagnosis and Therapy: Dissecting Networks at Tissue or Single-Cell Level)

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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 9929

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)

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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 2661

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)

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32 pages, 1387 KiB

Open AccessEditor’s ChoiceReview

Monoclonal Antibodies in the Treatment of Diffuse Large B-Cell Lymphoma: Moving beyond Rituximab

by Sotirios G. Papageorgiou, Thomas P. Thomopoulos, Athanasios Liaskas and Theodoros P. Vassilakopoulos

Cancers 2022, 14(8), 1917; https://doi.org/10.3390/cancers14081917 - 10 Apr 2022

Cited by 19 | Viewed by 10262

Abstract

Although rituximab has revolutionized the treatment of diffuse large B-cell lymphoma (DLBCL), a significant proportion of patients experience refractory disease or relapse early after the end of treatment. The lack of effective treatment options in the relapsed/refractory (R/R) setting had made the prognosis [...] Read more.

Although rituximab has revolutionized the treatment of diffuse large B-cell lymphoma (DLBCL), a significant proportion of patients experience refractory disease or relapse early after the end of treatment. The lack of effective treatment options in the relapsed/refractory (R/R) setting had made the prognosis of these patients dismal. The initial enthusiasm for novel anti-CD20 antibodies had been short-lived as they failed to prove their superiority to rituximab. Therefore, research has focused on developing novel agents with a unique mechanism of action. Among them, two antibody-drug conjugates, namely polatuzumab vedotin (PolaV) and loncastuximab tesirine, along with tafasitamab, an anti-CD19 bioengineered antibody, have been approved for the treatment of R/R DLBCL. Whereas PolaV has been FDA and EMA approved, EMA has not approved loncastuximab tesirine and tafasitamab yet. Results from randomized trials, as well as real-life data for PolaV have been promising. Novel agents as bispecific antibodies bridging CD3 on T-cells to CD20 have shown very promising results in clinical trials and are expected to gain approval for treatment of R/R DLBCL soon. As the therapeutic armamentarium against DLBCL is expanding, an improvement in survival of patients with R/R and higher cure rates might soon become evident. Full article

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17 pages, 1253 KiB

Open AccessEditor’s ChoiceReview

Regulation of ZEB1 Function and Molecular Associations in Tumor Progression and Metastasis

by Mabel Perez-Oquendo and Don L. Gibbons

Cancers 2022, 14(8), 1864; https://doi.org/10.3390/cancers14081864 - 7 Apr 2022

Cited by 49 | Viewed by 7539

Abstract

Zinc finger E-box binding homeobox 1 (ZEB1) is a pleiotropic transcription factor frequently expressed in carcinomas. ZEB1 orchestrates the transcription of genes in the control of several key developmental processes and tumor metastasis via the epithelial-to-mesenchymal transition (EMT). The biological function of ZEB1 [...] Read more.

Zinc finger E-box binding homeobox 1 (ZEB1) is a pleiotropic transcription factor frequently expressed in carcinomas. ZEB1 orchestrates the transcription of genes in the control of several key developmental processes and tumor metastasis via the epithelial-to-mesenchymal transition (EMT). The biological function of ZEB1 is regulated through pathways that influence its transcription and post-transcriptional mechanisms. Diverse signaling pathways converge to induce ZEB1 activity; however, only a few studies have focused on the molecular associations or functional changes of ZEB1 by post-translational modifications (PTMs). Due to the robust effect of ZEB1 as a transcription repressor of epithelial genes during EMT, the contribution of PTMs in the regulation of ZEB1-targeted gene expression is an active area of investigation. Herein, we review the pivotal roles that phosphorylation, acetylation, ubiquitination, sumoylation, and other modifications have in regulating the molecular associations and behavior of ZEB1. We also outline several questions regarding the PTM-mediated regulation of ZEB1 that remain unanswered. The areas of research covered in this review are contributing to new treatment strategies for cancer by improving our mechanistic understanding of ZEB1-mediated EMT. Full article

