cancers-logo

Journal Browser

Journal Browser

Editor’s Choice Articles

Editor’s Choice articles are based on recommendations by the scientific editors of MDPI journals from around the world. Editors select a small number of articles recently published in the journal that they believe will be particularly interesting to readers, or important in the respective research area. The aim is to provide a snapshot of some of the most exciting work published in the various research areas of the journal.

Order results
Result details
Results per page
Select all
Export citation of selected articles as:
30 pages, 908 KiB  
Review
The Role of Bruton’s Kinase Inhibitors in Chronic Lymphocytic Leukemia: Current Status and Future Directions
by Tadeusz Robak, Magda Witkowska and Piotr Smolewski
Cancers 2022, 14(3), 771; https://doi.org/10.3390/cancers14030771 - 2 Feb 2022
Cited by 51 | Viewed by 7593
Abstract
The use of Bruton’s tyrosine kinase (BTK) inhibitors has changed the management and clinical history of patients with chronic lymphocytic leukemia (CLL). BTK is a critical molecule that interconnects B-cell antigen receptor (BCR) signaling. BTKis are classified into two categories: irreversible (covalent) inhibitors [...] Read more.
The use of Bruton’s tyrosine kinase (BTK) inhibitors has changed the management and clinical history of patients with chronic lymphocytic leukemia (CLL). BTK is a critical molecule that interconnects B-cell antigen receptor (BCR) signaling. BTKis are classified into two categories: irreversible (covalent) inhibitors and reversible (non-covalent) inhibitors. Ibrutinib was the first irreversible BTK inhibitor approved by the U.S. Food and Drug Administration in 2013 as a breakthrough therapy in CLL patients. Subsequently, several studies have evaluated the efficacy and safety of new agents with reduced toxicity when compared with ibrutinib. Two other irreversible, second-generation BTK inhibitors, acalabrutinib and zanubrutinib, were developed to reduce ibrutinib-mediated adverse effects. Additionally, new reversible BTK inhibitors are currently under development in early-phase studies to improve their activity and to diminish adverse effects. This review summarizes the pharmacology, clinical efficacy, safety, dosing, and drug–drug interactions associated with the treatment of CLL with BTK inhibitors and examines their further implications. Full article
(This article belongs to the Special Issue Non-Hodgkin Lymphomas)
Show Figures

Figure 1

24 pages, 14975 KiB  
Systematic Review
Molecular Systems Architecture of Interactome in the Acute Myeloid Leukemia Microenvironment
by V. A. Shiva Ayyadurai, Prabhakar Deonikar, Kevin G. McLure and Kathleen M. Sakamoto
Cancers 2022, 14(3), 756; https://doi.org/10.3390/cancers14030756 - 1 Feb 2022
Cited by 11 | Viewed by 5444
Abstract
A molecular systems architecture is presented for acute myeloid leukemia (AML) to provide a framework for organizing the complexity of biomolecular interactions. AML is a multifactorial disease resulting from impaired differentiation and increased proliferation of hematopoietic precursor cells involving genetic mutations, signaling pathways [...] Read more.
A molecular systems architecture is presented for acute myeloid leukemia (AML) to provide a framework for organizing the complexity of biomolecular interactions. AML is a multifactorial disease resulting from impaired differentiation and increased proliferation of hematopoietic precursor cells involving genetic mutations, signaling pathways related to the cancer cell genetics, and molecular interactions between the cancer cell and the tumor microenvironment, including endothelial cells, fibroblasts, myeloid-derived suppressor cells, bone marrow stromal cells, and immune cells (e.g., T-regs, T-helper 1 cells, T-helper 17 cells, T-effector cells, natural killer cells, and dendritic cells). This molecular systems architecture provides a layered understanding of intra- and inter-cellular interactions in the AML cancer cell and the cells in the stromal microenvironment. The molecular systems architecture may be utilized for target identification and the discovery of single and combination therapeutics and strategies to treat AML. Full article
(This article belongs to the Section Systematic Review or Meta-Analysis in Cancer Research)
Show Figures

Figure 1

17 pages, 3623 KiB  
Article
Characterization of Cellular and Acellular Analytes from Pre-Cystectomy Liquid Biopsies in Patients Newly Diagnosed with Primary Bladder Cancer
by Stephanie N. Shishido, Salmaan Sayeed, George Courcoubetis, Hooman Djaladat, Gus Miranda, Kenneth J. Pienta, Jorge Nieva, Donna E. Hansel, Mihir Desai, Inderbir S. Gill, Peter Kuhn and Jeremy Mason
Cancers 2022, 14(3), 758; https://doi.org/10.3390/cancers14030758 - 1 Feb 2022
Cited by 16 | Viewed by 5026
Abstract
Urinary bladder cancer (BCa) is the 10th most frequent cancer in the world, most commonly found among the elderly population, and becomes highly lethal once cells have spread from the primary tumor to surrounding tissues and distant organs. Cystectomy, alone or with other [...] Read more.
Urinary bladder cancer (BCa) is the 10th most frequent cancer in the world, most commonly found among the elderly population, and becomes highly lethal once cells have spread from the primary tumor to surrounding tissues and distant organs. Cystectomy, alone or with other treatments, is used to treat most BCa patients, as it offers the best chance of cure. However, even with curative intent, 29% of patients experience relapse of the cancer, 50% of which occur within the first year of surgery. This study aims to use the liquid biopsy to noninvasively detect disease and discover prognostic markers for disease progression. Using the third generation high-definition single cell assay (HDSCA3.0), 50 bladder cancer patient samples and 50 normal donor (ND) samples were analyzed for circulating rare events in the peripheral blood (PB), including circulating tumor cells (CTCs) and large extracellular vesicles (LEVs). Here, we show that (i) CTCs and LEVs are detected in the PB of BCa patients prior to cystectomy, (ii) there is a high heterogeneity of CTCs, and (iii) liquid biopsy analytes correlate with clinical data elements. We observed a significant difference in the incidence of rare cells and LEVs between BCa and ND samples (median of 74.61 cells/mL and 30.91 LEVs/mL vs. 34.46 cells/mL and 3.34 LEVs/mL, respectively). Furthermore, using classification models for the liquid biopsy data, we achieved a sensitivity of 78% and specificity of 92% for the identification of BCa patient samples. Taken together, these data support the clinical utility of the liquid biopsy in detecting BCa, as well as the potential for predicting cancer recurrence and survival post-cystectomy to better inform treatment decisions in BCa care. Full article
(This article belongs to the Special Issue Targetable Pathways in Advanced Bladder Cancer)
Show Figures

Graphical abstract

24 pages, 5669 KiB  
Review
Utility of Cell-Free DNA Detection in Transplant Oncology
by Tejaswini Reddy, Abdullah Esmail, Jenny C. Chang, Rafik Mark Ghobrial and Maen Abdelrahim
Cancers 2022, 14(3), 743; https://doi.org/10.3390/cancers14030743 - 31 Jan 2022
Cited by 20 | Viewed by 5795
Abstract
Transplant oncology is an emerging field in cancer treatment that applies transplant medicine, surgery, and oncology to improve cancer patient survival and quality of life. A critical concept that must be addressed to ensure the successful application of transplant oncology to patient care [...] Read more.
Transplant oncology is an emerging field in cancer treatment that applies transplant medicine, surgery, and oncology to improve cancer patient survival and quality of life. A critical concept that must be addressed to ensure the successful application of transplant oncology to patient care is efficient monitoring of tumor burden pre-and post-transplant and transplant rejection. Cell-free DNA (cfDNA) detection has emerged as a vital tool in revolutionizing the management of cancer patients who undergo organ transplantation. The advances in cfDNA technology have provided options to perform a pre-transplant evaluation of minimal residual disease (MRD) and post-transplant evaluation of cancer recurrence and transplant rejection. This review aims to provide a comprehensive overview of the history and emergence of cfDNA technology, its applications to specifically monitor tumor burden at pre-and post-transplant stages, and evaluate transplant rejection. Full article
(This article belongs to the Special Issue Precision Medicine in Gastrointestinal Oncology)
Show Figures

Figure 1

13 pages, 1638 KiB  
Article
Sex Differences in the Effect of Vitamin D on Fatigue in Palliative Cancer Care—A Post Hoc Analysis of the Randomized, Controlled Trial ‘Palliative-D’
by Caritha Klasson, Maria Helde Frankling, Anna Warnqvist, Carina Sandberg, Marie Nordström, Carina Lundh-Hagelin and Linda Björkhem-Bergman
Cancers 2022, 14(3), 746; https://doi.org/10.3390/cancers14030746 - 31 Jan 2022
Cited by 4 | Viewed by 5065
Abstract
In the randomized, placebo-controlled, double-blind trial ‘Palliative-D’, vitamin D treatment of 4000 IE/day for 12 weeks reduced opioid use and fatigue in vitamin-D-deficient cancer patients. In screening data from this trial, lower levels of vitamin D were associated with more fatigue in men [...] Read more.
In the randomized, placebo-controlled, double-blind trial ‘Palliative-D’, vitamin D treatment of 4000 IE/day for 12 weeks reduced opioid use and fatigue in vitamin-D-deficient cancer patients. In screening data from this trial, lower levels of vitamin D were associated with more fatigue in men but not in women. The aim of the present study was to investigate possible sex differences in the effect of vitamin D in patients with advanced cancer, with a specific focus on fatigue. A post hoc analysis of sex differences in patients completing the Palliative-D study (n = 150) was performed. Fatigue assessed with the Edmonton Symptom Assessment Scale (ESAS) was reduced in vitamin-D-treated men; −1.50 ESAS points (95%CI −2.57 to −0.43; p = 0.007) but not in women; −0.75 (95%CI −1.85 to 0.36; p = 0.18). Fatigue measured with EORTC QLQ-C15-PAL had a borderline significant effect in men (−0.33 (95%CI −0.67 to 0.03; p = 0.05)) but not in women (p = 0.55). The effect on fatigue measured with ESAS in men remained the same after adjustment for opioid doses (p = 0.01). In conclusion, the positive effect of the correction of vitamin D deficiency on fatigue may be more pronounced in men than in women. However, studies focused on analyzing sex differences in this context must be performed before firm conclusions can be drawn. Full article
(This article belongs to the Special Issue Palliative and Supportive Care in Oncology: An Update)
Show Figures

Figure 1

35 pages, 6290 KiB  
Review
Exosomal Proteins and Lipids as Potential Biomarkers for Lung Cancer Diagnosis, Prognosis, and Treatment
by Ming-Tsung Hsu, Yu-Ke Wang and Yufeng Jane Tseng
Cancers 2022, 14(3), 732; https://doi.org/10.3390/cancers14030732 - 30 Jan 2022
Cited by 71 | Viewed by 8489
Abstract
Exosomes participate in cell–cell communication by transferring molecular components between cells. Previous studies have shown that exosomal molecules derived from cancer cells and liquid biopsies can serve as biomarkers for cancer diagnosis and prognosis. The exploration of the molecules transferred by lung cancer-derived [...] Read more.
Exosomes participate in cell–cell communication by transferring molecular components between cells. Previous studies have shown that exosomal molecules derived from cancer cells and liquid biopsies can serve as biomarkers for cancer diagnosis and prognosis. The exploration of the molecules transferred by lung cancer-derived exosomes can advance the understanding of exosome-mediated signaling pathways and mechanisms. However, the molecular characterization and functional indications of exosomal proteins and lipids have not been comprehensively organized. This review thoroughly collected data concerning exosomal proteins and lipids from various lung cancer samples, including cancer cell lines and cancer patients. As potential diagnostic and prognostic biomarkers, exosomal proteins and lipids are available for clinical use in lung cancer. Potential therapeutic targets are mentioned for the future development of lung cancer therapy. Molecular functions implying their possible roles in exosome-mediated signaling are also discussed. Finally, we emphasized the importance and value of lung cancer stem cell-derived exosomes in lung cancer therapy. In summary, this review presents a comprehensive description of the protein and lipid composition and function of lung cancer-derived exosomes for lung cancer diagnosis, prognosis, and treatment. Full article
Show Figures

