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.

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30 pages, 1177 KiB  
Review
Dietary Interventions in Cancer Treatment and Response: A Comprehensive Review
by Benjamin D. Mercier, Eemon Tizpa, Errol J. Philip, Qianhua Feng, Ziyi Huang, Reeny M. Thomas, Sumanta K. Pal, Tanya B. Dorff and Yun R. Li
Cancers 2022, 14(20), 5149; https://doi.org/10.3390/cancers14205149 - 20 Oct 2022
Cited by 9 | Viewed by 5778
Abstract
Chemotherapy and radiotherapy are first-line treatments in the management of advanced solid tumors. Whereas these treatments are directed at eliminating cancer cells, they cause significant adverse effects that can be detrimental to a patient’s quality of life and even life-threatening. Diet is a [...] Read more.
Chemotherapy and radiotherapy are first-line treatments in the management of advanced solid tumors. Whereas these treatments are directed at eliminating cancer cells, they cause significant adverse effects that can be detrimental to a patient’s quality of life and even life-threatening. Diet is a modifiable risk factor that has been shown to affect cancer risk, recurrence, and treatment toxicity, but little information is known how diet interacts with cancer treatment modalities. Although dietary interventions, such as intermittent fasting and ketogenic diets, have shown promise in pre-clinical studies by reducing the toxicity and increasing the efficacy of chemotherapeutics, there remains a limited number of clinical studies in this space. This review surveys the impact of dietary interventions (caloric restriction, intermittent and short-term fasting, and ketogenic diet) on cancer treatment outcomes in both pre-clinical and clinical studies. Early studies support a complementary role for these dietary interventions in improving patient quality of life across multiple cancer types by reducing toxicity and perhaps a benefit in treatment efficacy. Larger, phase III, randomized clinical trials are ultimately necessary to evaluate the efficacy of these dietary interventions in improving oncologic or quality of life outcomes for patients that are undergoing chemotherapy or radiotherapy. Full article
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34 pages, 4145 KiB  
Article
Involvement of HHV-4 (Epstein–Barr Virus) and HHV-5 (Cytomegalovirus) in Inflammatory Bowel Disease and Colorectal Cancer: A Meta-Analysis
by Luigi Marongiu, Sascha Venturelli and Heike Allgayer
Cancers 2022, 14(20), 5085; https://doi.org/10.3390/cancers14205085 - 17 Oct 2022
Cited by 3 | Viewed by 2194
Abstract
Gastrointestinal diseases (GDs) include colorectal cancer (CRC), gastric cancer (GC), and inflammatory bowel disease (IBD). CRC and GC are typically diagnosed at later stages of development, reducing patients’ chances of survival. IBD is characterized by chronic intestinal inflammation and is a significant risk [...] Read more.
Gastrointestinal diseases (GDs) include colorectal cancer (CRC), gastric cancer (GC), and inflammatory bowel disease (IBD). CRC and GC are typically diagnosed at later stages of development, reducing patients’ chances of survival. IBD is characterized by chronic intestinal inflammation and is a significant risk factor for the development of CRC. Chronic bacterial infections have been shown to promote some GDs, but the role of viruses in the etiology of these diseases is less clear. The present meta-analysis retrieved literature on the viral prevalence in GD patients, measuring the GD risk in odd ratios. By quantifying the study heterogeneity, the literature bias was fundamentally included in the analysis. The analysis also included 11 metagenomic studies. Our meta-analysis retrieved 11,413 studies, with 196 suitable for analysis. HHV-4 (Epstein–Barr virus) was identified as a significant risk factor for the development of IBD, and HHV-5 (cytomegalovirus) as a risk factor for both CRC and IBD. Polyomaviruses and the Hepatitis B virus were also, less strongly, involved in the risk of CRC and IBD. No relations withstanding the literature bias were identified for GC. The study discusses these findings, as well as the role of other viruses in the etiology of CRC and IBD. Full article
(This article belongs to the Special Issue Biomarker in Metastatic Colorectal Cancer)
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21 pages, 2437 KiB  
Review
Chronotherapy: Circadian Rhythms and Their Influence in Cancer Therapy
by Ana Amiama-Roig, Eva M. Verdugo-Sivianes, Amancio Carnero and José-Ramón Blanco
Cancers 2022, 14(20), 5071; https://doi.org/10.3390/cancers14205071 - 17 Oct 2022
Cited by 17 | Viewed by 6103
Abstract
Living organisms present rhythmic fluctuations every 24 h in their behavior and metabolism to anticipate changes in the environment. These fluctuations are controlled by a very complex molecular mechanism, the circadian clock, that regulates the expression of multiple genes to ensure the right [...] Read more.
Living organisms present rhythmic fluctuations every 24 h in their behavior and metabolism to anticipate changes in the environment. These fluctuations are controlled by a very complex molecular mechanism, the circadian clock, that regulates the expression of multiple genes to ensure the right functioning of the body. An individual’s circadian system is altered during aging, and this is related to numerous age-associated pathologies and other alterations that could contribute to the development of cancer. Nowadays, there is an increasing interest in understanding how circadian rhythms could be used in the treatment of cancer. Chronotherapy aims to understand the impact that biological rhythms have on the response to a therapy to optimize its action, maximize health benefits and minimize possible adverse effects. Clinical trials so far have confirmed that optimal timing of treatment with chemo or immunotherapies could decrease drug toxicity and increase efficacy. Instead, chronoradiotherapy seems to minimize treatment-related symptoms rather than tumor progression or patient survival. In addition, potential therapeutic targets within the molecular clock have also been identified. Therefore, results of the application of chronotherapy in cancer therapy until now are challenging, feasible, and could be applied to clinical practice to improve cancer treatment without additional costs. However, different limitations and variables such as age, sex, or chronotypes, among others, should be overcome before chronotherapy can really be put into clinical practice. Full article
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24 pages, 11851 KiB  
Article
Development of a High-Affinity Antibody against the Tumor-Specific and Hyperactive 611-p95HER2 Isoform
by Esmaeil Dorraji, Elin Borgen, Dario Segura-Peña, Puneet Rawat, Eva Smorodina, Claire Dunn, Victor Greiff, Nikolina Sekulić, Hege Russnes and Jon Amund Kyte
Cancers 2022, 14(19), 4859; https://doi.org/10.3390/cancers14194859 - 05 Oct 2022
Viewed by 3063
Abstract
The expression of human epidermal growth factor receptor 2 (HER2) is a key classification factor in breast cancer. Many breast cancers express isoforms of HER2 with truncated carboxy-terminal fragments (CTF), collectively known as p95HER2. A common p95HER2 isoform, 611-CTF, is a biomarker for [...] Read more.
The expression of human epidermal growth factor receptor 2 (HER2) is a key classification factor in breast cancer. Many breast cancers express isoforms of HER2 with truncated carboxy-terminal fragments (CTF), collectively known as p95HER2. A common p95HER2 isoform, 611-CTF, is a biomarker for aggressive disease and confers resistance to therapy. Contrary to full-length HER2, 611-p95HER2 has negligible normal tissue expression. There is currently no approved diagnostic assay to identify this subgroup and no therapy targeting this mechanism of tumor escape. The purpose of this study was to develop a monoclonal antibody (mAb) against 611-CTF-p95HER2. Hybridomas were generated from rats immunized with cells expressing 611-CTF. A hybridoma producing a highly specific Ab was identified and cloned further as a mAb. This mAb, called Oslo-2, gave strong staining for 611-CTF and no binding to full-length HER2, as assessed in cell lines and tissues by flow cytometry, immunohistochemistry and immunofluorescence. No cross-reactivity against HER2 negative controls was detected. Surface plasmon resonance analysis demonstrated a high binding affinity (equilibrium dissociation constant 2 nM). The target epitope was identified at the N-terminal end, using experimental alanine scanning. Further, the mAb paratope was identified and characterized with hydrogen-deuterium-exchange, and a molecular model for the (Oslo-2 mAb:611-CTF-p95HER2) complex was generated by an experimental-information-driven docking approach. We conclude that the Oslo-2 mAb has a high affinity and is highly specific for 611-CTF-p95HER2. The Ab may be used to develop potent and safe therapies, overcoming p95HER2-mediated tumor escape, as well as for developing diagnostic assays. Full article
(This article belongs to the Section Methods and Technologies Development)
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15 pages, 1932 KiB  
Review
Challenges for Triple Negative Breast Cancer Treatment: Defeating Heterogeneity and Cancer Stemness
by Rinad Mahmoud, Paloma Ordóñez-Morán and Cinzia Allegrucci
Cancers 2022, 14(17), 4280; https://doi.org/10.3390/cancers14174280 - 01 Sep 2022
Cited by 16 | Viewed by 7807
Abstract
The Triple Negative Breast Cancer (TNBC) subtype is known to have a more aggressive clinical course compared to other breast cancer subtypes. Targeted therapies for this type of breast cancer are limited and patients are mostly treated with conventional chemo- and radio-therapies which [...] Read more.