(This article belongs to the Special Issue Understanding New Therapeutic Options and Promising Predictive Biomarkers for Lung Cancer Patients. A Selection of Papers from the Third Joint Meeting on Lung Cancer of the FHU OncoAge (Nice, France) and the MD Anderson Cancer Center (Houston, TX, USA))

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30 pages, 2934 KiB

Open AccessEditor’s ChoiceReview

Melanin and Melanin-Functionalized Nanoparticles as Promising Tools in Cancer Research—A Review

by Iasmina Marcovici, Dorina Coricovac, Iulia Pinzaru, Ioana Gabriela Macasoi, Roxana Popescu, Raul Chioibas, Istvan Zupko and Cristina Adriana Dehelean

Cancers 2022, 14(7), 1838; https://doi.org/10.3390/cancers14071838 - 6 Apr 2022

Cited by 42 | Viewed by 7674

Abstract

Cancer poses an ongoing global challenge, despite the substantial progress made in the prevention, diagnosis, and treatment of the disease. The existing therapeutic methods remain limited by undesirable outcomes such as systemic toxicity and lack of specificity or long-term efficacy, although innovative alternatives [...] Read more.

Cancer poses an ongoing global challenge, despite the substantial progress made in the prevention, diagnosis, and treatment of the disease. The existing therapeutic methods remain limited by undesirable outcomes such as systemic toxicity and lack of specificity or long-term efficacy, although innovative alternatives are being continuously investigated. By offering a means for the targeted delivery of therapeutics, nanotechnology (NT) has emerged as a state-of-the-art solution for augmenting the efficiency of currently available cancer therapies while combating their drawbacks. Melanin, a polymeric pigment of natural origin that is widely spread among many living organisms, became a promising candidate for NT-based cancer treatment owing to its unique physicochemical properties (e.g., high biocompatibility, redox behavior, light absorption, chelating ability) and innate antioxidant, photoprotective, anti-inflammatory, and antitumor effects. The latest research on melanin and melanin-like nanoparticles has extended considerably on many fronts, allowing not only efficient cancer treatments via both traditional and modern methods, but also early disease detection and diagnosis. The current paper provides an updated insight into the applicability of melanin in cancer therapy as antitumor agent, molecular target, and delivery nanoplatform. Full article

(This article belongs to the Special Issue Recent Advances in Nanotechnologies for Cancer Detection and Treatment)

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28 pages, 1150 KiB

Open AccessEditor’s ChoiceReview

MMP9: A Tough Target for Targeted Therapy for Cancer

by Katarzyna Augoff, Anita Hryniewicz-Jankowska, Renata Tabola and Kamilla Stach

Cancers 2022, 14(7), 1847; https://doi.org/10.3390/cancers14071847 - 6 Apr 2022

Cited by 163 | Viewed by 15236

Abstract

Having the capability to proteolyze diverse structural and signaling proteins, matrix metalloproteinase 9 (MMP9), one of the best-studied secretory endopeptidases, has been identified as a crucial mediator of processes closely associated with tumorigenesis, such as the extracellular matrix reorganization, epithelial to mesenchymal transition, [...] Read more.

Having the capability to proteolyze diverse structural and signaling proteins, matrix metalloproteinase 9 (MMP9), one of the best-studied secretory endopeptidases, has been identified as a crucial mediator of processes closely associated with tumorigenesis, such as the extracellular matrix reorganization, epithelial to mesenchymal transition, cell migration, new blood vessel formation, and immune response. In this review, we present the current state of knowledge on MMP9 and its role in cancer growth in the context of cell adhesion/migration, cancer-related inflammation, and tumor microenvironment formation. We also summarize recent achievements in the development of selective MMP9 inhibitors and the limitations of using them as anticancer drugs. Full article

(This article belongs to the Section Cancer Therapy)