Figure 1

16 pages, 3181 KiB  
Review
Fecal Microbiota Transplant for Hematologic and Oncologic Diseases: Principle and Practice
by Maroun Bou Zerdan, Stephanie Niforatos, Sandy Nasr, Dayana Nasr, Mulham Ombada, Savio John, Dibyendu Dutta and Seah H. Lim
Cancers 2022, 14(3), 691; https://doi.org/10.3390/cancers14030691 - 29 Jan 2022
Cited by 15 | Viewed by 14287
Abstract
Understanding of the importance of the normal intestinal microbial community in regulating microbial homeostasis, host metabolism, adaptive immune responses, and gut barrier functions has opened up the possibility of manipulating the microbial composition to modulate the activity of various intestinal and systemic diseases [...] Read more.
Understanding of the importance of the normal intestinal microbial community in regulating microbial homeostasis, host metabolism, adaptive immune responses, and gut barrier functions has opened up the possibility of manipulating the microbial composition to modulate the activity of various intestinal and systemic diseases using fecal microbiota transplant (FMT). It is therefore not surprising that use of FMT, especially for treating relapsed/refractory Clostridioides difficile infections (CDI), has increased over the last decade. Due to the complexity associated with and treatment for these diseases, patients with hematologic and oncologic diseases are particularly susceptible to complications related to altered intestinal microbial composition. Therefore, they are an ideal population for exploring FMT as a therapeutic approach. However, there are inherent factors presenting as obstacles for the use of FMT in these patients. In this review paper, we discussed the principles and biologic effects of FMT, examined the factors rendering patients with hematologic and oncologic conditions to increased risks for relapsed/refractory CDI, explored ongoing FMT studies, and proposed novel uses for FMT in these groups of patients. Finally, we also addressed the challenges of applying FMT to these groups of patients and proposed ways to overcome these challenges. Full article
Show Figures

Figure 1

18 pages, 6998 KiB  
Article
Early-Stage Lung Adenocarcinoma MDM2 Genomic Amplification Predicts Clinical Outcome and Response to Targeted Therapy
by Abhilasha Sinha, Yong Zou, Ayushi S. Patel, Seungyeul Yoo, Feng Jiang, Takashi Sato, Ranran Kong, Hideo Watanabe, Jun Zhu, Pierre P. Massion, Alain C. Borczuk and Charles A. Powell
Cancers 2022, 14(3), 708; https://doi.org/10.3390/cancers14030708 - 29 Jan 2022
Cited by 15 | Viewed by 5067
Abstract
Lung cancer is the most common cause of cancer-related deaths in both men and women, accounting for one-quarter of total cancer-related mortality globally. Lung adenocarcinoma is the major subtype of non-small cell lung cancer (NSCLC) and accounts for around 40% of lung cancer [...] Read more.
Lung cancer is the most common cause of cancer-related deaths in both men and women, accounting for one-quarter of total cancer-related mortality globally. Lung adenocarcinoma is the major subtype of non-small cell lung cancer (NSCLC) and accounts for around 40% of lung cancer cases. Lung adenocarcinoma is a highly heterogeneous disease and patients often display variable histopathological morphology, genetic alterations, and genomic aberrations. Recent advances in transcriptomic and genetic profiling of lung adenocarcinoma by investigators, including our group, has provided better stratification of this heterogeneous disease, which can facilitate devising better treatment strategies suitable for targeted patient cohorts. In a recent study we have shown gene expression profiling identified novel clustering of early stage LUAD patients and correlated with tumor invasiveness and patient survival. In this study, we focused on copy number alterations in LUAD patients. SNP array data identified amplification at chromosome 12q15 on MDM2 locus and protein overexpression in a subclass of LUAD patients with an invasive subtype of the disease. High copy number amplification and protein expression in this subclass correlated with poor overall survival. We hypothesized that MDM2 copy number and overexpression predict response to MDM2-targeted therapy. In vitro functional data on a panel of LUAD cells showed that MDM2-targeted therapy effectively suppresses cell proliferation, migration, and invasion in cells with MDM2 amplification/overexpression but not in cells without MDM2 amplification, independent of p53 status. To determine the key signaling mechanisms, we used RNA sequencing (RNA seq) to examine the response to therapy in MDM2-amplified/overexpressing p53 mutant and wild-type LUAD cells. RNA seq data shows that in MDM2-amplified/overexpression with p53 wild-type condition, the E2F → PEG10 → MMPs pathway is operative, while in p53 mutant genetic background, MDM2-targeted therapy abrogates tumor progression in LUAD cells by suppressing epithelial to mesenchymal transition (EMT) signaling. Our study provides a potentially clinically relevant strategy of selecting LUAD patients for MDM2-targeted therapy that may provide for increased response rates and, thus, better survival. Full article
(This article belongs to the Special Issue Tumor Heterogeneity)
Show Figures

Figure 1

19 pages, 1643 KiB  
Review
Update on Management Recommendations for Advanced Cutaneous Squamous Cell Carcinoma
by Jesús García-Foncillas, Antonio Tejera-Vaquerizo, Onofre Sanmartín, Federico Rojo, Javier Mestre, Salvador Martín, Ignacio Azinovic and Ricard Mesía
Cancers 2022, 14(3), 629; https://doi.org/10.3390/cancers14030629 - 27 Jan 2022
Cited by 27 | Viewed by 12443
Abstract
Cutaneous squamous cell carcinoma (cSCC) is the second most common form of skin cancer, the incidence of which has risen over the last years. Although cSCC rarely metastasizes, early detection and treatment of primary tumours are critical to limit progression and local invasion. [...] Read more.
Cutaneous squamous cell carcinoma (cSCC) is the second most common form of skin cancer, the incidence of which has risen over the last years. Although cSCC rarely metastasizes, early detection and treatment of primary tumours are critical to limit progression and local invasion. Several prognostic factors related to patients’ clinicopathologic profile and tumour features have been identified as high-risk markers and included in the stratification scales, but their association with regional control or survival is uncertain. Therefore, decision-making on the diagnosis and management of cSCC should be made based on each individual patient’s characteristics. Recent advances in non-invasive imaging techniques and molecular testing have enhanced clinical diagnostic accuracy. Surgical excision is the mainstay of local treatment, whereas radiotherapy (RT) is recommended for patients with inoperable disease or in specific circumstances. Novel systemic treatments including immunotherapies and targeted therapies have changed the therapeutic landscape for cSCC. The anti-PD-1 agent cemiplimab is currently the only FDA/EMA-approved first-line therapy for patients with locally advanced or metastatic cSCC who are not candidates for curative surgery or RT. Given the likelihood of recurrence and the increased risk of developing multiple cSCC, close follow-up should be performed during the first years of treatment and continued long-term surveillance is warranted. Full article
(This article belongs to the Special Issue Prevention, Diagnosis and Treatment of Skin Cancer)
Show Figures

Figure 1

23 pages, 14888 KiB  
Review
Cancer-on-a-Chip: Models for Studying Metastasis
by Xiaojun Zhang, Mazharul Karim, Md Mahedi Hasan, Jacob Hooper, Riajul Wahab, Sourav Roy and Taslim A. Al-Hilal
Cancers 2022, 14(3), 648; https://doi.org/10.3390/cancers14030648 - 27 Jan 2022
Cited by 45 | Viewed by 10515
Abstract
The microfluidic-based cancer-on-a-chip models work as a powerful tool to study the tumor microenvironment and its role in metastasis. The models recapitulate and systematically simplify the in vitro tumor microenvironment. This enables the study of a metastatic process in unprecedented detail. This review [...] Read more.
The microfluidic-based cancer-on-a-chip models work as a powerful tool to study the tumor microenvironment and its role in metastasis. The models recapitulate and systematically simplify the in vitro tumor microenvironment. This enables the study of a metastatic process in unprecedented detail. This review examines the development of cancer-on-a-chip microfluidic platforms at the invasion/intravasation, extravasation, and angiogenesis steps over the last three years. The on-chip modeling of mechanical cues involved in the metastasis cascade are also discussed. Finally, the popular design of microfluidic chip models for each step are discussed along with the challenges and perspectives of cancer-on-a-chip models. Full article
(This article belongs to the Special Issue Modeling Cancer in Microfluidic Chips)
Show Figures

Figure 1

42 pages, 5014 KiB  
Review
Targeting Tumor Glycans for Cancer Therapy: Successes, Limitations, and Perspectives
by Nora Berois, Alvaro Pittini and Eduardo Osinaga
Cancers 2022, 14(3), 645; https://doi.org/10.3390/cancers14030645 - 27 Jan 2022
Cited by 89 | Viewed by 12614
Abstract
Aberrant glycosylation is a hallmark of cancer and can lead to changes that influence tumor behavior. Glycans can serve as a source of novel clinical biomarker developments, providing a set of specific targets for therapeutic intervention. Different mechanisms of aberrant glycosylation lead to [...] Read more.
Aberrant glycosylation is a hallmark of cancer and can lead to changes that influence tumor behavior. Glycans can serve as a source of novel clinical biomarker developments, providing a set of specific targets for therapeutic intervention. Different mechanisms of aberrant glycosylation lead to the formation of tumor-associated carbohydrate antigens (TACAs) suitable for selective cancer-targeting therapy. The best characterized TACAs are truncated O-glycans (Tn, TF, and sialyl-Tn antigens), gangliosides (GD2, GD3, GM2, GM3, fucosyl-GM1), globo-serie glycans (Globo-H, SSEA-3, SSEA-4), Lewis antigens, and polysialic acid. In this review, we analyze strategies for cancer immunotherapy targeting TACAs, including different antibody developments, the production of vaccines, and the generation of CAR-T cells. Some approaches have been approved for clinical use, such as anti-GD2 antibodies. Moreover, in terms of the antitumor mechanisms against different TACAs, we show results of selected clinical trials, considering the horizons that have opened up as a result of recent developments in technologies used for cancer control. Full article
(This article belongs to the Special Issue Advances in Tumor Glycans)
Show Figures

Figure 1

57 pages, 2143 KiB  
Review
Clinical Evidence for Thermometric Parameters to Guide Hyperthermia Treatment
by Adela Ademaj, Danai P. Veltsista, Pirus Ghadjar, Dietmar Marder, Eva Oberacker, Oliver J. Ott, Peter Wust, Emsad Puric, Roger A. Hälg, Susanne Rogers, Stephan Bodis, Rainer Fietkau, Hans Crezee and Oliver Riesterer
Cancers 2022, 14(3), 625; https://doi.org/10.3390/cancers14030625 - 26 Jan 2022
Cited by 28 | Viewed by 5445
Abstract
Hyperthermia (HT) is a cancer treatment modality which targets malignant tissues by heating to 40–43 °C. In addition to its direct antitumor effects, HT potently sensitizes the tumor to radiotherapy (RT) and chemotherapy (CT), thereby enabling complete eradication of some tumor entities as [...] Read more.
Hyperthermia (HT) is a cancer treatment modality which targets malignant tissues by heating to 40–43 °C. In addition to its direct antitumor effects, HT potently sensitizes the tumor to radiotherapy (RT) and chemotherapy (CT), thereby enabling complete eradication of some tumor entities as shown in randomized clinical trials. Despite the proven efficacy of HT in combination with classic cancer treatments, there are limited international standards for the delivery of HT in the clinical setting. Consequently, there is a large variability in reported data on thermometric parameters, including the temperature obtained from multiple reference points, heating duration, thermal dose, time interval, and sequence between HT and other treatment modalities. Evidence from some clinical trials indicates that thermal dose, which correlates with heating time and temperature achieved, could be used as a predictive marker for treatment efficacy in future studies. Similarly, other thermometric parameters when chosen optimally are associated with increased antitumor efficacy. This review summarizes the existing clinical evidence for the prognostic and predictive role of the most important thermometric parameters to guide the combined treatment of RT and CT with HT. In conclusion, we call for the standardization of thermometric parameters and stress the importance for their validation in future prospective clinical studies. Full article
Show Figures

Figure 1

27 pages, 12636 KiB  
Review
Chemotherapy Side-Effects: Not All DNA Damage Is Equal
by Winnie M. C. van den Boogaard, Daphne S. J. Komninos and Wilbert P. Vermeij
Cancers 2022, 14(3), 627; https://doi.org/10.3390/cancers14030627 - 26 Jan 2022
Cited by 264 | Viewed by 26974
Abstract
Recent advances have increased survival rates of children and adults suffering from cancer thanks to effective anti-cancer therapy, such as chemotherapy. However, during treatment and later in life they are frequently confronted with the severe negative side-effects of their life-saving treatment. The occurrence [...] Read more.
Recent advances have increased survival rates of children and adults suffering from cancer thanks to effective anti-cancer therapy, such as chemotherapy. However, during treatment and later in life they are frequently confronted with the severe negative side-effects of their life-saving treatment. The occurrence of numerous features of accelerated aging, seriously affecting quality of life, has now become one of the most pressing problems associated with (pediatric) cancer treatment. Chemotherapies frequently target and damage the DNA, causing mutations or genome instability, a major hallmark of both cancer and aging. However, there are numerous types of chemotherapeutic drugs that are genotoxic and interfere with DNA metabolism in different ways, each with their own biodistribution, kinetics, and biological fate. Depending on the type of DNA lesion produced (e.g., interference with DNA replication or RNA transcription), the organ or cell type inflicted (e.g., cell cycle or differentiation status, metabolic state, activity of clearance and detoxification mechanisms, the cellular condition or micro-environment), and the degree of exposure, outcomes of cancer treatment can largely differ. These considerations provide a conceptual framework in which different classes of chemotherapeutics contribute to the development of toxicities and accelerated aging of different organ systems. Here, we summarize frequently observed side-effects in (pediatric) ex-cancer patients and discuss which types of DNA damage might be responsible. Full article
(This article belongs to the Special Issue Genomic Instability in Tumor Evolution and Therapy Response)
Show Figures