The Triple Negative Breast Cancer (TNBC) subtype is known to have a more aggressive clinical course compared to other breast cancer subtypes. Targeted therapies for this type of breast cancer are limited and patients are mostly treated with conventional chemo- and radio-therapies which are not specific and do not target resistant cells. Therefore, one of the major clinical challenges is to find compounds that target the drug-resistant cell populations which are responsible for reforming secondary tumours. The molecular profiling of the different TNBC subtypes holds a promise for better defining these resistant cells specific to each tumour. To this end, a better understanding of TNBC heterogeneity and cancer stemness is required, and extensive genomic analysis can help to understand the disease complexity and distinguish new molecular drivers that can be targeted in the clinics. The use of persister cancer cell-targeting therapies combined with other therapies may provide a big advance to improve TNBC patients’ survival. Full article
(This article belongs to the Collection Stemness and Drug-Persistence in Cancer)
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14 pages, 1022 KiB  
Review
Heterogeneity of Cancer-Associated Fibroblasts and the Tumor Immune Microenvironment in Pancreatic Cancer
by Tomohiko Shinkawa, Kenoki Ohuchida and Masafumi Nakamura
Cancers 2022, 14(16), 3994; https://doi.org/10.3390/cancers14163994 - 18 Aug 2022
Cited by 14 | Viewed by 3973
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal cancers, with a 5-year survival rate of 9%. Cancer-associated fibroblasts (CAFs) have historically been considered tumor-promoting. However, multiple studies reporting that suppression of CAFs in PDAC mouse models resulted in more aggressive tumors [...] Read more.
Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal cancers, with a 5-year survival rate of 9%. Cancer-associated fibroblasts (CAFs) have historically been considered tumor-promoting. However, multiple studies reporting that suppression of CAFs in PDAC mouse models resulted in more aggressive tumors and worse prognosis have suggested the existence of a tumor-suppressive population within CAFs, leading to further research on heterogeneity within CAFs. In recent years, the benefits of cancer immunotherapy have been reported in various carcinomas. Unfortunately, the efficacy of immunotherapies in PDAC has been limited, and the CAF-driven cancer immunosuppressive microenvironment has been suggested as the cause. Thus, clarification of heterogeneity within the tumor microenvironment, including CAFs and tumor immunity, is urgently needed to establish effective therapeutic strategies for PDAC. In this review, we report the latest findings on the heterogeneity of CAFs and the functions of each major CAF subtype, which have been revealed by single-cell RNA sequencing in recent years. We also describe reports of tumor-suppressive CAF subtypes and the existence of CAFs that maintain a differentiated PDAC phenotype and review the potential for targeted therapy. Full article
(This article belongs to the Special Issue Tumor Microenvironment and Pancreatic Cancer)
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13 pages, 696 KiB  
Review
New Therapeutic Interventions for Kidney Carcinoma: Looking to the Future
by Lucio Dell’Atti, Nicoletta Bianchi and Gianluca Aguiari
Cancers 2022, 14(15), 3616; https://doi.org/10.3390/cancers14153616 - 25 Jul 2022
Cited by 15 | Viewed by 4650
Abstract
Patients suffering from metastatic renal cell carcinoma (mRCC) show an overall survival rate of lower than 10% after 5 years from diagnosis. Currently, the first-line treatment for mRCC patients is based on antiangiogenic drugs that are able to inhibit tyrosine kinase receptors (TKI) [...] Read more.
Patients suffering from metastatic renal cell carcinoma (mRCC) show an overall survival rate of lower than 10% after 5 years from diagnosis. Currently, the first-line treatment for mRCC patients is based on antiangiogenic drugs that are able to inhibit tyrosine kinase receptors (TKI) in combination with immuno-oncology (IO) therapy or IO-IO treatments. Second-line therapy involves the use of other TKIs, immunotherapeutic drugs, and mTOR inhibitors. Nevertheless, many patients treated with mTOR and TK inhibitors acquire drug resistance, making the therapy ineffective. Therefore, the research of new therapeutic targets is crucial for improving the overall survival and quality of life of mRCC patients. The investigation of the molecular basis of RCC, especially in clear cell renal cell carcinoma (ccRCC), has led to the identification of different signaling pathways that are involved in renal carcinogenesis. Most of ccRCCs are associated with mutation in VHL gene, which mediates the degradation of hypoxia-inducible factors (HIFs), that, in turn, regulate the pathways related to tumorigenesis, including angiogenesis and invasion. Renal tumorigenesis is also associated with the activation of tyrosine kinases that modulate the PI3K-Akt-mTOR pathway, promoting cell proliferation and survival. In ccRCC, the abnormal activity of mTOR activates the MDM2 protein, which leads to the degradation of tumor suppressor p53 via proteasome machinery. In addition, p53 may be degraded by autophagy in a mechanism involving the enzyme transglutaminase 2 (TG2). Suppression of wild-type p53 promotes cell growth, invasion, and drug resistance. Finally, the activation of ferroptosis appears to inhibit cancer progression in RCC. In conclusion, these pathways might represent new therapeutic targets for mRCC. Full article
(This article belongs to the Special Issue Advances in the Treatment of Renal Cell Carcinoma)
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15 pages, 918 KiB  
Review
The Emerging Impact of Tumor Budding in Oral Squamous Cell Carcinoma: Main Issues and Clinical Relevance of a New Prognostic Marker
by Lucrezia Togni, Vito Carlo Alberto Caponio, Nicoletta Zerman, Giuseppe Troiano, Khrystyna Zhurakivska, Lorenzo Lo Muzio, Andrea Balercia, Marco Mascitti and Andrea Santarelli
Cancers 2022, 14(15), 3571; https://doi.org/10.3390/cancers14153571 - 22 Jul 2022
Cited by 16 | Viewed by 3549
Abstract
Tumor Budding (TB) represents a single cancer cell or a small cluster of less than five cancer cells on the infiltrative tumor front. Accumulating evidence suggests TB is an independent prognostic factor in oral squamous cell carcinoma (OSCC). However, its exact role is [...] Read more.
Tumor Budding (TB) represents a single cancer cell or a small cluster of less than five cancer cells on the infiltrative tumor front. Accumulating evidence suggests TB is an independent prognostic factor in oral squamous cell carcinoma (OSCC). However, its exact role is not yet elucidated, and a standardized scoring system is still necessary. The study aims to extensively review the literature data regarding the prognostic role of TB in OSCC. The results of TB are an independent prognostic factor of poor survival outcomes in OSCC. To date, the manual detection of hematoxylin and eosin-staining or pancytokeratin-immunostaining sections are the most commonly used methods. Between the several cut-offs, the two-tier system with five buds/field cut-offs provides better risk stratification. The prognostic role of the BD model in predicting survival outcomes was extensively validated; however, the inclusion of DOI, which is already a staging parameter, encouraged other authors to propose other models, integrating TB count with other adverse risk factors, such as the tumor–stroma ratio and tumor-infiltrated lymphocytes. The prognostic relevance of TB in OSCC highlights its evaluation in daily pathological practice. Therefore, the TB detection method and the TB scoring system should be validated based on tumor stage and site. Full article
(This article belongs to the Special Issue Advances in Oral Cancer: From Pathology to Treatment)
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28 pages, 724 KiB  
Review
Origin and Therapies of Osteosarcoma
by Brice Moukengue, Morgane Lallier, Louise Marchandet, Marc Baud’huin, Franck Verrecchia, Benjamin Ory and Francois Lamoureux
Cancers 2022, 14(14), 3503; https://doi.org/10.3390/cancers14143503 - 19 Jul 2022
Cited by 25 | Viewed by 3647
Abstract
Osteosarcoma (OS) is the most frequent primary bone tumor, mainly affecting children and young adults. Despite therapeutic advances, the 5-year survival rate is 70% but drastically decreases to 20–30% for poor responders to therapies or for patients with metastasis. No real evolution of [...] Read more.
Osteosarcoma (OS) is the most frequent primary bone tumor, mainly affecting children and young adults. Despite therapeutic advances, the 5-year survival rate is 70% but drastically decreases to 20–30% for poor responders to therapies or for patients with metastasis. No real evolution of the survival rates has been observed for four decades, explained by poor knowledge of the origin, difficulties related to diagnosis and the lack of targeted therapies for this pediatric tumor. This review will describe a non-exhaustive overview of osteosarcoma disease from a clinical and biological point of view, describing the origin, diagnosis and therapies. Full article
(This article belongs to the Special Issue Diagnosis and Treatment for Bone Tumor and Sarcoma)
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22 pages, 2945 KiB  
Article
Factors Predicting Surgical Effort Using Explainable Artificial Intelligence in Advanced Stage Epithelial Ovarian Cancer
by Alexandros Laios, Evangelos Kalampokis, Racheal Johnson, Sarika Munot, Amudha Thangavelu, Richard Hutson, Tim Broadhead, Georgios Theophilou, Chris Leach, David Nugent and Diederick De Jong
Cancers 2022, 14(14), 3447; https://doi.org/10.3390/cancers14143447 - 15 Jul 2022
Cited by 15 | Viewed by 3580
Abstract
(1) Background: Surgical cytoreduction for epithelial ovarian cancer (EOC) is a complex procedure. Encompassed within the performance skills to achieve surgical precision, intra-operative surgical decision-making remains a core feature. The use of eXplainable Artificial Intelligence (XAI) could potentially interpret the influence of human [...] Read more.