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19 pages, 2138 KiB

Open AccessEditor’s ChoiceReview

Impact of Lipid Metabolism on Antitumor Immune Response

by Nesrine Mabrouk, Baptiste Lecoeur, Ali Bettaieb, Catherine Paul and Frédérique Végran

Cancers 2022, 14(7), 1850; https://doi.org/10.3390/cancers14071850 - 6 Apr 2022

Cited by 30 | Viewed by 4866

Abstract

Over the past decade, metabolic reprogramming has been defined as a hallmark of cancer. More recently, a large number of studies have demonstrated that metabolic reprogramming can modulate the differentiation and functions of immune cells, and thus modify the antitumor response. Increasing evidence [...] Read more.

Over the past decade, metabolic reprogramming has been defined as a hallmark of cancer. More recently, a large number of studies have demonstrated that metabolic reprogramming can modulate the differentiation and functions of immune cells, and thus modify the antitumor response. Increasing evidence suggests that modified energy metabolism could be responsible for the failure of antitumor immunity. Indeed, tumor-infiltrating immune cells play a key role in cancer, and metabolic switching in these cells has been shown to help determine their phenotype: tumor suppressive or immune suppressive. Recent studies in the field of immunometabolism focus on metabolic reprogramming in the tumor microenvironment (TME) by targeting innate and adaptive immune cells and their associated anti- or protumor phenotypes. In this review, we discuss the lipid metabolism of immune cells in the TME as well as the effects of lipids; finally, we expose the link between therapies and lipid metabolism. Full article

(This article belongs to the Collection Deciphering the Crosstalk between Tumor Cells and Their Microenvironment: From Molecular Aspects to Therapeutic Implications)

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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 44 | Viewed by 5874

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)

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22 pages, 1841 KiB

Open AccessEditor’s ChoiceReview

Ferroptosis in Hepatocellular Carcinoma: Mechanisms, Drug Targets and Approaches to Clinical Translation

by Dino Bekric, Matthias Ocker, Christian Mayr, Sebastian Stintzing, Markus Ritter, Tobias Kiesslich and Daniel Neureiter

Cancers 2022, 14(7), 1826; https://doi.org/10.3390/cancers14071826 - 4 Apr 2022

Cited by 41 | Viewed by 7024

Abstract

Ferroptosis, an iron and reactive oxygen species (ROS)-dependent non-apoptotic type of regulated cell death, is characterized by a massive iron overload and peroxidation of polyunsaturated fatty acids (PUFAs), which finally results in cell death. Recent studies suggest that ferroptosis can influence carcinogenesis negatively [...] Read more.

Ferroptosis, an iron and reactive oxygen species (ROS)-dependent non-apoptotic type of regulated cell death, is characterized by a massive iron overload and peroxidation of polyunsaturated fatty acids (PUFAs), which finally results in cell death. Recent studies suggest that ferroptosis can influence carcinogenesis negatively and therefore may be used as a novel anti-cancer strategy. Hepatocellular carcinoma (HCC) is a deadly malignancy with poor chances of survival and is the second leading cause of cancer deaths worldwide. Diagnosis at an already late stage and general resistance to current therapies may be responsible for the dismal outcome. As the liver acts as a key factor in iron metabolism, ferroptosis is shown to play an important role in HCC carcinogenesis and, more importantly, may hold the potential to eradicate HCC. In this review, we summarize the current knowledge we have of the role of ferroptosis in HCC and the application of ferroptosis as a therapy option and provide an overview of the potential translation of ferroptosis in the clinical practice of HCC. Full article

(This article belongs to the Section Cancer Therapy)

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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 4584

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?)