Figure 1

16 pages, 862 KiB  
Review
Machine Learning and Deep Learning Applications in Multiple Myeloma Diagnosis, Prognosis, and Treatment Selection
by Alessandro Allegra, Alessandro Tonacci, Raffaele Sciaccotta, Sara Genovese, Caterina Musolino, Giovanni Pioggia and Sebastiano Gangemi
Cancers 2022, 14(3), 606; https://doi.org/10.3390/cancers14030606 - 25 Jan 2022
Cited by 59 | Viewed by 8448
Abstract
Artificial intelligence has recently modified the panorama of oncology investigation thanks to the use of machine learning algorithms and deep learning strategies. Machine learning is a branch of artificial intelligence that involves algorithms that analyse information, learn from that information, and then employ [...] Read more.
Artificial intelligence has recently modified the panorama of oncology investigation thanks to the use of machine learning algorithms and deep learning strategies. Machine learning is a branch of artificial intelligence that involves algorithms that analyse information, learn from that information, and then employ their discoveries to make abreast choice, while deep learning is a field of machine learning basically represented by algorithms inspired by the organization and function of the brain, named artificial neural networks. In this review, we examine the possibility of the artificial intelligence applications in multiple myeloma evaluation, and we report the most significant experimentations with respect to the machine and deep learning procedures in the relevant field. Multiple myeloma is one of the most common haematological malignancies in the world, and among them, it is one of the most difficult ones to cure due to the high occurrence of relapse and chemoresistance. Machine learning- and deep learning-based studies are expected to be among the future strategies to challenge this negative-prognosis tumour via the detection of new markers for their prompt discovery and therapy selection and by a better evaluation of its relapse and survival. Full article
Show Figures

Figure 1

20 pages, 1950 KiB  
Review
Peptide Receptor Radionuclide Therapy with [177Lu]Lu-DOTA-TATE in Patients with Advanced GEP NENS: Present and Future Directions
by Maria I. del Olmo-García, Stefan Prado-Wohlwend, Pilar Bello, Angel Segura and Juan F. Merino-Torres
Cancers 2022, 14(3), 584; https://doi.org/10.3390/cancers14030584 - 24 Jan 2022
Cited by 19 | Viewed by 6314
Abstract
This review article summarizes findings published in the last years on peptide receptor radionuclide therapy in GEP NENs, as well as potential future developments and directions. Unanswered questions remain, such as the following: Which is the correct dose and individual dosimetry? Which is [...] Read more.
This review article summarizes findings published in the last years on peptide receptor radionuclide therapy in GEP NENs, as well as potential future developments and directions. Unanswered questions remain, such as the following: Which is the correct dose and individual dosimetry? Which is the place for salvage PRRT-Lu? Whicht is the role of PRRT-Lu in the pediatric population? Which is the optimal sequencing of PRRT-Lu in advanced GEP NETs? Which is the place of PRRT-Lu in G3 NENs? These, and future developments such as inclusion new radiopharmaceuticals and combination therapy with different agents, such as radiosensitizers, will be discussed. Full article
(This article belongs to the Special Issue Molecular Targeting in Cancer: Imaging and Therapy)
Show Figures

Figure 1

14 pages, 635 KiB  
Review
Strategies for Improving the Efficacy of CAR T Cells in Solid Cancers
by Jon Amund Kyte
Cancers 2022, 14(3), 571; https://doi.org/10.3390/cancers14030571 - 23 Jan 2022
Cited by 16 | Viewed by 6167
Abstract
Therapy with T cells equipped with chimeric antigen receptors (CARs) shows strong efficacy against leukaemia and lymphoma, but not yet against solid cancers. This has been attributed to insufficient T cell persistence, tumour heterogeneity and an immunosuppressive tumour microenvironment. The present article provides [...] Read more.
Therapy with T cells equipped with chimeric antigen receptors (CARs) shows strong efficacy against leukaemia and lymphoma, but not yet against solid cancers. This has been attributed to insufficient T cell persistence, tumour heterogeneity and an immunosuppressive tumour microenvironment. The present article provides an overview of key strategies that are currently investigated to overcome these hurdles. Basic aspects of CAR design are revisited, relevant for tuning the stimulatory signal to the requirements of solid tumours. Novel approaches for enhancing T cell persistence are highlighted, based on epigenetic or post-translational modifications. Further, the article describes CAR T strategies that are being developed for overcoming tumour heterogeneity and the escape of cancer stem cells, as well as for countering prevalent mechanisms of immune suppression in solid cancers. In general, personalised medicine is faced with a lack of drugs matching the patient’s profile. The advances and flexibility of modern gene engineering may allow for the filling of some of these gaps with tailored CAR T approaches addressing mechanisms identified as important in the individual patient. At this point, however, CAR T cell therapy remains unproved in solid cancers. The further progress of the field will depend on bringing novel strategies into clinical evaluation, while maintaining safety. Full article
(This article belongs to the Special Issue Current Advances in Chimeric Antigen Receptor Technology)
Show Figures

Figure 1

19 pages, 4641 KiB  
Article
Slip versus Slop: A Head-to-Head Comparison of UV-Protective Clothing to Sunscreen
by Elizabeth G. Berry, Joshua Bezecny, Michael Acton, Taylor P. Sulmonetti, David M. Anderson, Haskell W. Beckham, Rebecca A. Durr, Takahiro Chiba, Jennifer Beem, Douglas E. Brash, Rajan Kulkarni, Pamela B. Cassidy and Sancy A. Leachman
Cancers 2022, 14(3), 542; https://doi.org/10.3390/cancers14030542 - 21 Jan 2022
Cited by 28 | Viewed by 10942
Abstract
Ultraviolet radiation (UVR) exposure is the most important modifiable risk factor for skin cancer development. Although sunscreen and sun-protective clothing are essential tools to minimize UVR exposure, few studies have compared the two modalities head-to-head. This study evaluates the UV-protective capacity of four [...] Read more.
Ultraviolet radiation (UVR) exposure is the most important modifiable risk factor for skin cancer development. Although sunscreen and sun-protective clothing are essential tools to minimize UVR exposure, few studies have compared the two modalities head-to-head. This study evaluates the UV-protective capacity of four modern, sun-protective textiles and two broad-spectrum, organic sunscreens (SPF 30 and 50). Sun Protection Factor (SPF), Ultraviolet Protection Factor (UPF), Critical Wavelength (CW), and % UVA- and % UVB-blocking were measured for each fabric. UPF, CW, % UVA- and % UVB-blocking were measured for each sunscreen at 2 mg/cm2 (recommended areal density) and 1 mg/cm2 (simulating real-world consumer application). The four textiles provided superior UVR protection when compared to the two sunscreens tested. All fabrics blocked erythemogenic UVR better than the sunscreens, as measured by SPF, UPF, and % UVB-blocking. Each fabric was superior to the sunscreens in blocking full-spectrum UVR, as measured by CW and % UVA-blocking. Our data demonstrate the limitations of sunscreen and UV-protective clothing labeling and suggest the combination of SPF or UPF with % UVA-blocking may provide more suitable measures for broad-spectrum protection. While sunscreen remains an important photoprotective modality (especially for sites where clothing is impractical), these data suggest that clothing should be considered the cornerstone of UV protection. Full article
(This article belongs to the Special Issue Melanoma: Prevention and Molecular Epidemiology)
Show Figures

Figure 1

16 pages, 1064 KiB  
Review
Emerging Role of Epigenetic Alterations as Biomarkers and Novel Targets for Treatments in Pancreatic Ductal Adenocarcinoma
by Marcus T. T. Roalsø, Øyvind H. Hald, Marina Alexeeva and Kjetil Søreide
Cancers 2022, 14(3), 546; https://doi.org/10.3390/cancers14030546 - 21 Jan 2022
Cited by 10 | Viewed by 3982
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is a lethal disease with limited treatment options. Emerging evidence shows that epigenetic alterations are present in PDAC. The changes are potentially reversible and therefore promising therapeutic targets. Epigenetic aberrations also influence the tumor microenvironment with the potential to [...] Read more.
Pancreatic ductal adenocarcinoma (PDAC) is a lethal disease with limited treatment options. Emerging evidence shows that epigenetic alterations are present in PDAC. The changes are potentially reversible and therefore promising therapeutic targets. Epigenetic aberrations also influence the tumor microenvironment with the potential to modulate and possibly enhance immune-based treatments. Epigenetic marks can also serve as diagnostic screening tools, as epigenetic changes occur at early stages of the disease. Further, epigenetics can be used in prognostication. The field is evolving, and this review seeks to provide an updated overview of the emerging role of epigenetics in the diagnosis, treatment, and prognostication of PDAC. Full article
(This article belongs to the Special Issue Epigenetic Detection and Regulation of Cancer Biomarkers)
Show Figures

Figure 1

18 pages, 2848 KiB  
Article
Platelet Count and Survival after Cancer
by Vasily Giannakeas, Joanne Kotsopoulos, Jennifer D. Brooks, Matthew C. Cheung, Laura Rosella, Lorraine Lipscombe, Mohammad R. Akbari, Peter C. Austin and Steven A. Narod
Cancers 2022, 14(3), 549; https://doi.org/10.3390/cancers14030549 - 21 Jan 2022
Cited by 36 | Viewed by 7690
Abstract
Thrombocytosis is associated with cancer progression and death for many cancer types. It is unclear if platelet count is also associated with cancer survival. We conducted a cohort study of 112,231 adults in Ontario with a diagnosis of cancer between January 2007 and [...] Read more.
Thrombocytosis is associated with cancer progression and death for many cancer types. It is unclear if platelet count is also associated with cancer survival. We conducted a cohort study of 112,231 adults in Ontario with a diagnosis of cancer between January 2007 and December 2016. We included patients who had a complete blood count (CBC) completed in the 30 days prior to their cancer diagnosis. Subjects were assigned to one of three categories according to platelet count: low (≤25th percentile), medium (>25 to <75th percentile), and high (≥75th percentile). Study subjects were followed from the date of their cancer diagnosis for cancer-specific death. Of the 112,231 eligible cancer patients in the cohort study, 40,329 (35.9%) died from their cancer in the follow-up period. Relative to those with a medium platelet count, the rate of cancer-specific death was higher among individuals with a high platelet count (HR 1.52; 95%CI 1.48–1.55) and was lower among individuals with a low platelet count (HR 0.91; 95%CI 0.88–0.93). A high platelet count was associated with poor survival for many cancer types. Platelet count could potentially be used as a risk stratification measure for cancer patients. Full article
Show Figures

Figure 1

24 pages, 2004 KiB  
Review
Novel Cellular Therapies for Hepatocellular Carcinoma
by Harriet Roddy, Tim Meyer and Claire Roddie
Cancers 2022, 14(3), 504; https://doi.org/10.3390/cancers14030504 - 20 Jan 2022
Cited by 23 | Viewed by 6270
Abstract
Hepatocellular carcinoma (HCC) is one of the leading causes of cancer related death worldwide. Most patients present with advanced disease, and current gold-standard management using tyrosine kinase inhibitors or immune checkpoint inhibitors (ICIs) offers modest clinical benefit. Cellular immune therapies targeting HCC are [...] Read more.
Hepatocellular carcinoma (HCC) is one of the leading causes of cancer related death worldwide. Most patients present with advanced disease, and current gold-standard management using tyrosine kinase inhibitors or immune checkpoint inhibitors (ICIs) offers modest clinical benefit. Cellular immune therapies targeting HCC are currently being tested in the laboratory and in clinical trials. Here, we review the landscape of cellular immunotherapy for HCC, defining antigenic targets, outlining the range of cell therapy products being applied in HCC (such as CAR-T and TCR-T), and exploring how advanced engineering solutions may further enhance this therapeutic approach. Full article
(This article belongs to the Collection Novel Therapies for Hepatocellular Carcinoma)
Show Figures