(1) Background: Surgical cytoreduction for epithelial ovarian cancer (EOC) is a complex procedure. Encompassed within the performance skills to achieve surgical precision, intra-operative surgical decision-making remains a core feature. The use of eXplainable Artificial Intelligence (XAI) could potentially interpret the influence of human factors on the surgical effort for the cytoreductive outcome in question; (2) Methods: The retrospective cohort study evaluated 560 consecutive EOC patients who underwent cytoreductive surgery between January 2014 and December 2019 in a single public institution. The eXtreme Gradient Boosting (XGBoost) and Deep Neural Network (DNN) algorithms were employed to develop the predictive model, including patient- and operation-specific features, and novel features reflecting human factors in surgical heuristics. The precision, recall, F1 score, and area under curve (AUC) were compared between both training algorithms. The SHapley Additive exPlanations (SHAP) framework was used to provide global and local explainability for the predictive model; (3) Results: A surgical complexity score (SCS) cut-off value of five was calculated using a Receiver Operator Characteristic (ROC) curve, above which the probability of incomplete cytoreduction was more likely (area under the curve [AUC] = 0.644; 95% confidence interval [CI] = 0.598–0.69; sensitivity and specificity 34.1%, 86.5%, respectively; p = 0.000). The XGBoost outperformed the DNN assessment for the prediction of the above threshold surgical effort outcome (AUC = 0.77; 95% [CI] 0.69–0.85; p < 0.05 vs. AUC 0.739; 95% [CI] 0.655–0.823; p < 0.95). We identified “turning points” that demonstrated a clear preference towards above the given cut-off level of surgical effort; in consultant surgeons with <12 years of experience, age <53 years old, who, when attempting primary cytoreductive surgery, recorded the presence of ascites, an Intraoperative Mapping of Ovarian Cancer score >4, and a Peritoneal Carcinomatosis Index >7, in a surgical environment with the optimization of infrastructural support. (4) Conclusions: Using XAI, we explain how intra-operative decisions may consider human factors during EOC cytoreduction alongside factual knowledge, to maximize the magnitude of the selected trade-off in effort. XAI techniques are critical for a better understanding of Artificial Intelligence frameworks, and to enhance their incorporation in medical applications. Full article
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14 pages, 900 KiB  
Article
Accurate Screening for Early-Stage Breast Cancer by Detection and Profiling of Circulating Tumor Cells
by Timothy Crook, Robert Leonard, Kefah Mokbel, Alastair Thompson, Michael Michell, Raymond Page, Ashok Vaid, Ravi Mehrotra, Anantbhushan Ranade, Sewanti Limaye, Darshana Patil, Dadasaheb Akolkar, Vineet Datta, Pradip Fulmali, Sachin Apurwa, Stefan Schuster, Ajay Srinivasan and Rajan Datar
Cancers 2022, 14(14), 3341; https://doi.org/10.3390/cancers14143341 - 09 Jul 2022
Cited by 17 | Viewed by 8335
Abstract
Background: The early detection of breast cancer (BrC) is associated with improved survival. We describe a blood-based breast cancer detection test based on functional enrichment of breast-adenocarcinoma-associated circulating tumor cells (BrAD-CTCs) and their identification via multiplexed fluorescence immunocytochemistry (ICC) profiling for GCDFP15, GATA3, [...] Read more.
Background: The early detection of breast cancer (BrC) is associated with improved survival. We describe a blood-based breast cancer detection test based on functional enrichment of breast-adenocarcinoma-associated circulating tumor cells (BrAD-CTCs) and their identification via multiplexed fluorescence immunocytochemistry (ICC) profiling for GCDFP15, GATA3, EpCAM, PanCK, and CD45 status. Methods: The ability of the test to differentiate BrC cases (N = 548) from healthy women (N = 9632) was evaluated in a case–control clinical study. The ability of the test to differentiate BrC cases from those with benign breast conditions was evaluated in a prospective clinical study of women (N = 141) suspected of BrC. Results: The test accurately detects BrAD-CTCs in breast cancers, irrespective of age, ethnicity, disease stage, grade, or hormone receptor status. Analytical validation established the high accuracy and reliability of the test under intended use conditions. The test detects and differentiates BrC cases from healthy women with 100% specificity and 92.07% overall sensitivity in a case–control study. In a prospective clinical study, the test shows 93.1% specificity and 94.64% overall sensitivity in differentiating breast cancer cases (N = 112) from benign breast conditions (N = 29). Conclusion: The findings reported in this manuscript support the clinical potential of this test for blood-based BrC detection. Full article
(This article belongs to the Special Issue Breast Development and Cancer)
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31 pages, 1368 KiB  
Review
Resistance to TKIs in EGFR-Mutated Non-Small Cell Lung Cancer: From Mechanisms to New Therapeutic Strategies
by Andreas Koulouris, Christos Tsagkaris, Anna Chiara Corriero, Giulio Metro and Giannis Mountzios
Cancers 2022, 14(14), 3337; https://doi.org/10.3390/cancers14143337 - 08 Jul 2022
Cited by 19 | Viewed by 4950
Abstract
Resistance to tyrosine kinase inhibitors (TKIs) of the epidermal growth factor receptor (EGFR) in advanced mutant Non-Small Cell Lung Cancer (NSCLC) constitutes a therapeutic challenge. This review intends to summarize the existing knowledge about the mechanisms of resistance to TKIs in the context [...] Read more.
Resistance to tyrosine kinase inhibitors (TKIs) of the epidermal growth factor receptor (EGFR) in advanced mutant Non-Small Cell Lung Cancer (NSCLC) constitutes a therapeutic challenge. This review intends to summarize the existing knowledge about the mechanisms of resistance to TKIs in the context of EGFR mutant NSCLC and discuss its clinical and therapeutic implications. EGFR-dependent and independent molecular pathways have the potential to overcome or circumvent the activity of EGFR-targeted agents including the third-generation TKI, osimertinib, negatively impacting clinical outcomes. CNS metastases occur frequently in patients on EGFR-TKIs, due to the inability of first and second-generation agents to overcome both the BBB and the acquired resistance of cancer cells in the CNS. Newer-generation TKIs, TKIs targeting EGFR-independent resistance mechanisms, bispecific antibodies and antibody-drug conjugates or combinations of TKIs with other TKIs or chemotherapy, immunotherapy and Anti-Vascular Endothelial Growth Factors (anti-VEGFs) are currently in use or under investigation in EGFR mutant NSCLC. Liquid biopsies detecting mutant cell-free DNA (cfDNA) provide a window of opportunity to attack mutant clones before they become clinically apparent. Overall, EGFR TKIs-resistant NSCLC constitutes a multifaceted therapeutic challenge. Mapping its underlying mutational landscape, accelerating the detection of resistance mechanisms and diversifying treatment strategies are essential for the management of the disease. Full article
(This article belongs to the Special Issue Mechanisms of Resistance in EGFR-Mutated Non-Small Cell Lung Cancer)
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15 pages, 2997 KiB  
Article
Brain Functional Connectivity in Low- and High-Grade Gliomas: Differences in Network Dynamics Associated with Tumor Grade and Location
by Luca Pasquini, Mehrnaz Jenabi, Onur Yildirim, Patrick Silveira, Kyung K. Peck and Andrei I. Holodny
Cancers 2022, 14(14), 3327; https://doi.org/10.3390/cancers14143327 - 08 Jul 2022
Cited by 17 | Viewed by 3662
Abstract
Brain tumors lead to modifications of brain networks. Graph theory plays an important role in clarifying the principles of brain connectivity. Our objective was to investigate network modifications related to tumor grade and location using resting-state functional magnetic resonance imaging (fMRI) and graph [...] Read more.
Brain tumors lead to modifications of brain networks. Graph theory plays an important role in clarifying the principles of brain connectivity. Our objective was to investigate network modifications related to tumor grade and location using resting-state functional magnetic resonance imaging (fMRI) and graph theory. We retrospectively studied 30 low-grade (LGG), 30 high-grade (HGG) left-hemispheric glioma patients and 20 healthy controls (HC) with rs-fMRI. Tumor location was labeled as: frontal, temporal, parietal, insular or occipital. We collected patients’ clinical data from records. We analyzed whole-brain and hemispheric networks in all patients and HC. Subsequently, we studied lobar networks in subgroups of patients divided by tumor location. Seven graph-theoretical metrics were calculated (FDR p < 0.05). Connectograms were computed for significant nodes. The two-tailed Student t-test or Mann–Whitney U-test (p < 0.05) were used to compare graph metrics and clinical data. The hemispheric network analysis showed increased ipsilateral connectivity for LGG (global efficiency p = 0.03) and decreased contralateral connectivity for HGG (degree/cost p = 0.028). Frontal and temporal tumors showed bilateral modifications; parietal and insular tumors showed only local effects. Temporal tumors led to a bilateral decrease in all graph metrics. Tumor grade and location influence the pattern of network reorganization. LGG may show more favorable network changes than HGG, reflecting fewer clinical deficits. Full article
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16 pages, 1829 KiB  
Article
Urine CA125 and HE4 for the Triage of Symptomatic Women with Suspected Endometrial Cancer
by Kelechi Njoku, Chloe E. Barr, Caroline J. J. Sutton and Emma J. Crosbie
Cancers 2022, 14(14), 3306; https://doi.org/10.3390/cancers14143306 - 06 Jul 2022
Cited by 8 | Viewed by 3153
Abstract
A simple, noninvasive and accurate detection tool that can triage women with suspected endometrial cancer for definitive testing will transform patient care. The aim of this study was to evaluate urine CA125 and HE4 levels for the detection of endometrial cancer in symptomatic [...] Read more.