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23 pages, 1280 KiB

Open AccessEditor’s ChoiceSystematic Review

PSMA and Choline PET for the Assessment of Response to Therapy and Survival Outcomes in Prostate Cancer Patients: A Systematic Review from the Literature

by Pierpaolo Alongi, Riccardo Laudicella, Helena Lanzafame, Andrea Farolfi, Paola Mapelli, Maria Picchio, Irene A. Burger, Andrei Iagaru, Fabio Minutoli and Laura Evangelista

Cancers 2022, 14(7), 1770; https://doi.org/10.3390/cancers14071770 - 31 Mar 2022

Cited by 34 | Viewed by 4726

Abstract

The aims of this systematic review were to (1) assess the utility of PSMA-PET and choline-PET in the assessment of response to systemic and local therapy, and to (2) determine the value of both tracers for the prediction of response to therapy and [...] Read more.

The aims of this systematic review were to (1) assess the utility of PSMA-PET and choline-PET in the assessment of response to systemic and local therapy, and to (2) determine the value of both tracers for the prediction of response to therapy and survival outcomes in prostate cancer. We performed a systematic literature search in PubMed/Scopus/Google Scholar/Cochrane/EMBASE databases (between January 2010 and October 2021) accordingly. The quality of the included studies was evaluated following the “Quality Assessment of Prognostic Accuracy Studies” tool (QUAPAS-2). We selected 40 articles: 23 articles discussed the use of PET imaging with [⁶⁸Ga]PSMA-11 (16 articles/1123 patients) or [¹¹C]/[¹⁸F]Choline (7 articles/356 patients) for the prediction of response to radiotherapy (RT) and survival outcomes. Seven articles (three with [⁶⁸Ga]PSMA-11, three with [¹¹C]Choline, one with [¹⁸F]Choline) assessed the role of PET imaging in the evaluation of response to docetaxel (as neoadjuvant therapy in one study, as first-line therapy in five studies, and as a palliative regimen in one study). Seven papers with radiolabeled [¹⁸F]Choline PET/CT (n = 121 patients) and three with [⁶⁸Ga]PSMA-11 PET (n = 87 patients) were selected before and after enzalutamide/abiraterone acetate. Finally, [¹⁸F]Choline and [⁶⁸Ga]PSMA-11 PET/CT as gatekeepers for the treatment of metastatic prostate cancer with Radium-223 were assessed in three papers. In conclusion, in patients undergoing RT, radiolabeled choline and [⁶⁸Ga]PSMA-11 have an important prognostic role. In the case of systemic therapies, the role of such new-generation imaging techniques is still controversial without sufficient data, thus requiring additional in this scenario. Full article

(This article belongs to the Special Issue PET/CT in Prostate Cancer)

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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 4135

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)

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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 24 | Viewed by 7396

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)

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15 pages, 7403 KiB

Open AccessFeature PaperEditor’s ChoiceReview

Lung Adenocarcinoma Tumor Origin: A Guide for Personalized Medicine

by Laetitia Seguin, Manon Durandy and Chloe C. Feral

Cancers 2022, 14(7), 1759; https://doi.org/10.3390/cancers14071759 - 30 Mar 2022

Cited by 110 | Viewed by 11695

Abstract

Lung adenocarcinoma, the major form of lung cancer, is the deadliest cancer worldwide, due to its late diagnosis and its high heterogeneity. Indeed, lung adenocarcinoma exhibits pronounced inter- and intra-tumor heterogeneity cofounding precision medicine. Tumor heterogeneity is a clinical challenge driving tumor progression [...] Read more.

Lung adenocarcinoma, the major form of lung cancer, is the deadliest cancer worldwide, due to its late diagnosis and its high heterogeneity. Indeed, lung adenocarcinoma exhibits pronounced inter- and intra-tumor heterogeneity cofounding precision medicine. Tumor heterogeneity is a clinical challenge driving tumor progression and drug resistance. Several key pieces of evidence demonstrated that lung adenocarcinoma results from the transformation of progenitor cells that accumulate genetic abnormalities. Thus, a better understanding of the cell of origin of lung adenocarcinoma represents an opportunity to unveil new therapeutic alternatives and stratify patient tumors. While the lung is remarkably quiescent during homeostasis, it presents an extensive ability to respond to injury and regenerate lost or damaged cells. As the lung is constantly exposed to potential insult, its regenerative potential is assured by several stem and progenitor cells. These can be induced to proliferate in response to injury as well as differentiate into multiple cell types. A better understanding of how genetic alterations and perturbed microenvironments impact progenitor-mediated tumorigenesis and treatment response is of the utmost importance to develop new therapeutic opportunities. Full article