Figure 1

21 pages, 3019 KiB  
Article
CXCR2 Mediates Distinct Neutrophil Behavior in Brain Metastatic Breast Tumor
by Simrit Safarulla, Ankit Madan, Fei Xing and Arvind Chandrasekaran
Cancers 2022, 14(3), 515; https://doi.org/10.3390/cancers14030515 - 20 Jan 2022
Cited by 23 | Viewed by 5949
Abstract
Brain metastasis is one of the main causes of mortality among breast cancer patients, but the origins and the mechanisms that drive this process remain poorly understood. Here, we report that the upregulation of certain CXCR2-associated ligands in the brain metastatic variants of [...] Read more.
Brain metastasis is one of the main causes of mortality among breast cancer patients, but the origins and the mechanisms that drive this process remain poorly understood. Here, we report that the upregulation of certain CXCR2-associated ligands in the brain metastatic variants of the breast cancer cells (BrM) dynamically activate the corresponding CXCR2 receptors on the neutrophils, thereby resulting in the modulation of certain key functional neutrophil responses towards the BrM. Using established neutrophil-tumor biomimetic co-culture models, we show that the upregulation of CXCR2 increases the recruitment of Tumor-Associated Neutrophils (TANs) towards the BrM, to enable location-favored formation of Neutrophil Extracellular Traps (NETs). Inhibition of CXCR2 using small molecule antagonist AZD5069 reversed this behavior, limiting the neutrophil responses to the BrM and retarding the reciprocal tumor development. We further demonstrate that abrogation of NETs formation using Neutrophil Elastase Inhibitor (NEI) significantly decreases the influx of neutrophils towards BrM but not to their parental tumor, suggesting that CXCR2 activation could be used by the brain metastatic tumors as a mechanism to program the tumor-infiltrating TANs into a pro-NETotic state, so as to assume a unique spatial distribution that assists in the subsequent migration and invasion of the metastatic tumor cells. This new perspective indicates that CXCR2 is a critical target for suppressing neutrophilic inflammation in brain metastasis. Full article
(This article belongs to the Special Issue Neutrophils in Cancer: Role and Therapeutic Strategies)
Show Figures

Figure 1

15 pages, 1412 KiB  
Review
AXL Receptor Tyrosine Kinase as a Promising Therapeutic Target Directing Multiple Aspects of Cancer Progression and Metastasis
by Marie-Anne Goyette and Jean-François Côté
Cancers 2022, 14(3), 466; https://doi.org/10.3390/cancers14030466 - 18 Jan 2022
Cited by 47 | Viewed by 6908
Abstract
The receptor tyrosine kinase AXL is emerging as a key player in tumor progression and metastasis and its expression correlates with poor survival in a plethora of cancers. While studies have shown the benefits of AXL inhibition for the treatment of metastatic cancers, [...] Read more.
The receptor tyrosine kinase AXL is emerging as a key player in tumor progression and metastasis and its expression correlates with poor survival in a plethora of cancers. While studies have shown the benefits of AXL inhibition for the treatment of metastatic cancers, additional roles for AXL in cancer progression are still being explored. This review discusses recent advances in understanding AXL’s functions in different tumor compartments including cancer, vascular, and immune cells. AXL is required at multiple steps of the metastatic cascade where its activation in cancer cells leads to EMT, invasion, survival, proliferation and therapy resistance. AXL activation in cancer cells and various stromal cells also results in tumor microenvironment deregulation, leading to modulation of angiogenesis, fibrosis, immune response and hypoxia. A better understanding of AXL’s role in these processes could lead to new therapeutic approaches that would benefit patients suffering from metastatic diseases. Full article
(This article belongs to the Special Issue From Progression to Metastasis of Solid Cancer)
Show Figures

Figure 1

15 pages, 701 KiB  
Review
Molecular Targets of Triple-Negative Breast Cancer: Where Do We Stand?
by Emma E. Newton, Lauren E. Mueller, Scout M. Treadwell, Cindy A. Morris and Heather L. Machado
Cancers 2022, 14(3), 482; https://doi.org/10.3390/cancers14030482 - 18 Jan 2022
Cited by 38 | Viewed by 6747
Abstract
Triple-negative breast cancer (TNBC) is a highly aggressive form of breast cancer. Due to its heterogeneity and lack of hormone receptor expression, this subtype is more likely to metastasize and resist treatment attempts than are other forms of breast cancer. Due to the [...] Read more.
Triple-negative breast cancer (TNBC) is a highly aggressive form of breast cancer. Due to its heterogeneity and lack of hormone receptor expression, this subtype is more likely to metastasize and resist treatment attempts than are other forms of breast cancer. Due to the absence of targetable receptors, chemotherapy and breast conserving surgery have been the predominant treatment options for patients. However, resistance to chemotherapy and local recurrence of the tumors is frequent. Emerging immunotherapies have begun to change treatment plans for patients diagnosed with TNBC. In this review, we discuss the various immune pathways identified in TNBC and the role they play as targets for new potential treatment choices. Various therapeutic options that inhibit key pathways in cellular growth cycles, DNA repair mechanisms, epithelial mesenchymal transition, and immunosuppression have been shown to improve survival in patients with this disease. With promising results thus far, continued studies of immunotherapy and neoadjuvant therapy options for TNBC are likely to alter the treatment course for these diagnoses in the future. Full article
Show Figures

Figure 1

24 pages, 1884 KiB  
Review
Tumor Cell Infiltration into the Brain in Glioblastoma: From Mechanisms to Clinical Perspectives
by Fidan Seker-Polat, Nareg Pinarbasi Degirmenci, Ihsan Solaroglu and Tugba Bagci-Onder
Cancers 2022, 14(2), 443; https://doi.org/10.3390/cancers14020443 - 17 Jan 2022
Cited by 129 | Viewed by 13117
Abstract
Glioblastoma is the most common and malignant primary brain tumor, defined by its highly aggressive nature. Despite the advances in diagnostic and surgical techniques, and the development of novel therapies in the last decade, the prognosis for glioblastoma is still extremely poor. One [...] Read more.
Glioblastoma is the most common and malignant primary brain tumor, defined by its highly aggressive nature. Despite the advances in diagnostic and surgical techniques, and the development of novel therapies in the last decade, the prognosis for glioblastoma is still extremely poor. One major factor for the failure of existing therapeutic approaches is the highly invasive nature of glioblastomas. The extreme infiltrating capacity of tumor cells into the brain parenchyma makes complete surgical removal difficult; glioblastomas almost inevitably recur in a more therapy-resistant state, sometimes at distant sites in the brain. Therefore, there are major efforts to understand the molecular mechanisms underpinning glioblastoma invasion; however, there is no approved therapy directed against the invasive phenotype as of now. Here, we review the major molecular mechanisms of glioblastoma cell invasion, including the routes followed by glioblastoma cells, the interaction of tumor cells within the brain environment and the extracellular matrix components, and the roles of tumor cell adhesion and extracellular matrix remodeling. We also include a perspective of high-throughput approaches utilized to discover novel players for invasion and clinical targeting of invasive glioblastoma cells. Full article
(This article belongs to the Special Issue Research in Aggressive Brain Tumors: Biology and Precision Therapy)
Show Figures

Figure 1

16 pages, 14033 KiB  
Article
Biglycan Promotes Cancer Stem Cell Properties, NFκB Signaling and Metastatic Potential in Breast Cancer Cells
by Kanakaraju Manupati, Ritama Paul, Mingang Hao, Michael Haas, Zhaoqun Christine Bian, Tammy M. Holm, Jun-Lin Guan and Syn Kok Yeo
Cancers 2022, 14(2), 455; https://doi.org/10.3390/cancers14020455 - 17 Jan 2022
Cited by 16 | Viewed by 4099
Abstract
It is a major challenge to treat metastasis due to the presence of heterogenous BCSCs. Therefore, it is important to identify new molecular targets and their underlying molecular mechanisms in various BCSCs to improve treatment of breast cancer metastasis. Here, we performed RNA [...] Read more.
It is a major challenge to treat metastasis due to the presence of heterogenous BCSCs. Therefore, it is important to identify new molecular targets and their underlying molecular mechanisms in various BCSCs to improve treatment of breast cancer metastasis. Here, we performed RNA sequencing on two distinct co-existing BCSC populations, ALDH+ and CD29hi CD61+ from PyMT mammary tumor cells and detected upregulation of biglycan (BGN) in these BCSCs. Genetic depletion of BGN reduced BCSC proportions and tumorsphere formation. Furthermore, BCSC associated aggressive traits such as migration and invasion were significantly reduced by depletion of BGN. Glycolytic and mitochondrial metabolic assays also revealed that BCSCs exhibited decreased metabolism upon loss of BGN. BCSCs showed decreased activation of the NFκB transcription factor, p65, and phospho-IκB levels upon BGN ablation, indicating regulation of NFκB pathway by BGN. To further support our data, we also characterized CD24/CD44+ BCSCs from human luminal MCF-7 breast cancer cells. These CD24/CD44+ BCSCs similarly exhibited reduced tumorigenic phenotypes, metabolism and attenuation of NFκB pathway after knockdown of BGN. Finally, loss of BGN in ALDH+ and CD29hi CD61+ BCSCs showed decreased metastatic potential, suggesting BGN serves as an important therapeutic target in BCSCs for treating metastasis of breast cancer. Full article
(This article belongs to the Special Issue Signalling Pathways of Cancer Stem Cells)
Show Figures

Figure 1

14 pages, 1672 KiB  
Article
Comprehensive Approach to Distinguish Patients with Solid Tumors from Healthy Controls by Combining Androgen Receptor Mutation p.H875Y with Cell-Free DNA Methylation and Circulating miRNAs
by Elena Tomeva, Olivier J. Switzeny, Clemens Heitzinger, Berit Hippe and Alexander G. Haslberger
Cancers 2022, 14(2), 462; https://doi.org/10.3390/cancers14020462 - 17 Jan 2022
Cited by 23 | Viewed by 7756
Abstract
Liquid biopsy-based tests emerge progressively as an important tool for cancer diagnostics and management. Currently, researchers focus on a single biomarker type and one tumor entity. This study aimed to create a multi-analyte liquid biopsy test for the simultaneous detection of several solid [...] Read more.
Liquid biopsy-based tests emerge progressively as an important tool for cancer diagnostics and management. Currently, researchers focus on a single biomarker type and one tumor entity. This study aimed to create a multi-analyte liquid biopsy test for the simultaneous detection of several solid cancers. For this purpose, we analyzed cell-free DNA (cfDNA) mutations and methylation, as well as circulating miRNAs (miRNAs) in plasma samples from 97 patients with cancer (20 bladder, 9 brain, 30 breast, 28 colorectal, 29 lung, 19 ovarian, 12 pancreas, 27 prostate, 23 stomach) and 15 healthy controls via real-time qPCR. Androgen receptor p.H875Y mutation (AR) was detected for the first time in bladder, lung, stomach, ovarian, brain, and pancreas cancer, all together in 51.3% of all cancer samples and in none of the healthy controls. A discriminant function model, comprising cfDNA mutations (COSM10758, COSM18561), cfDNA methylation markers (MLH1, MDR1, GATA5, SFN) and miRNAs (miR-17-5p, miR-20a-5p, miR-21-5p, miR-26a-5p, miR-27a-3p, miR-29c-3p, miR-92a-3p, miR-101-3p, miR-133a-3p, miR-148b-3p, miR-155-5p, miR-195-5p) could further classify healthy and tumor samples with 95.4% accuracy, 97.9% sensitivity, 80% specificity. This multi-analyte liquid biopsy-based test may help improve the simultaneous detection of several cancer types and underlines the importance of combining genetic and epigenetic biomarkers. Full article
(This article belongs to the Special Issue Liquid Nucleic Acid-Based Biomarkers in Solid Tumors)
Show Figures