A simple, noninvasive and accurate detection tool that can triage women with suspected endometrial cancer for definitive testing will transform patient care. The aim of this study was to evaluate urine CA125 and HE4 levels for the detection of endometrial cancer in symptomatic women. This was a cross-sectional diagnostic accuracy study of 153 symptomatic women who underwent urgent diagnostic investigations for suspected endometrial cancer at a large gynecological cancer center. Urine samples were collected prior to routine clinical procedures. Urine CA125 and HE4 levels were determined using automated chemiluminescent enzyme immunoassays. Univariate and multivariable receiver operating characteristic (ROC) curve analyses were performed. Urine CA125 and HE4 were discovered to be significantly elevated in women with endometrial cancer, compared to controls (p < 0.001 and p = 0.01, respectively). Urine CA125 and HE4 detected endometrial cancer with an area under the ROC curve (AUC) of 0.89 (0.81, 0.98) and 0.69 (0.55, 0.83), respectively. CA125 exhibited good discriminatory potential for Type I and early-stage tumors (AUC 0.93 and 0.90, respectively). A diagnostic model that combined urine CA125 and transvaginal ultrasound-measured endometrial thickness predicted endometrial cancer with an AUC of 0.96 (0.91, 1.00). Urine CA125 displays potential as a diagnostic tool for symptomatic women with suspected endometrial cancer. When combined with transvaginal ultrasound-measured endometrial thickness, this patient-friendly, urine-based test could help triage women for invasive diagnostics or safe reassurance, reducing costs and improving patient experience. Full article
(This article belongs to the Special Issue Cancer Detection in Primary Care)
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7 pages, 249 KiB  
Review
Defining Oligometastatic Disease in the New Era of PSMA-PET Imaging for Primary Staging of Prostate Cancer
by Samuel J. Galgano, Andrew M. McDonald, Janelle T. West and Soroush Rais-Bahrami
Cancers 2022, 14(14), 3302; https://doi.org/10.3390/cancers14143302 - 06 Jul 2022
Cited by 10 | Viewed by 1882
Abstract
Oligometastatic prostate cancer has traditionally been defined in the literature as a limited number of metastatic lesions (either to soft tissue or bone), typically based on findings seen on CT, MRI, and skeletal scintigraphy. Although definitions have varied among research studies, many important [...] Read more.
Oligometastatic prostate cancer has traditionally been defined in the literature as a limited number of metastatic lesions (either to soft tissue or bone), typically based on findings seen on CT, MRI, and skeletal scintigraphy. Although definitions have varied among research studies, many important clinical trials have documented effective treatments and prognostication in patients with oligometastatic prostate cancer. In current clinical practice, prostate-specific membrane antigen (PSMA)-PET/CT is increasingly utilized for the initial staging of high-risk patients and, in many cases, detecting metastases that would have otherwise been undetected with conventional staging imaging. Thus, patients with presumed localized and/or oligometastatic prostate cancer undergo stage migration based on more novel molecular imaging. As a result, it is challenging to apply the data from the era before widespread PET utilization to current clinical practice and to relate current trials using PSMA-PET/CT for disease detection to older studies using conventional staging imaging alone. This manuscript aims to review the definition of oligometastatic prostate cancer, summarize important studies utilizing both PSMA-PET/CT and conventional anatomic imaging, discuss the concept of stage migration, and discuss current problems and challenges with the current definition of oligometastatic disease. Full article
18 pages, 1316 KiB  
Review
Liquid Biopsy in Prostate Cancer Management—Current Challenges and Future Perspectives
by Felice Crocetto, Gianluca Russo, Erika Di Zazzo, Pasquale Pisapia, Benito Fabio Mirto, Alessandro Palmieri, Francesco Pepe, Claudio Bellevicine, Alessandro Russo, Evelina La Civita, Daniela Terracciano, Umberto Malapelle, Giancarlo Troncone and Biagio Barone
Cancers 2022, 14(13), 3272; https://doi.org/10.3390/cancers14133272 - 04 Jul 2022
Cited by 42 | Viewed by 5464
Abstract
Although appreciable attempts in screening and diagnostic approaches have been achieved, prostate cancer (PCa) remains a widespread malignancy, representing the second leading cause of cancer-related death in men. Drugs currently used in PCa therapy initially show a potent anti-tumor effect, but frequently induce [...] Read more.
Although appreciable attempts in screening and diagnostic approaches have been achieved, prostate cancer (PCa) remains a widespread malignancy, representing the second leading cause of cancer-related death in men. Drugs currently used in PCa therapy initially show a potent anti-tumor effect, but frequently induce resistance and PCa progresses toward metastatic castration-resistant forms (mCRPC), virtually incurable. Liquid biopsy has emerged as an attractive and promising strategy complementary to invasive tissue biopsy to guide PCa diagnosis and treatment. Liquid biopsy shows the ability to represent the tumor microenvironment, allow comprehensive information and follow-up the progression of the tumor, enabling the development of different treatment strategies as well as permitting the monitoring of therapy response. Liquid biopsy, indeed, is endowed with a significant potential to modify PCa management. Several blood biomarkers could be analyzed for diagnostic, prognostic and predictive purposes, including circulating tumor cells (CTCs), extracellular vesicles (EVs), circulating tumor DNA (ctDNA) and RNA (ctRNA). In addition, several other body fluids may be adopted (i.e., urine, sperm, etc.) beyond blood. This review dissects recent advancements and future perspectives of liquid biopsies, highlighting their strength and weaknesses in PCa management. Full article
(This article belongs to the Topic Prostate Cancer: Symptoms, Diagnosis & Treatment)
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16 pages, 3171 KiB  
Article
Prognostic and Predictive Role of Body Composition in Metastatic Neuroendocrine Tumor Patients Treated with Everolimus: A Real-World Data Analysis
by Nicoletta Ranallo, Andrea Prochoswski Iamurri, Flavia Foca, Chiara Liverani, Alessandro De Vita, Laura Mercatali, Chiara Calabrese, Chiara Spadazzi, Carlo Fabbri, Davide Cavaliere, Riccardo Galassi, Stefano Severi, Maddalena Sansovini, Andreas Tartaglia, Federica Pieri, Laura Crudi, David Bianchini, Domenico Barone, Giovanni Martinelli, Giovanni Luca Frassineti, Toni Ibrahim, Luana Calabrò, Rossana Berardi and Alberto Bongiovanniadd Show full author list remove Hide full author list
Cancers 2022, 14(13), 3231; https://doi.org/10.3390/cancers14133231 - 30 Jun 2022
Cited by 5 | Viewed by 1963
Abstract
Neuroendocrine tumors (NETs) are rare neoplasms frequently characterized by an upregulation of the mammalian rapamycin targeting (mTOR) pathway resulting in uncontrolled cell proliferation. The mTOR pathway is also involved in skeletal muscle protein synthesis and in adipose tissue metabolism. Everolimus inhibits the mTOR [...] Read more.