(This article belongs to the Special Issue Understanding New Therapeutic Options and Promising Predictive Biomarkers for Lung Cancer Patients. A Selection of Papers from the Third Joint Meeting on Lung Cancer of the FHU OncoAge (Nice, France) and the MD Anderson Cancer Center (Houston, TX, USA))

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15 pages, 1257 KiB

Open AccessEditor’s ChoiceReview

Energy Sources for Exosome Communication in a Cancer Microenvironment

by Abhimanyu Thakur, Amanda Johnson, Emily Jacobs, Kui Zhang, Jonathan Chen, Zhubo Wei, Qizhou Lian and Huanhuan Joyce Chen

Cancers 2022, 14(7), 1698; https://doi.org/10.3390/cancers14071698 - 27 Mar 2022

Cited by 41 | Viewed by 5480

Abstract

Exosomes are crucial extracellular vesicles (EVs) with a diameter of approximately 30–200 nm. They are released by most cell types in their extracellular milieu and carry various biomolecules, including proteins and nucleic acids. Exosomes are increasingly studied in various diseases, including cancer, due [...] Read more.

Exosomes are crucial extracellular vesicles (EVs) with a diameter of approximately 30–200 nm. They are released by most cell types in their extracellular milieu and carry various biomolecules, including proteins and nucleic acids. Exosomes are increasingly studied in various diseases, including cancer, due to their role in local and distant cell–cell communication in which they can promote tumor growth, cancer progression, and metastasis. Interestingly, a tremendous number of exosomes is released by malignant cancer cells, and these are then taken up by autologous and heterologous recipient stromal cells such as immune cells, cancer stem cells, and endothelial cells. All these events demand an enormous amount of energy and require that exosomes remain stable while having the capacity to reach distant sites and cross physical barriers. Nevertheless, there is a dearth of research pertaining to the energy sources of exosomes, and questions remain about how they maintain their motility in the tumor microenvironment (TME) and beyond. Moreover, exosomes can produce adenosine triphosphate (ATP), an important energy molecule required by all cells, and mitochondria have been identified as one of the exosomal cargoes. These findings strengthen the prospect of exosomal communication via transfer of mitochondria and the bioenergetics of target recipient cells. In the TME, the accumulation of ATP and lactate may facilitate the entry of exosomes into cancer cells to promote metastasis, as well as help to target cancer cells at the tumor site. This review highlights how exosomes obtain sufficient energy to thrive in the TME and communicate with distant physiological destinations. Full article

(This article belongs to the Special Issue Cell-Cell Communication and Extracellular Vesicles in Cancer)

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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 6127

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)

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33 pages, 1563 KiB

Open AccessEditor’s ChoiceReview

Using Quantitative Imaging for Personalized Medicine in Pancreatic Cancer: A Review of Radiomics and Deep Learning Applications

by Kiersten Preuss, Nate Thach, Xiaoying Liang, Michael Baine, Justin Chen, Chi Zhang, Huijing Du, Hongfeng Yu, Chi Lin, Michael A. Hollingsworth and Dandan Zheng

Cancers 2022, 14(7), 1654; https://doi.org/10.3390/cancers14071654 - 24 Mar 2022

Cited by 54 | Viewed by 10210

Abstract

As the most lethal major cancer, pancreatic cancer is a global healthcare challenge. Personalized medicine utilizing cutting-edge multi-omics data holds potential for major breakthroughs in tackling this critical problem. Radiomics and deep learning, two trendy quantitative imaging methods that take advantage of data [...] Read more.