Graphical abstract

16 pages, 1973 KiB  
Article
Machine Learning Using Real-World and Translational Data to Improve Treatment Selection for NSCLC Patients Treated with Immunotherapy
by Arsela Prelaj, Mattia Boeri, Alessandro Robuschi, Roberto Ferrara, Claudia Proto, Giuseppe Lo Russo, Giulia Galli, Alessandro De Toma, Marta Brambilla, Mario Occhipinti, Sara Manglaviti, Teresa Beninato, Achille Bottiglieri, Giacomo Massa, Emma Zattarin, Rosaria Gallucci, Edoardo Gregorio Galli, Monica Ganzinelli, Gabriella Sozzi, Filippo G. M. de Braud, Marina Chiara Garassino, Marcello Restelli, Alessandra Laura Giulia Pedrocchi and Francesco Trovo'add Show full author list remove Hide full author list
Cancers 2022, 14(2), 435; https://doi.org/10.3390/cancers14020435 - 16 Jan 2022
Cited by 24 | Viewed by 4591
Abstract
(1) Background: In advanced non-small cell lung cancer (aNSCLC), programmed death ligand 1 (PD-L1) remains the only biomarker for candidate patients to immunotherapy (IO). This study aimed at using artificial intelligence (AI) and machine learning (ML) tools to improve response and efficacy predictions [...] Read more.
(1) Background: In advanced non-small cell lung cancer (aNSCLC), programmed death ligand 1 (PD-L1) remains the only biomarker for candidate patients to immunotherapy (IO). This study aimed at using artificial intelligence (AI) and machine learning (ML) tools to improve response and efficacy predictions in aNSCLC patients treated with IO. (2) Methods: Real world data and the blood microRNA signature classifier (MSC) were used. Patients were divided into responders (R) and non-responders (NR) to determine if the overall survival of the patients was likely to be shorter or longer than 24 months from baseline IO. (3) Results: One-hundred sixty-four out of 200 patients (i.e., only those ones with PD-L1 data available) were considered in the model, 73 (44.5%) were R and 91 (55.5%) NR. Overall, the best model was the linear regression (RL) and included 5 features. The model predicting R/NR of patients achieved accuracy ACC = 0.756, F1 score F1 = 0.722, and area under the ROC curve AUC = 0.82. LR was also the best-performing model in predicting patients with long survival (24 months OS), achieving ACC = 0.839, F1 = 0.908, and AUC = 0.87. (4) Conclusions: The results suggest that the integration of multifactorial data provided by ML techniques is a useful tool to select NSCLC patients as candidates for IO. Full article
(This article belongs to the Special Issue Cancer: Advances in T Cell-Based Clinical Immunotherapies)
Show Figures

Figure 1

20 pages, 993 KiB  
Review
STAT3 Signaling in Breast Cancer: Multicellular Actions and Therapeutic Potential
by Sarah Q. To, Rhynelle S. Dmello, Anna K. Richards, Matthias Ernst and Ashwini L. Chand
Cancers 2022, 14(2), 429; https://doi.org/10.3390/cancers14020429 - 15 Jan 2022
Cited by 55 | Viewed by 17495
Abstract
Interleukin (IL)-6 family cytokines, such as IL-6 and IL-11, are defined by the shared use of the gp130 receptor for the downstream activation of STAT3 signaling and the activation of genes which contribute to the “hallmarks of cancer”, including proliferation, survival, invasion and [...] Read more.
Interleukin (IL)-6 family cytokines, such as IL-6 and IL-11, are defined by the shared use of the gp130 receptor for the downstream activation of STAT3 signaling and the activation of genes which contribute to the “hallmarks of cancer”, including proliferation, survival, invasion and metastasis. Increased expression of these cytokines, or the ligand-specific receptors IL-6R and IL-11RA, in breast tumors positively correlate to disease progression and poorer patient outcome. In this review, we examine evidence from pre-clinical studies that correlate enhanced IL-6 and IL-11 mediated gp130/STAT3 signaling to the progression of breast cancer. Key processes by which the IL-6 family cytokines contribute to the heterogeneous nature of breast cancer, immune evasion and metastatic potential, are discussed. We examine the latest research into the therapeutic targeting of IL-6 family cytokines that inhibit STAT3 transcriptional activity as a potential breast cancer treatment, including current clinical trials. The importance of the IL-6 family of cytokines in cellular processes that promote the development and progression of breast cancer warrants further understanding of the molecular basis for its actions to help guide the development of future therapeutic targets. Full article
(This article belongs to the Special Issue Multicellular Effects of STAT3 in the Tumour Microenvironment)
Show Figures

Figure 1

16 pages, 1073 KiB  
Review
The Evolution of Ovarian Carcinoma Subclassification
by Martin Köbel and Eun Young Kang
Cancers 2022, 14(2), 416; https://doi.org/10.3390/cancers14020416 - 14 Jan 2022
Cited by 66 | Viewed by 18743
Abstract
The phenotypically informed histotype classification remains the mainstay of ovarian carcinoma subclassification. Histotypes of ovarian epithelial neoplasms have evolved with each edition of the WHO Classification of Female Genital Tumours. The current fifth edition (2020) lists five principal histotypes: high-grade serous carcinoma (HGSC), [...] Read more.
The phenotypically informed histotype classification remains the mainstay of ovarian carcinoma subclassification. Histotypes of ovarian epithelial neoplasms have evolved with each edition of the WHO Classification of Female Genital Tumours. The current fifth edition (2020) lists five principal histotypes: high-grade serous carcinoma (HGSC), low-grade serous carcinoma (LGSC), mucinous carcinoma (MC), endometrioid carcinoma (EC) and clear cell carcinoma (CCC). Since histotypes arise from different cells of origin, cell lineage-specific diagnostic immunohistochemical markers and histotype-specific oncogenic alterations can confirm the morphological diagnosis. A four-marker immunohistochemical panel (WT1/p53/napsin A/PR) can distinguish the five principal histotypes with high accuracy, and additional immunohistochemical markers can be used depending on the diagnostic considerations. Histotypes are further stratified into molecular subtypes and assessed with predictive biomarker tests. HGSCs have recently been subclassified based on mechanisms of chromosomal instability, mRNA expression profiles or individual candidate biomarkers. ECs are composed of the same molecular subtypes (POLE-mutated/mismatch repair-deficient/no specific molecular profile/p53-abnormal) with the same prognostic stratification as their endometrial counterparts. Although methylation analyses and gene expression and sequencing showed at least two clusters, the molecular subtypes of CCCs remain largely elusive to date. Mutational and immunohistochemical data on LGSC have suggested five molecular subtypes with prognostic differences. While our understanding of the molecular composition of ovarian carcinomas has significantly advanced and continues to evolve, the need for treatment options suitable for these alterations is becoming more obvious. Further preclinical studies using histotype-defined and molecular subtype-characterized model systems are needed to expand the therapeutic spectrum for women diagnosed with ovarian carcinomas. Full article
Show Figures

Figure 1

12 pages, 3312 KiB  
Review
A Breakthrough Brought about by Targeting KRASG12C: Nonconformity Is Punished
by Wenjuan Ning, Zhang Yang, Gregor J. Kocher, Patrick Dorn and Ren-Wang Peng
Cancers 2022, 14(2), 390; https://doi.org/10.3390/cancers14020390 - 13 Jan 2022
Cited by 14 | Viewed by 5072
Abstract
KRAS is the most frequently mutated oncogene in lung carcinomas, accounting for 25% of total incidence, with half of them being KRASG12C mutations. In past decades, KRAS enjoyed the notorious reputation of being untargetable—that is, until the advent of G12C inhibitors, which [...] Read more.
KRAS is the most frequently mutated oncogene in lung carcinomas, accounting for 25% of total incidence, with half of them being KRASG12C mutations. In past decades, KRAS enjoyed the notorious reputation of being untargetable—that is, until the advent of G12C inhibitors, which put an end to this legend by covalently targeting the G12C (glycine to cysteine) substitution in the switch-II pocket of the protein, inhibiting the affinity of the mutant KRAS with GTP and subsequently the downstream signaling pathways, such as Raf/MEK/ERK. KRASG12C-selective inhibitors, e.g., the FDA-approved AMG510 and MRTX849, have demonstrated potent clinical efficacy and selectivity in patients with KRASG12C-driven cancers only, which spares other driver KRAS mutations (e.g., G12D/V/S, G13D, and Q61H) and has ushered in an unprecedented breakthrough in the field in recent decades. However, accumulating evidence from preclinical and clinical studies has shown that G12C-targeted therapeutics as single agents are inevitably thwarted by drug resistance, a persistent problem associated with targeted therapies. A promising strategy to optimize G12C inhibitor therapy is combination treatments with other therapeutic agents, the identification of which is empowered by the insightful appreciation of compensatory signaling pathways or evasive mechanisms, such as those that attenuate immune responses. Here, we review recent advances in targeting KRASG12C and discuss the challenges of KRASG12C inhibitor therapy, as well as future directions. Full article
(This article belongs to the Special Issue Targeting KRAS: Elucidating Mechanisms of Sensitivity and Resistance)
Show Figures

Figure 1

27 pages, 3431 KiB  
Article
The Anti-Proliferative Effect of PI3K/mTOR and ERK Inhibition in Monolayer and Three-Dimensional Ovarian Cancer Cell Models
by Elizabeth Dunn, Kenny Chitcholtan, Peter Sykes and Ashley Garrill
Cancers 2022, 14(2), 395; https://doi.org/10.3390/cancers14020395 - 13 Jan 2022
Cited by 12 | Viewed by 3607
Abstract
Most ovarian cancer patients are diagnosed with advanced stage disease, which becomes unresponsive to chemotherapeutic treatments. The PI3K/AKT/mTOR and the RAS/RAF/MEK/ERK kinase signaling pathways are attractive targets for potential therapeutic inhibitors, due to the high frequency of mutations to PTEN, PIK3CA, KRAS and [...] Read more.
Most ovarian cancer patients are diagnosed with advanced stage disease, which becomes unresponsive to chemotherapeutic treatments. The PI3K/AKT/mTOR and the RAS/RAF/MEK/ERK kinase signaling pathways are attractive targets for potential therapeutic inhibitors, due to the high frequency of mutations to PTEN, PIK3CA, KRAS and BRAF in several ovarian cancer subtypes. However, monotherapies targeting one of these pathways have shown modest effects in clinical trials. This limited efficacy of the agents could be due to upregulation and increased signaling via the adjacent alternative pathway. In this study, the efficacy of combined PI3K/mTOR (BEZ235) and ERK inhibition (SCH772984) was investigated in four human ovarian cancer cell lines, grown as monolayer and three-dimensional cell aggregates. The inhibitor combination reduced cellular proliferation in a synergistic manner in OV-90 and OVCAR8 monolayers and in OV-90, OVCAR5 and SKOV3 aggregates. Sensitivity to the inhibitors was reduced in three-dimensional cell aggregates in comparison to monolayers. OV-90 cells cultured in large spheroids were sensitive to the inhibitors and displayed a robust synergistic antiproliferative response to the inhibitor combination. In contrast, OVCAR8 spheroids were resistant to the inhibitors. These findings suggest that combined PI3K/mTOR and ERK inhibition could be a useful strategy for overcoming treatment resistance in ovarian cancer and warrants further preclinical investigation. Additionally, in some cell lines the use of different three-dimensional models can influence cell line sensitivity to PI3K/mTOR and RAS/RAF/MEK/ERK pathway inhibitors. Full article
(This article belongs to the Special Issue Three-Dimensional Culture Systems in Cancer Research)
Show Figures

Figure 1

26 pages, 3675 KiB  
Review
Clinical Significance and Regulation of ERK5 Expression and Function in Cancer
by Matilde Monti, Jacopo Celli, Francesco Missale, Francesca Cersosimo, Mariapia Russo, Elisa Belloni, Anna Di Matteo, Silvia Lonardi, William Vermi, Claudia Ghigna and Emanuele Giurisato
Cancers 2022, 14(2), 348; https://doi.org/10.3390/cancers14020348 - 11 Jan 2022
Cited by 21 | Viewed by 5952
Abstract
Extracellular signal-regulated kinase 5 (ERK5) is a unique kinase among MAPKs family members, given its large structure characterized by the presence of a unique C-terminal domain. Despite increasing data demonstrating the relevance of the ERK5 pathway in the growth, survival, and differentiation of [...] Read more.
Extracellular signal-regulated kinase 5 (ERK5) is a unique kinase among MAPKs family members, given its large structure characterized by the presence of a unique C-terminal domain. Despite increasing data demonstrating the relevance of the ERK5 pathway in the growth, survival, and differentiation of normal cells, ERK5 has recently attracted the attention of several research groups given its relevance in inflammatory disorders and cancer. Accumulating evidence reported its role in tumor initiation and progression. In this review, we explore the gene expression profile of ERK5 among cancers correlated with its clinical impact, as well as the prognostic value of ERK5 and pERK5 expression levels in tumors. We also summarize the importance of ERK5 in the maintenance of a cancer stem-like phenotype and explore the major known contributions of ERK5 in the tumor-associated microenvironment. Moreover, although several questions are still open concerning ERK5 molecular regulation, different ERK5 isoforms derived from the alternative splicing process are also described, highlighting the potential clinical relevance of targeting ERK5 pathways. Full article
Show Figures