Neuroendocrine tumors (NETs) are rare neoplasms frequently characterized by an upregulation of the mammalian rapamycin targeting (mTOR) pathway resulting in uncontrolled cell proliferation. The mTOR pathway is also involved in skeletal muscle protein synthesis and in adipose tissue metabolism. Everolimus inhibits the mTOR pathway, resulting in blockade of cell growth and tumor progression. The aim of this study is to investigate the role of body composition indexes in patients with metastatic NETs treated with everolimus. The study population included 30 patients with well-differentiated (G1-G2), metastatic NETs treated with everolimus at the IRCCS Romagnolo Institute for the Study of Tumors (IRST) “Dino Amadori”, Meldola (FC), Italy. The body composition indexes (skeletal muscle index [SMI] and adipose tissue indexes) were assessed by measuring on a computed tomography (CT) scan the cross-sectional area at L3 at baseline and at the first radiological assessment after the start of treatment. The body mass index (BMI) was assessed at baseline. The median progression-free survival (PFS) was 8.9 months (95% confidence interval [CI]: 3.4–13.7 months). The PFS stratified by tertiles was 3.2 months (95% CI: 0.9–10.1 months) in patients with low SMI (tertile 1), 14.2 months (95% CI: 2.3 months-not estimable [NE]) in patients with intermediate SMI (tertile 2), and 9.1 months (95% CI: 2.7 months-NE) in patients with high SMI (tertile 3) (p = 0.039). Similarly, the other body composition indexes also showed a statistically significant difference in the three groups on the basis of tertiles. The median PFS was 3.2 months (95% CI: 0.9–6.7 months) in underweight patients (BMI ≤ 18.49 kg/m2) and 10.1 months (95% CI: 3.7–28.4 months) in normal-weight patients (p = 0.011). There were no significant differences in terms of overall survival. The study showed a correlation between PFS and the body composition indexes in patients with NETs treated with everolimus, underlining the role of adipose and muscle tissue in these patients. Full article
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17 pages, 1459 KiB  
Review
Radon and Lung Cancer: Current Trends and Future Perspectives
by Mariona Riudavets, Marta Garcia de Herreros, Benjamin Besse and Laura Mezquita
Cancers 2022, 14(13), 3142; https://doi.org/10.3390/cancers14133142 - 27 Jun 2022
Cited by 37 | Viewed by 5035
Abstract
Lung cancer is a public health problem and the first cause of cancer death worldwide. Radon is a radioactive gas that tends to accumulate inside homes, and it is the second lung cancer risk factor after smoking, and the first one in non-smokers. [...] Read more.
Lung cancer is a public health problem and the first cause of cancer death worldwide. Radon is a radioactive gas that tends to accumulate inside homes, and it is the second lung cancer risk factor after smoking, and the first one in non-smokers. In Europe, there are several radon-prone areas, and although the 2013/59 EURATOM directive is aimed to regulate indoor radon exposition, regulating measures can vary between countries. Radon emits alpha-ionizing radiation that has been linked to a wide variety of cytotoxic and genotoxic effects; however, the link between lung cancer and radon from the genomic point of view remains poorly described. Driver molecular alterations have been recently identified in non-small lung cancer (NSCLC), such as somatic mutations (EGFR, BRAF, HER2, MET) or chromosomal rearrangements (ALK, ROS1, RET, NTRK), mainly in the non-smoking population, where no risk factor has been identified yet. An association between radon exposure and oncogenic NSCLC in non-smokers has been hypothesised. This paper provides a practical, concise and updated review on the implications of indoor radon in lung cancer carcinogenesis, and especially of its potential relation with NSCLC with driver genomic alterations. Full article
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14 pages, 1986 KiB  
Systematic Review
Proton Pump Inhibitor Use and Risk of Gastric Cancer: Current Evidence from Epidemiological Studies and Critical Appraisal
by Tahmina Nasrin Poly, Ming-Chin Lin, Shabbir Syed-Abdul, Chih-Wei Huang, Hsuan-Chia Yang and Yu-Chuan (Jack) Li
Cancers 2022, 14(13), 3052; https://doi.org/10.3390/cancers14133052 - 21 Jun 2022
Cited by 13 | Viewed by 3457
Abstract
Proton pump inhibitors (PPIs) are used for maintaining or improving gastric problems. Evidence from observational studies indicates that PPI therapy is associated with an increased risk of gastric cancer. However, the evidence for PPIs increasing the risk of gastric cancer is still being [...] Read more.
Proton pump inhibitors (PPIs) are used for maintaining or improving gastric problems. Evidence from observational studies indicates that PPI therapy is associated with an increased risk of gastric cancer. However, the evidence for PPIs increasing the risk of gastric cancer is still being debated. Therefore, we aimed to investigate whether long-term PPI use is associated with an increased risk of gastric cancer. We systematically searched the relevant literature in electronic databases, including PubMed, EMBASE, Scopus, and Web of Science. The search and collection of eligible studies was between 1 January 2000 and 1 July 2021. Two independent authors were responsible for the study selection process, and they considered only observational studies that compared the risk of gastric cancer with PPI treatment. We extracted relevant information from selected studies, and assessed the quality using the Newcastle−Ottawa scale (NOS). Finally, we calculated overall risk ratios (RRs) with 95% confidence intervals (CIs) of gastric cancer in the group receiving PPI therapy and the control group. Thirteen observational studies, comprising 10,557 gastric cancer participants, were included. Compared with patients who did not take PPIs, the pooled RR for developing gastric cancer in patients receiving PPIs was 1.80 (95% CI, 1.46–2.22, p < 0.001). The overall risk of gastric cancer also increased in patients with gastroesophageal reflux disease (GERD), H. pylori treatment, and various adjusted factors. The findings were also consistent across several sensitivity analyses. PPI use is associated with an increased risk of gastric cancer in patients compared with those with no PPI treatment. The findings of this updated study could be used in making clinical decisions between physicians and patients about the initiation and continuation of PPI therapy, especially in patients at high risk of gastric cancer. Additionally, large randomized controlled trials are needed to determine whether PPIs are associated with a higher risk of gastric cancer. Full article
(This article belongs to the Section Cancer Epidemiology and Prevention)
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38 pages, 1873 KiB  
Review
Drug Resistance in Colorectal Cancer: From Mechanism to Clinic
by Qianyu Wang, Xiaofei Shen, Gang Chen and Junfeng Du
Cancers 2022, 14(12), 2928; https://doi.org/10.3390/cancers14122928 - 14 Jun 2022
Cited by 36 | Viewed by 4725
Abstract
Colorectal cancer (CRC) is one of the leading causes of death worldwide. The 5-year survival rate is 90% for patients with early CRC, 70% for patients with locally advanced CRC, and 15% for patients with metastatic CRC (mCRC). In fact, most CRC patients [...] Read more.
Colorectal cancer (CRC) is one of the leading causes of death worldwide. The 5-year survival rate is 90% for patients with early CRC, 70% for patients with locally advanced CRC, and 15% for patients with metastatic CRC (mCRC). In fact, most CRC patients are at an advanced stage at the time of diagnosis. Although chemotherapy, molecularly targeted therapy and immunotherapy have significantly improved patient survival, some patients are initially insensitive to these drugs or initially sensitive but quickly become insensitive, and the emergence of such primary and secondary drug resistance is a significant clinical challenge. The most direct cause of resistance is the aberrant anti-tumor drug metabolism, transportation or target. With more in-depth research, it is found that cell death pathways, carcinogenic signals, compensation feedback loop signal pathways and tumor immune microenvironment also play essential roles in the drug resistance mechanism. Here, we assess the current major mechanisms of CRC resistance and describe potential therapeutic interventions. Full article
(This article belongs to the Collection Drug Resistance and Novel Therapies in Cancers)
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16 pages, 1771 KiB  
Review
Bias and Class Imbalance in Oncologic Data—Towards Inclusive and Transferrable AI in Large Scale Oncology Data Sets
by Erdal Tasci, Ying Zhuge, Kevin Camphausen and Andra V. Krauze
Cancers 2022, 14(12), 2897; https://doi.org/10.3390/cancers14122897 - 12 Jun 2022
Cited by 30 | Viewed by 13696
Abstract
Recent technological developments have led to an increase in the size and types of data in the medical field derived from multiple platforms such as proteomic, genomic, imaging, and clinical data. Many machine learning models have been developed to support precision/personalized medicine initiatives [...] Read more.
Recent technological developments have led to an increase in the size and types of data in the medical field derived from multiple platforms such as proteomic, genomic, imaging, and clinical data. Many machine learning models have been developed to support precision/personalized medicine initiatives such as computer-aided detection, diagnosis, prognosis, and treatment planning by using large-scale medical data. Bias and class imbalance represent two of the most pressing challenges for machine learning-based problems, particularly in medical (e.g., oncologic) data sets, due to the limitations in patient numbers, cost, privacy, and security of data sharing, and the complexity of generated data. Depending on the data set and the research question, the methods applied to address class imbalance problems can provide more effective, successful, and meaningful results. This review discusses the essential strategies for addressing and mitigating the class imbalance problems for different medical data types in the oncologic domain. Full article
(This article belongs to the Special Issue Bioinformatics, Big Data and Cancer)
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26 pages, 2015 KiB  
Review
Clinical Viability of Boron Neutron Capture Therapy for Personalized Radiation Treatment
by Dominika Skwierawska, José Antonio López-Valverde, Marcin Balcerzyk and Antonio Leal
Cancers 2022, 14(12), 2865; https://doi.org/10.3390/cancers14122865 - 10 Jun 2022
Cited by 13 | Viewed by 3481
Abstract
Boron Neutron Capture Therapy (BNCT) is a promising binary disease-targeted therapy, as neutrons preferentially kill cells labeled with boron (10B), which makes it a precision medicine treatment modality that provides a therapeutic effect exclusively on patient-specific tumor spread. Contrary to what [...] Read more.