As the most lethal major cancer, pancreatic cancer is a global healthcare challenge. Personalized medicine utilizing cutting-edge multi-omics data holds potential for major breakthroughs in tackling this critical problem. Radiomics and deep learning, two trendy quantitative imaging methods that take advantage of data science and modern medical imaging, have shown increasing promise in advancing the precision management of pancreatic cancer via diagnosing of precursor diseases, early detection, accurate diagnosis, and treatment personalization and optimization. Radiomics employs manually-crafted features, while deep learning applies computer-generated automatic features. These two methods aim to mine hidden information in medical images that is missed by conventional radiology and gain insights by systematically comparing the quantitative image information across different patients in order to characterize unique imaging phenotypes. Both methods have been studied and applied in various pancreatic cancer clinical applications. In this review, we begin with an introduction to the clinical problems and the technology. After providing technical overviews of the two methods, this review focuses on the current progress of clinical applications in precancerous lesion diagnosis, pancreatic cancer detection and diagnosis, prognosis prediction, treatment stratification, and radiogenomics. The limitations of current studies and methods are discussed, along with future directions. With better standardization and optimization of the workflow from image acquisition to analysis and with larger and especially prospective high-quality datasets, radiomics and deep learning methods could show real hope in the battle against pancreatic cancer through big data-based high-precision personalization. Full article

(This article belongs to the Collection Radiomics and Cancers)

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22 pages, 1333 KiB

Open AccessEditor’s ChoiceReview

Advances in Immunotherapy for the Treatment of Adult Glioblastoma: Overcoming Chemical and Physical Barriers

by Mirna Lechpammer, Rohan Rao, Sanjit Shah, Mona Mirheydari, Debanjan Bhattacharya, Abigail Koehler, Donatien Kamdem Toukam, Kevin J. Haworth, Daniel Pomeranz Krummel and Soma Sengupta

Cancers 2022, 14(7), 1627; https://doi.org/10.3390/cancers14071627 - 23 Mar 2022

Cited by 11 | Viewed by 5699

Abstract

Glioblastoma, or glioblastoma multiforme (GBM, WHO Grade IV), is a highly aggressive adult glioma. Despite extensive efforts to improve treatment, the current standard-of-care (SOC) regimen, which consists of maximal resection, radiotherapy, and temozolomide (TMZ), achieves only a 12–15 month survival. The clinical improvements [...] Read more.

Glioblastoma, or glioblastoma multiforme (GBM, WHO Grade IV), is a highly aggressive adult glioma. Despite extensive efforts to improve treatment, the current standard-of-care (SOC) regimen, which consists of maximal resection, radiotherapy, and temozolomide (TMZ), achieves only a 12–15 month survival. The clinical improvements achieved through immunotherapy in several extracranial solid tumors, including non-small-cell lung cancer, melanoma, and non-Hodgkin lymphoma, inspired investigations to pursue various immunotherapeutic interventions in adult glioblastoma patients. Despite some encouraging reports from preclinical and early-stage clinical trials, none of the tested agents have been convincing in Phase III clinical trials. One, but not the only, factor that is accountable for the slow progress is the blood–brain barrier, which prevents most antitumor drugs from reaching the target in appreciable amounts. Herein, we review the current state of immunotherapy in glioblastoma and discuss the significant challenges that prevent advancement. We also provide thoughts on steps that may be taken to remediate these challenges, including the application of ultrasound technologies. Full article

(This article belongs to the Special Issue Response, Toxicity and Resistance to Immune Checkpoint Inhibitor Cancer Therapy: Biological Mechanisms and Promising Solutions to Improve Future Outcomes)

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24 pages, 1677 KiB

Open AccessEditor’s ChoiceReview

Clinical Applications of Short Non-Coding RNA-Based Therapies in the Era of Precision Medicine

by Ellen S. Smith, Eric Whitty, Byunghee Yoo, Anna Moore, Lorenzo F. Sempere and Zdravka Medarova

Cancers 2022, 14(6), 1588; https://doi.org/10.3390/cancers14061588 - 21 Mar 2022

Cited by 51 | Viewed by 6594

Abstract

Traditional targeted therapeutic agents have relied on small synthetic molecules or large proteins, such as monoclonal antibodies. These agents leave a lot of therapeutic targets undruggable because of the lack or inaccessibility of active sites and/or pockets in their three-dimensional structure that can [...] Read more.