Figure 1

34 pages, 1631 KiB  
Review
Pathophysiological Integration of Metabolic Reprogramming in Breast Cancer
by Roberto Corchado-Cobos, Natalia García-Sancha, Marina Mendiburu-Eliçabe, Aurora Gómez-Vecino, Alejandro Jiménez-Navas, Manuel Jesús Pérez-Baena, Marina Holgado-Madruga, Jian-Hua Mao, Javier Cañueto, Sonia Castillo-Lluva and Jesús Pérez-Losada
Cancers 2022, 14(2), 322; https://doi.org/10.3390/cancers14020322 - 10 Jan 2022
Cited by 17 | Viewed by 5898
Abstract
Metabolic changes that facilitate tumor growth are one of the hallmarks of cancer. The triggers of these metabolic changes are located in the tumor parenchymal cells, where oncogenic mutations induce an imperative need to proliferate and cause tumor initiation and progression. Cancer cells [...] Read more.
Metabolic changes that facilitate tumor growth are one of the hallmarks of cancer. The triggers of these metabolic changes are located in the tumor parenchymal cells, where oncogenic mutations induce an imperative need to proliferate and cause tumor initiation and progression. Cancer cells undergo significant metabolic reorganization during disease progression that is tailored to their energy demands and fluctuating environmental conditions. Oxidative stress plays an essential role as a trigger under such conditions. These metabolic changes are the consequence of the interaction between tumor cells and stromal myofibroblasts. The metabolic changes in tumor cells include protein anabolism and the synthesis of cell membranes and nucleic acids, which all facilitate cell proliferation. They are linked to catabolism and autophagy in stromal myofibroblasts, causing the release of nutrients for the cells of the tumor parenchyma. Metabolic changes lead to an interstitium deficient in nutrients, such as glucose and amino acids, and acidification by lactic acid. Together with hypoxia, they produce functional changes in other cells of the tumor stroma, such as many immune subpopulations and endothelial cells, which lead to tumor growth. Thus, immune cells favor tissue growth through changes in immunosuppression. This review considers some of the metabolic changes described in breast cancer. Full article
(This article belongs to the Special Issue Understanding and Modelling Metabolic Reprogramming in Breast Cancer)
Show Figures

Figure 1

20 pages, 4654 KiB  
Article
Metabolomic Phenotyping of Gliomas: What Can We Get with Simplified Protocol for Intact Tissue Analysis?
by Paulina Zofia Goryńska, Kamila Chmara, Bogumiła Kupcewicz, Krzysztof Goryński, Karol Jaroch, Dariusz Paczkowski, Jacek Furtak, Marek Harat and Barbara Bojko
Cancers 2022, 14(2), 312; https://doi.org/10.3390/cancers14020312 - 9 Jan 2022
Cited by 11 | Viewed by 3185
Abstract
Glioblastoma multiforme is one of the most malignant neoplasms among humans in their third and fourth decades of life, which is evidenced by short patient survival times and rapid tumor-cell proliferation after radiation and chemotherapy. At present, the diagnosis of gliomas and decisions [...] Read more.
Glioblastoma multiforme is one of the most malignant neoplasms among humans in their third and fourth decades of life, which is evidenced by short patient survival times and rapid tumor-cell proliferation after radiation and chemotherapy. At present, the diagnosis of gliomas and decisions related to therapeutic strategies are based on genetic testing and histological analysis of the tumor, with molecular biomarkers still being sought to complement the diagnostic panel. This work aims to enable the metabolomic characterization of cancer tissue and the discovery of potential biomarkers via high-resolution mass spectrometry coupled to liquid chromatography and a solvent-free sampling protocol that uses a microprobe to extract metabolites directly from intact tumors. The metabolomic analyses were performed independently from genetic and histological testing and at a later time. Despite the small cohort analyzed in this study, the results indicated that the proposed method is able to identify metabolites associated with different malignancy grades of glioma, as well as IDH and 1p19q codeletion mutations. A comparison of the constellation of identified metabolites and the results of standard tests indicated the validity of using the characterization of one comprehensive tumor phenotype as a reflection of all diagnostically meaningful information. Due to its simplicity, the proposed analytical approach was verified as being compatible with a surgical environment and applicable for large-scale studies. Full article
Show Figures

Figure 1

12 pages, 2379 KiB  
Review
Hyperthermia: A Potential Game-Changer in the Management of Cancers in Low-Middle-Income Group Countries
by Niloy R. Datta, Bharati M. Jain, Zatin Mathi, Sneha Datta, Satyendra Johari, Ashok R. Singh, Pallavi Kalbande, Pournima Kale, Vitaladevuni Shivkumar and Stephan Bodis
Cancers 2022, 14(2), 315; https://doi.org/10.3390/cancers14020315 - 9 Jan 2022
Cited by 22 | Viewed by 3960
Abstract
Loco-regional hyperthermia at 40–44 °C is a multifaceted therapeutic modality with the distinct triple advantage of being a potent radiosensitizer, a chemosensitizer and an immunomodulator. Risk difference estimates from pairwise meta-analysis have shown that the local tumour control could be improved by 22.3% [...] Read more.
Loco-regional hyperthermia at 40–44 °C is a multifaceted therapeutic modality with the distinct triple advantage of being a potent radiosensitizer, a chemosensitizer and an immunomodulator. Risk difference estimates from pairwise meta-analysis have shown that the local tumour control could be improved by 22.3% (p < 0.001), 22.1% (p < 0.001) and 25.5% (p < 0.001) in recurrent breast cancers, locally advanced cervix cancer (LACC) and locally advanced head and neck cancers, respectively by adding hyperthermia to radiotherapy over radiotherapy alone. Furthermore, thermochemoradiotherapy in LACC have shown to reduce the local failure rates by 10.1% (p = 0.03) and decrease deaths by 5.6% (95% CI: 0.6–11.8%) over chemoradiotherapy alone. As around one-third of the cancer cases in low-middle-income group countries belong to breast, cervix and head and neck regions, hyperthermia could be a potential game-changer and expected to augment the clinical outcomes of these patients in conjunction with radiotherapy and/or chemotherapy. Further, hyperthermia could also be a cost-effective therapeutic modality as the capital costs for setting up a hyperthermia facility is relatively low. Thus, the positive outcomes evident from various phase III randomized trials and meta-analysis with thermoradiotherapy or thermochemoradiotherapy justifies the integration of hyperthermia in the therapeutic armamentarium of clinical management of cancer, especially in low-middle-income group countries. Full article
Show Figures

Figure 1

19 pages, 1309 KiB  
Review
The Implementation of TNFRSF Co-Stimulatory Domains in CAR-T Cells for Optimal Functional Activity
by Yuan He, Martijn Vlaming, Tom van Meerten and Edwin Bremer
Cancers 2022, 14(2), 299; https://doi.org/10.3390/cancers14020299 - 8 Jan 2022
Cited by 26 | Viewed by 6827
Abstract
The Tumor Necrosis Factor Receptor Superfamily (TNFRSF) is a large and important immunoregulatory family that provides crucial co-stimulatory signals to many if not all immune effector cells. Each co-stimulatory TNFRSF member has a distinct expression profile and a unique functional impact on various [...] Read more.
The Tumor Necrosis Factor Receptor Superfamily (TNFRSF) is a large and important immunoregulatory family that provides crucial co-stimulatory signals to many if not all immune effector cells. Each co-stimulatory TNFRSF member has a distinct expression profile and a unique functional impact on various types of cells and at different stages of the immune response. Correspondingly, exploiting TNFRSF-mediated signaling for cancer immunotherapy has been a major field of interest, with various therapeutic TNFRSF-exploiting anti-cancer approaches such as 4-1BB and CD27 agonistic antibodies being evaluated (pre)clinically. A further application of TNFRSF signaling is the incorporation of the intracellular co-stimulatory domain of a TNFRSF into so-called Chimeric Antigen Receptor (CAR) constructs for CAR-T cell therapy, the most prominent example of which is the 4-1BB co-stimulatory domain included in the clinically approved product Kymriah. In fact, CAR-T cell function can be clearly influenced by the unique co-stimulatory features of members of the TNFRSF. Here, we review a select group of TNFRSF members (4-1BB, OX40, CD27, CD40, HVEM, and GITR) that have gained prominence as co-stimulatory domains in CAR-T cell therapy and illustrate the unique features that each confers to CAR-T cells. Full article
Show Figures

Figure 1

20 pages, 4267 KiB  
Article
PRMT1 Regulates EGFR and Wnt Signaling Pathways and Is a Promising Target for Combinatorial Treatment of Breast Cancer
by Samyuktha Suresh, Solène Huard, Amélie Brisson, Fariba Némati, Rayan Dakroub, Coralie Poulard, Mengliang Ye, Elise Martel, Cécile Reyes, David C. Silvestre, Didier Meseure, André Nicolas, David Gentien, Hussein Fayyad-Kazan, Muriel Le Romancer, Didier Decaudin, Sergio Roman-Roman and Thierry Dubois
Cancers 2022, 14(2), 306; https://doi.org/10.3390/cancers14020306 - 8 Jan 2022
Cited by 24 | Viewed by 4695
Abstract
Identifying new therapeutic strategies for triple-negative breast cancer (TNBC) patients is a priority as these patients are highly prone to relapse after chemotherapy. Here, we found that protein arginine methyltransferase 1 (PRMT1) is highly expressed in all breast cancer subtypes. PRMT1 depletion decreases [...] Read more.
Identifying new therapeutic strategies for triple-negative breast cancer (TNBC) patients is a priority as these patients are highly prone to relapse after chemotherapy. Here, we found that protein arginine methyltransferase 1 (PRMT1) is highly expressed in all breast cancer subtypes. PRMT1 depletion decreases cell survival by inducing DNA damage and apoptosis in various breast cancer cell lines. Transcriptomic analysis and chromatin immunoprecipitation revealed that PRMT1 regulates the epidermal growth factor receptor (EGFR) and the Wnt signaling pathways, reported to be activated in TNBC. PRMT1 enzymatic activity is also required to stimulate the canonical Wnt pathway. Type I PRMT inhibitors decrease breast cancer cell proliferation and show anti-tumor activity in a TNBC xenograft model. These inhibitors display synergistic interactions with some chemotherapies used to treat TNBC patients as well as erlotinib, an EGFR inhibitor. Therefore, targeting PRMT1 in combination with these chemotherapies may improve existing treatments for TNBC patients. Full article
(This article belongs to the Section Cancer Therapy)
Show Figures

Figure 1

17 pages, 596 KiB  
Review
Programmed Death-Ligand 1 (PD-L1) as Immunotherapy Biomarker in Breast Cancer
by Martín Núñez Abad, Silvia Calabuig-Fariñas, Miriam Lobo de Mena, Susana Torres-Martínez, Clara García González, José Ángel García García, Vega Iranzo González-Cruz and Carlos Camps Herrero
Cancers 2022, 14(2), 307; https://doi.org/10.3390/cancers14020307 - 8 Jan 2022
Cited by 48 | Viewed by 8099
Abstract
Breast cancer constitutes the most common malignant neoplasm in women around the world. Approximately 12% of patients are diagnosed with metastatic stage, and between 5 and 30% of early or locally advanced BC patients will relapse, making it an incurable disease. PD-L1 ligation [...] Read more.
Breast cancer constitutes the most common malignant neoplasm in women around the world. Approximately 12% of patients are diagnosed with metastatic stage, and between 5 and 30% of early or locally advanced BC patients will relapse, making it an incurable disease. PD-L1 ligation is an immune inhibitory molecule of the activation of T cells, playing a relevant role in numerous types of malignant tumors, including BC. The objective of the present review is to analyze the role of PD-L1 as a biomarker in the different BC subtypes, adding clinical trials with immune checkpoint inhibitors and their applicable results. Diverse trials using immunotherapy with anti-PD-1/PD-L1 in BC, as well as prospective or retrospective cohort studies about PD-L1 in BC, were included. Despite divergent results in the reviewed studies, PD-L1 seems to be correlated with worse prognosis in the hormone receptor positive subtype. Immune checkpoints inhibitors targeting the PD-1/PD-L1 axis have achieved great response rates in TNBC patients, especially in combination with chemotherapy, making immunotherapy a new treatment option in this scenario. However, the utility of PD-L1 as a predictive biomarker in the rest of BC subtypes remains unclear. In addition, predictive differences have been found in response to immunotherapy depending on the stage of the tumor disease. Therefore, a better understanding of tumor microenvironment, as well as identifying new potential biomarkers or combined index scores, is necessary in order to make a better selection of the subgroups of BC patients who will derive benefit from immune checkpoint inhibitors. Full article
(This article belongs to the Special Issue Advances in Breast Cancer Research: From Biology to Pathology)
Show Figures