Boron Neutron Capture Therapy (BNCT) is a promising binary disease-targeted therapy, as neutrons preferentially kill cells labeled with boron (10B), which makes it a precision medicine treatment modality that provides a therapeutic effect exclusively on patient-specific tumor spread. Contrary to what is usual in radiotherapy, BNCT proposes cell-tailored treatment planning rather than to the tumor mass. The success of BNCT depends mainly on the sufficient spatial biodistribution of 10B located around or within neoplastic cells to produce a high-dose gradient between the tumor and healthy tissue. However, it is not yet possible to precisely determine the concentration of 10B in a specific tissue in real-time using non-invasive methods. Critical issues remain to be resolved if BNCT is to become a valuable, minimally invasive, and efficient treatment. In addition, functional imaging technologies, such as PET, can be applied to determine biological information that can be used for the combined-modality radiotherapy protocol for each specific patient. Regardless, not only imaging methods but also proteomics and gene expression methods will facilitate BNCT becoming a modality of personalized medicine. This work provides an overview of the fundamental principles, recent advances, and future directions of BNCT as cell-targeted cancer therapy for personalized radiation treatment. Full article
(This article belongs to the Special Issue Personalized Radiation Therapy for Oncology)
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24 pages, 967 KiB  
Review
New Therapeutic Strategies for Adult Acute Myeloid Leukemia
by Hiroto Ishii and Shingo Yano
Cancers 2022, 14(11), 2806; https://doi.org/10.3390/cancers14112806 - 05 Jun 2022
Cited by 14 | Viewed by 5164
Abstract
Acute myeloid leukemia (AML) is a genetically heterogeneous hematological malignancy. Chromosomal and genetic analyses are important for the diagnosis and prognosis of AML. Some patients experience relapse or have refractory disease, despite conventional cytotoxic chemotherapies and allogeneic transplantation, and a variety of new [...] Read more.
Acute myeloid leukemia (AML) is a genetically heterogeneous hematological malignancy. Chromosomal and genetic analyses are important for the diagnosis and prognosis of AML. Some patients experience relapse or have refractory disease, despite conventional cytotoxic chemotherapies and allogeneic transplantation, and a variety of new agents and treatment strategies have emerged. After over 20 years during which no new drugs became available for the treatment of AML, the CD33-targeting antibody–drug conjugate gemtuzumab ozogamicin was developed. This is currently used in combination with standard chemotherapy or as a single agent. CPX-351, a liposomal formulation containing daunorubicin and cytarabine, has become one of the standard treatments for secondary AML in the elderly. FMS-like tyrosine kinase 3 (FLT3) inhibitors and isocitrate dehydrogenase 1/2 (IDH 1/2) inhibitors are mainly used for AML patients with actionable mutations. In addition to hypomethylating agents and venetoclax, a B-cell lymphoma-2 inhibitor is used in frail patients with newly diagnosed AML. Recently, tumor protein p53 inhibitors, cyclin-dependent kinase inhibitors, and NEDD8 E1-activating enzyme inhibitors have been gaining attention, and a suitable strategy for the use of these drugs is required. Antibody drugs targeting cell-surface markers and immunotherapies, such as antibody–drug conjugates and chimeric antigen receptor T-cell therapy, have also been developed for AML. Full article
(This article belongs to the Special Issue New Therapeutic Strategies for Acute Myeloid Leukemia)
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15 pages, 1164 KiB  
Review
The Kynurenine Pathway and Cancer: Why Keep It Simple When You Can Make It Complicated
by Roumaïssa Gouasmi, Carole Ferraro-Peyret, Stéphane Nancey, Isabelle Coste, Toufic Renno, Cédric Chaveroux, Nicolas Aznar and Stéphane Ansieau
Cancers 2022, 14(11), 2793; https://doi.org/10.3390/cancers14112793 - 04 Jun 2022
Cited by 22 | Viewed by 4537
Abstract
The kynurenine pathway has been highlighted as a gatekeeper of immune-privileged sites through its ability to generate from tryptophan a set of immunosuppressive metabolic intermediates. It additionally constitutes an important source of cellular NAD+ for the organism. Hijacking of its immunosuppressive functions, [...] Read more.
The kynurenine pathway has been highlighted as a gatekeeper of immune-privileged sites through its ability to generate from tryptophan a set of immunosuppressive metabolic intermediates. It additionally constitutes an important source of cellular NAD+ for the organism. Hijacking of its immunosuppressive functions, as recurrently observed in multiple cancers, facilitates immune evasion and promotes tumor development. Based on these observations, researchers have focused on characterizing indoleamine 2,3-dioxygenase (IDO1), the main enzyme catalyzing the first and limiting step of the pathway, and on developing therapies targeting it. Unfortunately, clinical trials studying IDO1 inhibitors have thus far not met expectations, highlighting the need to unravel this complex signaling pathway further. Recent advances demonstrate that these metabolites additionally promote tumor growth, metastatic dissemination and chemoresistance by a combination of paracrine and autocrine effects. Production of NAD+ also contributes to cancer progression by providing cancer cells with enhanced plasticity, invasive properties and chemoresistance. A comprehensive survey of this complexity is challenging but necessary to achieve medical success. Full article
(This article belongs to the Special Issue Targeting Amino Acid Signaling and Metabolism in Cancer)
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10 pages, 1606 KiB  
Review
Interconnected Adaptive Responses: A Way Out for Cancer Cells to Avoid Cellular Demise
by Gabriella D’Orazi and Mara Cirone
Cancers 2022, 14(11), 2780; https://doi.org/10.3390/cancers14112780 - 03 Jun 2022
Cited by 8 | Viewed by 1687
Abstract
Different from normal cells, cancer cells must hyperactivate a variety of integrated responses in order to survive their basal stress or its exacerbation caused by exposure to anti-cancer agents. As cancer cells become particularly dependent on these adaptive responses, namely UPR, DDR autophagy, [...] Read more.
Different from normal cells, cancer cells must hyperactivate a variety of integrated responses in order to survive their basal stress or its exacerbation caused by exposure to anti-cancer agents. As cancer cells become particularly dependent on these adaptive responses, namely UPR, DDR autophagy, anti-oxidant and heat shock responses, this turns out to be an Achille’s heel, which allows them to be selectively killed while sparing normal unstressed cells. Better knowledge of the cross-talk between these adaptive processes and their impact on the immune system is needed to design more effective anti-cancer therapies, as reviewed in this paper. Full article
(This article belongs to the Special Issue Advances in Immuno-Oncology Research)
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17 pages, 3161 KiB  
Article
Targeting Immunosuppressive Tumor-Associated Macrophages Using Innate T Cells for Enhanced Antitumor Reactivity
by Yan-Ruide Li, James Brown, Yanqi Yu, Derek Lee, Kuangyi Zhou, Zachary Spencer Dunn, Ryan Hon, Matthew Wilson, Adam Kramer, Yichen Zhu, Ying Fang and Lili Yang
Cancers 2022, 14(11), 2749; https://doi.org/10.3390/cancers14112749 - 01 Jun 2022
Cited by 26 | Viewed by 3937
Abstract
The field of T cell-based and chimeric antigen receptor (CAR)-engineered T (CAR-T) cell-based antitumor immunotherapy has seen substantial developments in the past decade; however, considerable issues, such as graft-versus-host disease (GvHD) and tumor-associated immunosuppression, have proven to be substantial roadblocks to widespread adoption [...] Read more.
The field of T cell-based and chimeric antigen receptor (CAR)-engineered T (CAR-T) cell-based antitumor immunotherapy has seen substantial developments in the past decade; however, considerable issues, such as graft-versus-host disease (GvHD) and tumor-associated immunosuppression, have proven to be substantial roadblocks to widespread adoption and implementation. Recent developments in innate immune cell-based CAR therapy have opened several doors for the expansion of this therapy, especially as it relates to allogeneic cell sources and solid tumor infiltration. This study establishes in vitro killing assays to examine the TAM-targeting efficacy of MAIT, iNKT, and γδT cells. This study also assesses the antitumor ability of CAR-engineered innate T cells, evaluating their potential adoption for clinical therapies. The in vitro trials presented in this study demonstrate the considerable TAM-killing abilities of all three innate T cell types, and confirm the enhanced antitumor abilities of CAR-engineered innate T cells. The tumor- and TAM-targeting capacity of these innate T cells suggest their potential for antitumor therapy that supplements cytotoxicity with remediation of tumor microenvironment (TME)-immunosuppression. Full article
(This article belongs to the Special Issue Engineering the Tumor Immune Microenvironment)
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21 pages, 2578 KiB  
Review
Surgical Treatment of Bone Sarcoma
by Felix Bläsius, Heide Delbrück, Frank Hildebrand and Ulf Krister Hofmann
Cancers 2022, 14(11), 2694; https://doi.org/10.3390/cancers14112694 - 29 May 2022
Cited by 17 | Viewed by 7689
Abstract
Bone sarcomas are rare primary malignant mesenchymal bone tumors. The three main entities are osteosarcoma, chondrosarcoma, and Ewing sarcoma. While prognosis has improved for affected patients over the past decades, bone sarcomas are still critical conditions that require an interdisciplinary diagnostic and therapeutic [...] Read more.