Traditional targeted therapeutic agents have relied on small synthetic molecules or large proteins, such as monoclonal antibodies. These agents leave a lot of therapeutic targets undruggable because of the lack or inaccessibility of active sites and/or pockets in their three-dimensional structure that can be chemically engaged. RNA presents an attractive, transformative opportunity to reach any genetic target with therapeutic intent. RNA therapeutic design is amenable to modularity and tunability and is based on a computational blueprint presented by the genetic code. Here, we will focus on short non-coding RNAs (sncRNAs) as a promising therapeutic modality because of their potency and versatility. We review recent progress towards clinical application of small interfering RNAs (siRNAs) for single-target therapy and microRNA (miRNA) activity modulators for multi-target therapy. siRNAs derive their potency from the fact that the underlying RNA interference (RNAi) mechanism is catalytic and reliant on post-transcriptional mRNA degradation. Therapeutic siRNAs can be designed against virtually any mRNA sequence in the transcriptome and specifically target a disease-causing mRNA variant. Two main classes of microRNA activity modulators exist to increase (miRNA mimics) or decrease (anti-miRNA inhibitors) the function of a specific microRNA. Since a single microRNA regulates the expression of multiple target genes, a miRNA activity modulator can have a more profound effect on global gene expression and protein output than siRNAs do. Both types of sncRNA-based drugs have been investigated in clinical trials and some siRNAs have already been granted FDA approval for the treatment of genetic, cardiometabolic, and infectious diseases. Here, we detail clinical results using siRNA and miRNA therapeutics and present an outlook for the potential of these sncRNAs in medicine. Full article

(This article belongs to the Collection Molecular Function and Clinical Value of Non-coding RNAs (ncRNAs) in Cancer Regulation)

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18 pages, 1147 KiB

Open AccessFeature PaperEditor’s ChoiceReview

Mesothelin: An Immunotherapeutic Target beyond Solid Tumors

by Joshua R. Faust, Darcy Hamill, Edward Anders Kolb, Anilkumar Gopalakrishnapillai and Sonali P. Barwe

Cancers 2022, 14(6), 1550; https://doi.org/10.3390/cancers14061550 - 18 Mar 2022

Cited by 52 | Viewed by 11865

Abstract

Modern targeted cancer therapies rely on the overexpression of tumor associated antigens with very little to no expression in normal cell types. Mesothelin is a glycosylphosphatidylinositol-anchored cell surface protein that has been identified in many different tumor types, including lung adenocarcinomas, ovarian carcinomas, [...] Read more.

Modern targeted cancer therapies rely on the overexpression of tumor associated antigens with very little to no expression in normal cell types. Mesothelin is a glycosylphosphatidylinositol-anchored cell surface protein that has been identified in many different tumor types, including lung adenocarcinomas, ovarian carcinomas, and most recently in hematological malignancies, including acute myeloid leukemia (AML). Although the function of mesothelin is widely unknown, interactions with MUC16/CA125 indicate that mesothelin plays a role in the regulation of proliferation, growth, and adhesion signaling. Most research on mesothelin currently focuses on utilizing mesothelin to design targeted cancer therapies such as monoclonal antibodies, antibody–drug conjugates, chimeric antigen receptor T and NK cells, bispecific T cell engaging molecules, and targeted alpha therapies, amongst others. Both in vitro and in vivo studies using different immunotherapeutic modalities in mesothelin-positive AML models highlight the potential impact of this approach as a unique opportunity to treat hard-to-cure AML. Full article

(This article belongs to the Special Issue Advances in Immunotherapy for Hematological Malignancies)

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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 6544

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)