Figure 1

24 pages, 2675 KiB  
Review
Dynamic Cancer Cell Heterogeneity: Diagnostic and Therapeutic Implications
by Valerie Jacquemin, Mathieu Antoine, Geneviève Dom, Vincent Detours, Carine Maenhaut and Jacques E. Dumont
Cancers 2022, 14(2), 280; https://doi.org/10.3390/cancers14020280 - 7 Jan 2022
Cited by 39 | Viewed by 9292
Abstract
Though heterogeneity of cancers is recognized and has been much discussed in recent years, the concept often remains overlooked in different routine examinations. Indeed, in clinical or biological articles, reviews, and textbooks, cancers and cancer cells are generally presented as evolving distinct entities [...] Read more.
Though heterogeneity of cancers is recognized and has been much discussed in recent years, the concept often remains overlooked in different routine examinations. Indeed, in clinical or biological articles, reviews, and textbooks, cancers and cancer cells are generally presented as evolving distinct entities rather than as an independent heterogeneous cooperative cell population with its self-oriented biology. There are, therefore, conceptual gaps which can mislead the interpretations/diagnostic and therapeutic approaches. In this short review, we wish to summarize and discuss various aspects of this dynamic evolving heterogeneity and its biological, pathological, clinical, diagnostic, and therapeutic implications, using thyroid carcinoma as an illustrative example. Full article
Show Figures

Figure 1

21 pages, 2241 KiB  
Article
ATX-101, a Peptide Targeting PCNA, Has Antitumor Efficacy Alone or in Combination with Radiotherapy in Murine Models of Human Glioblastoma
by Giovanni Luca Gravina, Alessandro Colapietro, Andrea Mancini, Alessandra Rossetti, Stefano Martellucci, Luca Ventura, Martina Di Franco, Francesco Marampon, Vincenzo Mattei, Leda Assunta Biordi, Marit Otterlei and Claudio Festuccia
Cancers 2022, 14(2), 289; https://doi.org/10.3390/cancers14020289 - 7 Jan 2022
Cited by 24 | Viewed by 3824
Abstract
Cell proliferation requires the orchestrated actions of a myriad of proteins regulating DNA replication, DNA repair and damage tolerance, and cell cycle. Proliferating cell nuclear antigen (PCNA) is a master regulator which interacts with multiple proteins functioning in these processes, and this makes [...] Read more.
Cell proliferation requires the orchestrated actions of a myriad of proteins regulating DNA replication, DNA repair and damage tolerance, and cell cycle. Proliferating cell nuclear antigen (PCNA) is a master regulator which interacts with multiple proteins functioning in these processes, and this makes PCNA an attractive target in anticancer therapies. Here, we show that a cell-penetrating peptide containing the AlkB homolog 2 PCNA-interacting motif (APIM), ATX-101, has antitumor activity in a panel of human glioblastoma multiforme (GBM) cell lines and patient-derived glioma-initiating cells (GICs). Their sensitivity to ATX-101 was not related to cellular levels of PCNA, or p53, PTEN, or MGMT status. However, ATX-101 reduced Akt/mTOR and DNA-PKcs signaling, and a correlation between high Akt activation and sensitivity for ATX-101 was found. ATX-101 increased the levels of γH2AX, DNA fragmentation, and apoptosis when combined with radiotherapy (RT). In line with the in vitro results, ATX-101 strongly reduced tumor growth in two subcutaneous xenografts and two orthotopic GBM models, both as a single agent and in combination with RT. The ability of ATX-101 to sensitize cells to RT is promising for further development of this compound for use in GBM. Full article
Show Figures

Figure 1

20 pages, 3735 KiB  
Review
Potential Role of CXCL13/CXCR5 Signaling in Immune Checkpoint Inhibitor Treatment in Cancer
by Ching-Hung Hsieh, Cheng-Zhe Jian, Liang-In Lin, Guan-Sian Low, Ping-Yun Ou, Chiun Hsu and Da-Liang Ou
Cancers 2022, 14(2), 294; https://doi.org/10.3390/cancers14020294 - 7 Jan 2022
Cited by 44 | Viewed by 8996
Abstract
Immune checkpoint inhibitors (ICIs), including antibodies that target programmed cell death protein 1 (PD-1), programmed death-ligand 1 (PD-L1), or cytotoxic T lymphocyte antigen 4 (CTLA4), represent some of the most important breakthroughs in new drug development for oncology therapy from the past decade. [...] Read more.
Immune checkpoint inhibitors (ICIs), including antibodies that target programmed cell death protein 1 (PD-1), programmed death-ligand 1 (PD-L1), or cytotoxic T lymphocyte antigen 4 (CTLA4), represent some of the most important breakthroughs in new drug development for oncology therapy from the past decade. CXC chemokine ligand 13 (CXCL13) exclusively binds CXC chemokine receptor type 5 (CXCR5), which plays a critical role in immune cell recruitment and activation and the regulation of the adaptive immune response. CXCL13 is a key molecular determinant of the formation of tertiary lymphoid structures (TLSs), which are organized aggregates of T, B, and dendritic cells that participate in the adaptive antitumor immune response. CXCL13 may also serve as a prognostic and predictive factor, and the role played by CXCL13 in some ICI-responsive tumor types has gained intense interest. This review discusses how CXCL13/CXCR5 signaling modulates cancer and immune cells to promote lymphocyte infiltration, activation by tumor antigens, and differentiation to increase the antitumor immune response. We also summarize recent preclinical and clinical evidence regarding the ICI-therapeutic implications of targeting the CXCL13/CXCR5 axis and discuss the potential role of this signaling pathway in cancer immunotherapy. Full article
(This article belongs to the Special Issue Emerging Roles of Chemokines in Cancer Immunotherapy)
Show Figures

Figure 1

39 pages, 7132 KiB  
Review
The Renaissance of Cyclin Dependent Kinase Inhibitors
by Tobias Ettl, Daniela Schulz and Richard Josef Bauer
Cancers 2022, 14(2), 293; https://doi.org/10.3390/cancers14020293 - 7 Jan 2022
Cited by 47 | Viewed by 11760
Abstract
Cyclin-dependent kinases (CDK) regulate cell cycle progression. During tumor development, altered expression and availability of CDKs strongly contribute to impaired cell proliferation, a hallmark of cancer. In recent years, targeted inhibition of CDKs has shown considerable therapeutic benefit in a variety of tumor [...] Read more.
Cyclin-dependent kinases (CDK) regulate cell cycle progression. During tumor development, altered expression and availability of CDKs strongly contribute to impaired cell proliferation, a hallmark of cancer. In recent years, targeted inhibition of CDKs has shown considerable therapeutic benefit in a variety of tumor entities. Their success is reflected in clinical approvals of specific CDK4/6 inhibitors for breast cancer. This review provides a detailed insight into the molecular mechanisms of CDKs as well as a general overview of CDK inhibition. It also summarizes the latest research approaches and current advances in the treatment of head and neck cancer with CDK inhibitors. Instead of monotherapies, combination therapies with CDK inhibitors may especially provide promising results in tumor therapy. Indeed, recent studies have shown a synergistic effect of CDK inhibition together with chemo- and radio- and immunotherapy in cancer treatment to overcome tumor evasion, which may lead to a renaissance of CDK inhibitors. Full article
(This article belongs to the Special Issue The Renaissance of CDK Inhibition in Cancer Therapy)
Show Figures

Figure 1

22 pages, 7485 KiB  
Article
Onco-miR-21 Promotes Stat3-Dependent Gastric Cancer Progression
by Janson Tse, Thomas Pierce, Annalisa L. E. Carli, Mariah G. Alorro, Stefan Thiem, Eric G. Marcusson, Matthias Ernst and Michael Buchert
Cancers 2022, 14(2), 264; https://doi.org/10.3390/cancers14020264 - 6 Jan 2022
Cited by 26 | Viewed by 3298
Abstract
MicroRNA-21 (miR-21) is a small, non-coding RNA overexpressed in gastric cancer and many other solid malignancies, where it exhibits both pro-and anti-tumourigenic properties. However, the pathways regulating miR-21 and the consequences of its inhibition in gastric cancer remain incompletely understood. By exploiting the [...] Read more.
MicroRNA-21 (miR-21) is a small, non-coding RNA overexpressed in gastric cancer and many other solid malignancies, where it exhibits both pro-and anti-tumourigenic properties. However, the pathways regulating miR-21 and the consequences of its inhibition in gastric cancer remain incompletely understood. By exploiting the spontaneous Stat3-dependent formation of inflammation-associated gastric tumors in Gp130F/F mice, we functionally established miR-21 as a Stat3-controlled driver of tumor growth and progression. We reconciled our discoveries by identifying several conserved Stat3 binding motifs upstream of the miR-21 gene promoter, and showed that the systemic administration of a miR-21-specific antisense oligonucleotide antagomir reduced the established gastric tumor burden in Gp130F/F mice. We molecularly delineated the therapeutic benefits of miR-21 inhibition with the functional restoration of PTEN in vitro and in vivo, alongside an attenuated epithelial-to-mesenchymal transition and the extracellular matrix remodeling phenotype of tumors. We corroborated our preclinical findings by correlating high STAT3 and miR-21 expression with the reduced survival probability of gastric cancer patients. Collectively, our results provide a molecular framework by which miR-21 mediates inflammation-associated gastric cancer progression, and establish miR-21 as a robust therapeutic target for solid malignancies characterized by excessive Stat3 activity. Full article
(This article belongs to the Special Issue Multicellular Effects of STAT3 in the Tumour Microenvironment)
Show Figures

Figure 1

17 pages, 4020 KiB  
Article
Upregulation of CD36, a Fatty Acid Translocase, Promotes Colorectal Cancer Metastasis by Increasing MMP28 and Decreasing E-Cadherin Expression
by James Drury, Piotr G. Rychahou, Courtney O. Kelson, Mariah E. Geisen, Yuanyuan Wu, Daheng He, Chi Wang, Eun Y. Lee, B. Mark Evers and Yekaterina Y. Zaytseva
Cancers 2022, 14(1), 252; https://doi.org/10.3390/cancers14010252 - 5 Jan 2022
Cited by 40 | Viewed by 6729
Abstract
Altered fatty acid metabolism continues to be an attractive target for therapeutic intervention in cancer. We previously found that colorectal cancer (CRC) cells with a higher metastatic potential express a higher level of fatty acid translocase (CD36). However, the role of CD36 in [...] Read more.
Altered fatty acid metabolism continues to be an attractive target for therapeutic intervention in cancer. We previously found that colorectal cancer (CRC) cells with a higher metastatic potential express a higher level of fatty acid translocase (CD36). However, the role of CD36 in CRC metastasis has not been studied. Here, we demonstrate that high expression of CD36 promotes invasion of CRC cells. Consistently, CD36 promoted lung metastasis in the tail vein model and GI metastasis in the cecum injection model. RNA-Seq analysis of CRC cells with altered expression of CD36 revealed an association between high expression of CD36 and upregulation of MMP28, a novel member of the metallopeptidase family of proteins. Using shRNA-mediated knockdown and overexpression of CD36, we confirmed that CD36 regulates MMP28 expression in CRC cells. siRNA-mediated knockdown of MMP28 decreases invasion of CRC cells, suggesting that MMP28 regulates the metastatic properties of cells downstream of CD36. Importantly, high expression of MMP28 leads to a significant decrease in active E-cadherin and an increase in the products of E-cadherin cleavage, CTF1 and CTF2. In summary, upregulation of CD36 expression promotes the metastatic properties of CRC via upregulation of MMP28 and an increase in E-cadherin cleavage, suggesting that targeting the CD36–MMP28 axis may be an effective therapeutic strategy for CRC metastasis. Full article
(This article belongs to the Special Issue Insight into Fatty Acid Metabolism in Colorectal Cancer)
Show Figures