Bone sarcomas are rare primary malignant mesenchymal bone tumors. The three main entities are osteosarcoma, chondrosarcoma, and Ewing sarcoma. While prognosis has improved for affected patients over the past decades, bone sarcomas are still critical conditions that require an interdisciplinary diagnostic and therapeutic approach. While radiotherapy plays a role especially in Ewing sarcoma and chemotherapy in Ewing sarcoma and osteosarcoma, surgery remains the main pillar of treatment in all three entities. After complete tumor resection, the created bone defects need to be reconstructed. Possible strategies are implantation of allografts or autografts including vascularized bone grafts (e.g., of the fibula). Around the knee joint, rotationplasty can be performed or, as an alternative, the implantation of (expandable) megaprostheses can be performed. Challenges still associated with the implantation of foreign materials are aseptic loosening and infection. Future improvements may come with advances in 3D printing of individualized resection blades/implants, thus also securing safe tumor resection margins while at the same time shortening the required surgical time. Faster osseointegration and lower infection rates may possibly be achieved through more elaborate implant surface structures. Full article
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19 pages, 2247 KiB  
Article
Gallic Acid: A Natural Phenolic Compound Exerting Antitumoral Activities in Colorectal Cancer via Interaction with G-Quadruplexes
by Victoria Sanchez-Martin, María del Carmen Plaza-Calonge, Ana Soriano-Lerma, Matilde Ortiz-Gonzalez, Angel Linde-Rodriguez, Virginia Perez-Carrasco, Inmaculada Ramirez-Macias, Marta Cuadros, Jose Gutierrez-Fernandez, Javier Murciano-Calles, Juan Carlos Rodríguez-Manzaneque, Miguel Soriano and Jose Antonio Garcia-Salcedo
Cancers 2022, 14(11), 2648; https://doi.org/10.3390/cancers14112648 - 26 May 2022
Cited by 13 | Viewed by 2307
Abstract
Natural phenolic compounds have gained momentum for the prevention and treatment of cancer, but their antitumoral mechanism of action is not yet well understood. In the present study, we screened the antitumoral potential of several phenolic compounds in a cellular model of colorectal [...] Read more.
Natural phenolic compounds have gained momentum for the prevention and treatment of cancer, but their antitumoral mechanism of action is not yet well understood. In the present study, we screened the antitumoral potential of several phenolic compounds in a cellular model of colorectal cancer (CRC). We selected gallic acid (GA) as a candidate in terms of potency and selectivity and extensively evaluated its biological activity. We report on the role of GA as a ligand of DNA G-quadruplexes (G4s), explaining several of its antitumoral effects, including the transcriptional inhibition of ribosomal and CMYC genes. In addition, GA shared with other established G4 ligands some effects such as cell cycle arrest, nucleolar stress, and induction of DNA damage. We further confirmed the antitumoral and G4-stabilizing properties of GA using a xenograft model of CRC. Finally, we succinctly demonstrate that GA could be explored as a therapeutic agent in a patient cohort with CRC. Our work reveals that GA, a natural bioactive compound present in the diet, affects gene expression by interaction with G4s both in vitro and in vivo and paves the way towards G4s targeting with phenolic compounds. Full article
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27 pages, 401 KiB  
Review
Breast Cancer—Epidemiology, Classification, Pathogenesis and Treatment (Review of Literature)
by Beata Smolarz, Anna Zadrożna Nowak and Hanna Romanowicz
Cancers 2022, 14(10), 2569; https://doi.org/10.3390/cancers14102569 - 23 May 2022
Cited by 86 | Viewed by 18247
Abstract
Breast cancer is the most-commonly diagnosed malignant tumor in women in the world, as well as the first cause of death from malignant tumors. The incidence of breast cancer is constantly increasing in all regions of the world. For this reason, despite the [...] Read more.
Breast cancer is the most-commonly diagnosed malignant tumor in women in the world, as well as the first cause of death from malignant tumors. The incidence of breast cancer is constantly increasing in all regions of the world. For this reason, despite the progress in its detection and treatment, which translates into improved mortality rates, it seems necessary to look for new therapeutic methods, and predictive and prognostic factors. Treatment strategies vary depending on the molecular subtype. Breast cancer treatment is multidisciplinary; it includes approaches to locoregional therapy (surgery and radiation therapy) and systemic therapy. Systemic therapies include hormone therapy for hormone-positive disease, chemotherapy, anti-HER2 therapy for HER2-positive disease, and quite recently, immunotherapy. Triple negative breast cancer is responsible for more than 15–20% of all breast cancers. It is of particular research interest as it presents a therapeutic challenge, mainly due to its low response to treatment and its highly invasive nature. Future therapeutic concepts for breast cancer aim to individualize therapy and de-escalate and escalate treatment based on cancer biology and early response to therapy. The article presents a review of the literature on breast carcinoma—a disease affecting women in the world. Full article
14 pages, 814 KiB  
Review
Immune Checkpoint Inhibitors as a Neoadjuvant/Adjuvant Treatment of Muscle-Invasive Bladder Cancer: A Systematic Review
by Biagio Barone, Armando Calogero, Luca Scafuri, Matteo Ferro, Giuseppe Lucarelli, Erika Di Zazzo, Enrico Sicignano, Alfonso Falcone, Lorenzo Romano, Luigi De Luca, Francesco Oliva, Benito Fabio Mirto, Federico Capone, Ciro Imbimbo and Felice Crocetto
Cancers 2022, 14(10), 2545; https://doi.org/10.3390/cancers14102545 - 21 May 2022
Cited by 35 | Viewed by 3167
Abstract
Bladder cancer is the ninth most common cancer worldwide. Over 75% of non-muscle invasive cancer patients require conservative local treatment, while the remaining 25% of patients undergo radical cystectomy or radiotherapy. Immune checkpoint inhibitors represent a novel class of immunotherapy drugs that restore [...] Read more.
Bladder cancer is the ninth most common cancer worldwide. Over 75% of non-muscle invasive cancer patients require conservative local treatment, while the remaining 25% of patients undergo radical cystectomy or radiotherapy. Immune checkpoint inhibitors represent a novel class of immunotherapy drugs that restore natural antitumoral immune activity via the blockage of inhibitory receptors and ligands expressed on antigen-presenting cells, T lymphocytes and tumour cells. The use of immune checkpoint inhibitors in bladder cancer has been expanded from the neoadjuvant setting, i.e., after radical cystectomy, to the adjuvant setting, i.e., before the operative time or chemotherapy, in order to improve the overall survival and to reduce the morbidity and mortality of both the disease and its treatment. However, some patients do not respond to checkpoint inhibitors. As result, the capability for identifying patients that are eligible for this immunotherapy represent one of the efforts of ongoing studies. The aim of this systematic review is to summarize the most recent evidence regarding the use of immune checkpoint inhibitors, in a neoadjuvant and adjuvant setting, in the treatment of muscle-invasive bladder cancer. Full article
(This article belongs to the Special Issue Advances in Immunotherapy for Genitourinary Malignancies)
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12 pages, 1890 KiB  
Article
Sex Differences in the Prevalence of Head and Neck Cancers: A 10-Year Follow-Up Study of 10 Million Healthy People
by Jun-Ook Park, Inn-Chul Nam, Choung-Soo Kim, Sung-Joon Park, Dong-Hyun Lee, Hyun-Bum Kim, Kyung-Do Han and Young-Hoon Joo
Cancers 2022, 14(10), 2521; https://doi.org/10.3390/cancers14102521 - 20 May 2022
Cited by 26 | Viewed by 2853
Abstract
Background: Descriptive epidemiologists have repeatedly reported that males are more susceptible to head and neck cancers. However, most published data are those of cross-sectional studies, and no population-based cohort study has yet been published. The aim of this study was to compare the [...] Read more.
Background: Descriptive epidemiologists have repeatedly reported that males are more susceptible to head and neck cancers. However, most published data are those of cross-sectional studies, and no population-based cohort study has yet been published. The aim of this study was to compare the prevalence of head and neck cancers in healthy males with females. Methods: A retrospective cohort study using the Korean National Health Insurance Service database on 9,598,085 individuals who underwent regular health checkups from 1 January to 31 December 2009. We sought head and neck cancers developed during the 10-year follow-up. Results: A total of 10,732 (incidence rate (IR) per 1000 person-years 0.25) individuals were newly diagnosed with head and neck cancer among the 9,598,085 individuals during the 10-year follow-up. The IR was 0.19 in males (8500 affected) and 0.06 in females (2232 affected). Notably, the male–female ratio increased with age below 70 years but decreased thereafter. The male–female difference was most apparent for laryngeal cancer; the male IR was 11-fold higher in the 40 s and 20-fold higher in the 60 s, followed by hypopharyngeal cancer (6.8- and 24.2-fold). Males smoked more and drank more alcohol than females (p < 0.0001 *, p < 0.0001 *). When never-smokers/-drinkers (only) were compared, males remained at a 2.9-fold higher risk of head and neck cancer than females. The hazard ratios for head and neck cancers in males tended to increase in the lower part of the upper aerodigestive tract: larynx (13.9) > hypopharynx (10.9) > oropharynx (4.4) > nasopharynx (2.9) > sinonasal region (1.8) > oral (1.6). Only the salivary gland cancer incidence did not differ between the sexes; the gland is not in the upper aerodigestive tract. Conclusion: Males are much more susceptible to head and neck cancers than females regardless of whether they drink alcohol or smoke tobacco. Sex differences in the incidence of head and neck cancer are most evident in the 60 s in the lower part of the upper aerodigestive tract, such as the larynx and hypopharynx. Full article
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12 pages, 902 KiB  
Article
Impact of HER2 Status on Pathological Response after Neoadjuvant Chemotherapy in Early Triple-Negative Breast Cancer
by Camille Domergue, Elodie Martin, Camille Lemarié, Pascal Jézéquel, Jean-Sebastien Frenel, Paule Augereau, Mario Campone and Anne Patsouris
Cancers 2022, 14(10), 2509; https://doi.org/10.3390/cancers14102509 - 19 May 2022
Cited by 22 | Viewed by 2082
Abstract
Purpose: Investigates the link between HER2 status and histological response after neoadjuvant chemotherapy in patients with early TNBC. Methods: We retrieved clinical and anatomopathological data retrospectively from 449 patients treated for the first time with standard neoadjuvant chemotherapy for early unilateral BC between [...] Read more.