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20 pages, 2006 KiB

Open AccessEditor’s ChoiceReview

The Role of Artificial Intelligence in Early Cancer Diagnosis

by Benjamin Hunter, Sumeet Hindocha and Richard W. Lee

Cancers 2022, 14(6), 1524; https://doi.org/10.3390/cancers14061524 - 16 Mar 2022

Cited by 198 | Viewed by 27942

Abstract

Improving the proportion of patients diagnosed with early-stage cancer is a key priority of the World Health Organisation. In many tumour groups, screening programmes have led to improvements in survival, but patient selection and risk stratification are key challenges. In addition, there are [...] Read more.

Improving the proportion of patients diagnosed with early-stage cancer is a key priority of the World Health Organisation. In many tumour groups, screening programmes have led to improvements in survival, but patient selection and risk stratification are key challenges. In addition, there are concerns about limited diagnostic workforces, particularly in light of the COVID-19 pandemic, placing a strain on pathology and radiology services. In this review, we discuss how artificial intelligence algorithms could assist clinicians in (1) screening asymptomatic patients at risk of cancer, (2) investigating and triaging symptomatic patients, and (3) more effectively diagnosing cancer recurrence. We provide an overview of the main artificial intelligence approaches, including historical models such as logistic regression, as well as deep learning and neural networks, and highlight their early diagnosis applications. Many data types are suitable for computational analysis, including electronic healthcare records, diagnostic images, pathology slides and peripheral blood, and we provide examples of how these data can be utilised to diagnose cancer. We also discuss the potential clinical implications for artificial intelligence algorithms, including an overview of models currently used in clinical practice. Finally, we discuss the potential limitations and pitfalls, including ethical concerns, resource demands, data security and reporting standards. Full article

(This article belongs to the Special Issue Early Diagnosis of Cancer)

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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 3763

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)

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28 pages, 1969 KiB

Open AccessEditor’s ChoiceReview

NRF2 and Key Transcriptional Targets in Melanoma Redox Manipulation

by Evan L. Carpenter, Alyssa L. Becker and Arup K. Indra

Cancers 2022, 14(6), 1531; https://doi.org/10.3390/cancers14061531 - 16 Mar 2022

Cited by 28 | Viewed by 6692

Abstract

Melanocytes are dendritic, pigment-producing cells located in the skin and are responsible for its protection against the deleterious effects of solar ultraviolet radiation (UVR), which include DNA damage and elevated reactive oxygen species (ROS). They do so by synthesizing photoprotective melanin pigments and [...] Read more.

Melanocytes are dendritic, pigment-producing cells located in the skin and are responsible for its protection against the deleterious effects of solar ultraviolet radiation (UVR), which include DNA damage and elevated reactive oxygen species (ROS). They do so by synthesizing photoprotective melanin pigments and distributing them to adjacent skin cells (e.g., keratinocytes). However, melanocytes encounter a large burden of oxidative stress during this process, due to both exogenous and endogenous sources. Therefore, melanocytes employ numerous antioxidant defenses to protect themselves; these are largely regulated by the master stress response transcription factor, nuclear factor erythroid 2-related factor 2 (NRF2). Key effector transcriptional targets of NRF2 include the components of the glutathione and thioredoxin antioxidant systems. Despite these defenses, melanocyte DNA often is subject to mutations that result in the dysregulation of the proliferative mitogen-activated protein kinase (MAPK) pathway and the cell cycle. Following tumor initiation, endogenous antioxidant systems are co-opted, a consequence of elevated oxidative stress caused by metabolic reprogramming, to establish an altered redox homeostasis. This altered redox homeostasis contributes to tumor progression and metastasis, while also complicating the application of exogenous antioxidant treatments. Further understanding of melanocyte redox homeostasis, in the presence or absence of disease, would contribute to the development of novel therapies to aid in the prevention and treatment of melanomas and other skin diseases Full article

(This article belongs to the Special Issue Study on the Complex Melanoma)

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