Figure 1

26 pages, 1734 KiB  
Review
Harnessing Antitumor CD4+ T Cells for Cancer Immunotherapy
by Myriam Ben Khelil, Yann Godet, Syrine Abdeljaoued, Christophe Borg, Olivier Adotévi and Romain Loyon
Cancers 2022, 14(1), 260; https://doi.org/10.3390/cancers14010260 - 5 Jan 2022
Cited by 44 | Viewed by 9074
Abstract
Over the past decades, CD4+ T cells have been considered as a supporting actor in the fields of cancer immunotherapy. Until recently, accumulating evidence has demonstrated the critical role of CD4+ T cells during antitumor immunity. CD4+ T cells can [...] Read more.
Over the past decades, CD4+ T cells have been considered as a supporting actor in the fields of cancer immunotherapy. Until recently, accumulating evidence has demonstrated the critical role of CD4+ T cells during antitumor immunity. CD4+ T cells can either suppress or promote the antitumor cytotoxic CD8+ T cell responses, either in secondary lymphoid organs or in the tumor. In this review, we provide an overview of the multifaceted role of different CD4+ T cell subsets in cancer immune response and their contribution during cancer therapies. Specifically, we focus on the latest progress regarding the impact of CD4+ T cell modulation on immunotherapies and other cancer therapies and discuss the prospect for harnessing CD4+ T cells to control tumor progression and prevent recurrence in patients. Full article
(This article belongs to the Special Issue CD4 T Cells and Cancer Immune Response)
Show Figures

Figure 1

13 pages, 2379 KiB  
Article
Delta-Radiomics Predicts Response to First-Line Oxaliplatin-Based Chemotherapy in Colorectal Cancer Patients with Liver Metastases
by Valentina Giannini, Laura Pusceddu, Arianna Defeudis, Giulia Nicoletti, Giovanni Cappello, Simone Mazzetti, Andrea Sartore-Bianchi, Salvatore Siena, Angelo Vanzulli, Francesco Rizzetto, Elisabetta Fenocchio, Luca Lazzari, Alberto Bardelli, Silvia Marsoni and Daniele Regge
Cancers 2022, 14(1), 241; https://doi.org/10.3390/cancers14010241 - 4 Jan 2022
Cited by 30 | Viewed by 7265
Abstract
The purpose of this paper is to develop and validate a delta-radiomics score to predict the response of individual colorectal cancer liver metastases (lmCRC) to first-line FOLFOX chemotherapy. Three hundred one lmCRC were manually segmented on both CT performed at baseline and after [...] Read more.
The purpose of this paper is to develop and validate a delta-radiomics score to predict the response of individual colorectal cancer liver metastases (lmCRC) to first-line FOLFOX chemotherapy. Three hundred one lmCRC were manually segmented on both CT performed at baseline and after the first cycle of first-line FOLFOX, and 107 radiomics features were computed by subtracting textural features of CT at baseline from those at timepoint 1 (TP1). LmCRC were classified as nonresponders (R−) if they showed progression of disease (PD), according to RECIST1.1, before 8 months, and as responders (R+), otherwise. After feature selection, we developed a decision tree statistical model trained using all lmCRC coming from one hospital. The final output was a delta-radiomics signature subsequently validated on an external dataset. Sensitivity, specificity, positive (PPV), and negative (NPV) predictive values in correctly classifying individual lesions were assessed on both datasets. Per-lesion sensitivity, specificity, PPV, and NPV were 99%, 94%, 95%, 99%, 85%, 92%, 90%, and 87%, respectively, in the training and validation datasets. The delta-radiomics signature was able to reliably predict R− lmCRC, which were wrongly classified by lesion RECIST as R+ at TP1, (93%, averaging training and validation set, versus 67% of RECIST). The delta-radiomics signature developed in this study can reliably predict the response of individual lmCRC to oxaliplatin-based chemotherapy. Lesions forecasted as poor or nonresponders by the signature could be further investigated, potentially paving the way to lesion-specific therapies. Full article
(This article belongs to the Collection Artificial Intelligence in Oncology)
Show Figures

Figure 1

14 pages, 1475 KiB  
Review
Fatty Acid Metabolism in Myeloid-Derived Suppressor Cells and Tumor-Associated Macrophages: Key Factor in Cancer Immune Evasion
by Sophiya Siddiqui and Rainer Glauben
Cancers 2022, 14(1), 250; https://doi.org/10.3390/cancers14010250 - 4 Jan 2022
Cited by 26 | Viewed by 5356
Abstract
The tumor microenvironment (TME) comprises various cell types, soluble factors, viz, metabolites or cytokines, which together play in promoting tumor metastasis. Tumor infiltrating immune cells play an important role against cancer, and metabolic switching in immune cells has been shown to affect activation, [...] Read more.
The tumor microenvironment (TME) comprises various cell types, soluble factors, viz, metabolites or cytokines, which together play in promoting tumor metastasis. Tumor infiltrating immune cells play an important role against cancer, and metabolic switching in immune cells has been shown to affect activation, differentiation, and polarization from tumor suppressive into immune suppressive phenotypes. Macrophages represent one of the major immune infiltrates into TME. Blood monocyte-derived macrophages and myeloid derived suppressor cells (MDSCs) infiltrating into the TME potentiate hostile tumor progression by polarizing into immunosuppressive tumor-associated macrophages (TAMs). Recent studies in the field of immunometabolism focus on metabolic reprogramming at the TME in polarizing tumor-associated macrophages (TAMs). Lipid droplets (LD), detected in almost every eukaryotic cell type, represent the major source for intra-cellular fatty acids. Previously, LDs were mainly described as storage sites for fatty acids. However, LDs are now recognized to play an integral role in cellular signaling and consequently in inflammation and metabolism-mediated phenotypical changes in immune cells. In recent years, the role of LD dependent metabolism in macrophage functionality and phenotype has been being investigated. In this review article, we discuss fatty acids stored in LDs, their role in modulating metabolism of tumor-infiltrating immune cells and, therefore, in shaping the cancer progression. Full article
(This article belongs to the Special Issue Epigenetic and Metabolic Alterations in the Tumor Microenvironment)
Show Figures

Figure 1

16 pages, 524 KiB  
Review
The Impact of Biomarkers in Pancreatic Ductal Adenocarcinoma on Diagnosis, Surveillance and Therapy
by Niklas Sturm, Thomas J. Ettrich and Lukas Perkhofer
Cancers 2022, 14(1), 217; https://doi.org/10.3390/cancers14010217 - 3 Jan 2022
Cited by 37 | Viewed by 4920
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is still difficult to treat due to insufficient methods for early diagnosis and prediction of therapy response. Furthermore, surveillance after curatively intended surgery lacks adequate methods for timely detection of recurrence. Therefore, several molecules have been analyzed as predictors [...] Read more.
Pancreatic ductal adenocarcinoma (PDAC) is still difficult to treat due to insufficient methods for early diagnosis and prediction of therapy response. Furthermore, surveillance after curatively intended surgery lacks adequate methods for timely detection of recurrence. Therefore, several molecules have been analyzed as predictors of recurrence or early detection of PDAC. Enhanced understanding of molecular tumorigenesis and treatment response triggered the identification of novel biomarkers as predictors for response to conventional chemotherapy or targeted therapy. In conclusion, progress has been made especially in the prediction of therapy response with biomarkers. The use of molecules for early detection and recurrence of PDAC is still at an early stage, but there are promising approaches in noninvasive biomarkers, composite panels and scores that can already ameliorate the current clinical practice. The present review summarizes the current state of research on biomarkers for diagnosis and therapy of pancreatic cancer. Full article
Show Figures

Figure 1

15 pages, 3727 KiB  
Article
Phototheranostics of Cervical Neoplasms with Chlorin e6 Photosensitizer
by Aida Gilyadova, Anton Ishchenko, Artem Shiryaev, Polina Alekseeva, Kanamat Efendiev, Radmila Karpova, Maxim Loshchenov, Victor Loschenov and Igor Reshetov
Cancers 2022, 14(1), 211; https://doi.org/10.3390/cancers14010211 - 2 Jan 2022
Cited by 20 | Viewed by 4498
Abstract
(1) Purpose: Improving the treatment effectiveness of intraepithelial neoplasia of the cervix associated with human papillomavirus infection, based on the application of the method of photodynamic therapy with simultaneous laser excitation of fluorescence to clarify the boundaries of cervical neoplasms. (2) Methods: Examination [...] Read more.
(1) Purpose: Improving the treatment effectiveness of intraepithelial neoplasia of the cervix associated with human papillomavirus infection, based on the application of the method of photodynamic therapy with simultaneous laser excitation of fluorescence to clarify the boundaries of cervical neoplasms. (2) Methods: Examination and treatment of 52 patients aged 22 to 53 years with morphologically and cytologically confirmed mild to severe intraepithelial cervix neoplasia, preinvasive, micro-invasive, and squamous cell cervix carcinoma. All patients were carriers of human papillomavirus infection. The patients underwent photodynamic therapy with simultaneous laser excitation of fluorescence. The combined use of video and spectral fluorescence diagnostics for cervical neoplasms made it possible to control the photodynamic therapy process at all stages of the procedure. Evaluation of the photodynamic therapy of intraepithelial cervical neoplasms was carried out with colposcopic examination, cytological conclusion, and morphological verification of the biopsy material after the photodynamic therapy course. The success of human papillomavirus therapy was assessed based on the results of the polymerase chain reaction. (3) Results. The possibility of simultaneous spectral fluorescence diagnostics and photodynamic therapy using a laser source with a wavelength of 660 nm has been established, making it possible to assess the fluorescence index in real-time and control the photobleaching of photosensitizers in the irradiated area. The treatment of all 52 patients was successful after the first photodynamic therapy procedure. According to the PCR test of the discharge from the cervical canal, the previously identified HPV types were not observed in 48 patients. Previously identified HPV types were absent after repeated PDT in four patients (CIN III (n = 2), CIS (n = 2)). In 80.8% of patients, regression of the lesion was noted. (4) Conclusions. The high efficiency of photodynamic therapy with intravenous photosensitizer administration of chlorin e6 has been demonstrated both in relation to eradication therapy of human papillomavirus and in relation to the treatment of intraepithelial lesions of the cervix. Full article
(This article belongs to the Special Issue Innovative Cancer Treatments and Photodynamic Therapy)
Show Figures

Figure 1

18 pages, 3590 KiB  
Article
Combining an Autophagy Inhibitor, MPT0L145, with Abemaciclib Is a New Therapeutic Strategy in GBM Treatment
by Tsung-Han Hsieh, Muh-Lii Liang, Jia-Huei Zheng, Yu-Chen Lin, Yu-Chen Yang, Thanh-Hoa Vo, Jing-Ping Liou, Yun Yen and Chun-Han Chen
Cancers 2021, 13(23), 6117; https://doi.org/10.3390/cancers13236117 - 4 Dec 2021
Cited by 6 | Viewed by 3974
Abstract
Glioblastoma multiforme (GBM) is the most malignant brain tumor in the world, only 25% of GBM patients were alive one year after diagnosis. Although Temozolamide combined with radiation therapy more effectively prolonged the survival rate than radiation alone, the overall survival rate is [...] Read more.
Glioblastoma multiforme (GBM) is the most malignant brain tumor in the world, only 25% of GBM patients were alive one year after diagnosis. Although Temozolamide combined with radiation therapy more effectively prolonged the survival rate than radiation alone, the overall survival rate is still dismal. Therefore, a new therapeutic strategy is urgently needed. CDK4/6 inhibitors are newly FDA-approved agents to treat HR-positive, HER2-negative advanced, and metastatic breast cancers, and preclinical results showed that CDK4/6 inhibitors significantly reduced cell proliferation and tumor growth. However, several studies have suggested that CDK4/6 inhibitor-induced non-genetic changes caused treatment failure, including autophagy activation. Therefore, this study aimed to combine an autophagy inhibitor, MPT0L145, with abemaciclib to improve therapeutic efficiency. The use of abemaciclib effectively inhibited cell proliferation via suppression of RB phosphorylation and induced autophagy activation in GBM cancer cells. MPT0L145 treatment alone not only blocked autophagy activation, but also induced generation of ROS and DNA damage in a concentration-dependent manner. Importantly, MPT0L145 had a comparable penetration ability to TMZ in our blood brain barrier permeability assay. Combined MPT0L145 with abemaciclib significantly reduced cell proliferation, suppressed RB phosphorylation, and increased ROS production. In conclusion, the data suggested that blocking autophagy by MPT0L145 synergistically sensitized GBM cancer cells to abemaciclib and represents a potential therapeutic strategy for treating GBM in the future. Full article
(This article belongs to the Special Issue Brain Tumors: Molecular and Cell Biology for Target Therapy)
Show Figures

Figure 1

Back to TopTop