Purpose: Investigates the link between HER2 status and histological response after neoadjuvant chemotherapy in patients with early TNBC. Methods: We retrieved clinical and anatomopathological data retrospectively from 449 patients treated for the first time with standard neoadjuvant chemotherapy for early unilateral BC between 2005 and 2020. The primary endpoint was pathological complete response (pCR, i.e., ypT0 ypN0), according to HER2 status. Secondary endpoints included invasive disease-free survival (I-DFS) and overall survival (OS). Results: 437 patients were included, and 121 (27.7%) patients had HER2-low tumours. The pCR rate was not significantly different between the HER2-low group vs. the HER2-0 group (35.7% versus 41.8%, p = 0.284) in either univariate analysis or multivariate analysis adjusted for TNM classification and grade (odds ratio [OR] = 0.70, confidence interval [CI] 95% 0.45–1.08). With a median follow-up of 72.9 months, no significant survival differences were observed between patients with HER2-low tumours vs. patients with HER2-0 tumours in terms of I-DFS (p = 0.487) and OS (p = 0.329). Conclusions: In our cohort, HER2 status was not significantly associated with pCR in a manner consistent with data published recently on TNBC. However, the prognostic impact of HER2-low expression among TNBC patients warrants further evaluation. Full article
(This article belongs to the Section Cancer Biomarkers)
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20 pages, 2934 KiB  
Review
Role of Cytokines and Chemokines in Angiogenesis in a Tumor Context
by Mannon GEINDREAU, Mélanie BRUCHARD and Frédérique VEGRAN
Cancers 2022, 14(10), 2446; https://doi.org/10.3390/cancers14102446 - 16 May 2022
Cited by 31 | Viewed by 3098
Abstract
During carcinogenesis, tumors set various mechanisms to help support their development. Angiogenesis is a crucial process for cancer development as it drives the creation of blood vessels within the tumor. These newly formed blood vessels insure the supply of oxygen and nutrients to [...] Read more.
During carcinogenesis, tumors set various mechanisms to help support their development. Angiogenesis is a crucial process for cancer development as it drives the creation of blood vessels within the tumor. These newly formed blood vessels insure the supply of oxygen and nutrients to the tumor, helping its growth. The main factors that regulate angiogenesis are the five members of the vascular endothelial growth factor (VEGF) family. Angiogenesis is a hallmark of cancer and has been the target of new therapies this past few years. However, angiogenesis is a complex phenomenon with many redundancy pathways that ensure its maintenance. In this review, we will first describe the consecutive steps forming angiogenesis, as well as its classical regulators. We will then discuss how the cytokines and chemokines present in the tumor microenvironment can induce or block angiogenesis. Finally, we will focus on the therapeutic arsenal targeting angiogenesis in cancer and the challenges they have to overcome. Full article
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21 pages, 4524 KiB  
Systematic Review
Current Trend of Artificial Intelligence Patents in Digital Pathology: A Systematic Evaluation of the Patent Landscape
by Muhammad Joan Ailia, Nishant Thakur, Jamshid Abdul-Ghafar, Chan Kwon Jung, Kwangil Yim and Yosep Chong
Cancers 2022, 14(10), 2400; https://doi.org/10.3390/cancers14102400 - 13 May 2022
Cited by 17 | Viewed by 4346
Abstract
The integration of digital pathology (DP) with artificial intelligence (AI) enables faster, more accurate, and thorough diagnoses, leading to more precise personalized treatment. As technology is advancing rapidly, it is critical to understand the current state of AI applications in DP. Therefore, a [...] Read more.
The integration of digital pathology (DP) with artificial intelligence (AI) enables faster, more accurate, and thorough diagnoses, leading to more precise personalized treatment. As technology is advancing rapidly, it is critical to understand the current state of AI applications in DP. Therefore, a patent analysis of AI in DP is required to assess the application and publication trends, major assignees, and leaders in the field. We searched five major patent databases, namely, those of the USPTO, EPO, KIPO, JPO, and CNIPA, from 1974 to 2021, using keywords such as DP, AI, machine learning, and deep learning. We discovered 6284 patents, 523 of which were used for trend analyses on time series, international distribution, top assignees; word cloud analysis; and subject category analyses. Patent filing and publication have increased exponentially over the past five years. The United States has published the most patents, followed by China and South Korea (248, 117, and 48, respectively). The top assignees were Paige.AI, Inc. (New York City, NY, USA) and Siemens, Inc. (Munich, Germany) The primary areas were whole-slide imaging, segmentation, classification, and detection. Based on these findings, we expect a surge in DP and AI patent applications focusing on the digitalization of pathological images and AI technologies that support the vital role of pathologists. Full article
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29 pages, 1779 KiB  
Review
Engineering Induced Pluripotent Stem Cells for Cancer Immunotherapy
by Yang Zhou, Miao Li, Kuangyi Zhou, James Brown, Tasha Tsao, Xinjian Cen, Tiffany Husman, Aarushi Bajpai, Zachary Spencer Dunn and Lili Yang
Cancers 2022, 14(9), 2266; https://doi.org/10.3390/cancers14092266 - 01 May 2022
Cited by 23 | Viewed by 8949
Abstract
Cell-based immunotherapy, such as chimeric antigen receptor (CAR) T cell therapy, has revolutionized the treatment of hematological malignancies, especially in patients who are refractory to other therapies. However, there are critical obstacles that hinder the widespread clinical applications of current autologous therapies, such [...] Read more.
Cell-based immunotherapy, such as chimeric antigen receptor (CAR) T cell therapy, has revolutionized the treatment of hematological malignancies, especially in patients who are refractory to other therapies. However, there are critical obstacles that hinder the widespread clinical applications of current autologous therapies, such as high cost, challenging large-scale manufacturing, and inaccessibility to the therapy for lymphopenia patients. Therefore, it is in great demand to generate the universal off-the-shelf cell products with significant scalability. Human induced pluripotent stem cells (iPSCs) provide an “unlimited supply” for cell therapy because of their unique self-renewal properties and the capacity to be genetically engineered. iPSCs can be differentiated into different immune cells, such as T cells, natural killer (NK) cells, invariant natural killer T (iNKT) cells, gamma delta T (γδ T), mucosal-associated invariant T (MAIT) cells, and macrophages (Mφs). In this review, we describe iPSC-based allogeneic cell therapy, the different culture methods of generating iPSC-derived immune cells (e.g., iPSC-T, iPSC-NK, iPSC-iNKT, iPSC-γδT, iPSC-MAIT and iPSC-Mφ), as well as the recent advances in iPSC-T and iPSC-NK cell therapies, particularly in combinations with CAR-engineering. We also discuss the current challenges and the future perspectives in this field towards the foreseeable applications of iPSC-based immune therapy. Full article
(This article belongs to the Special Issue Cell Therapy for Cancers)
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12 pages, 1601 KiB  
Article
Worldwide Burden, Risk Factors, and Temporal Trends of Ovarian Cancer: A Global Study
by Junjie Huang, Wing Chung Chan, Chun Ho Ngai, Veeleah Lok, Lin Zhang, Don Eliseo Lucero-Prisno III, Wanghong Xu, Zhi-Jie Zheng, Edmar Elcarte, Mellissa Withers, Martin C. S. Wong and on behalf of NCD Global Health Research Group of Association of Pacific Rim Universities (APRU)
Cancers 2022, 14(9), 2230; https://doi.org/10.3390/cancers14092230 - 29 Apr 2022
Cited by 67 | Viewed by 8782
Abstract
This study aimed to investigate the most updated worldwide incidence and mortality, risk factors, and epidemiologic trend of ovarian cancer in different countries, regions, and age groups. The Global Cancer Observatory database was used for incidence and mortality rates of ovarian cancer in [...] Read more.
This study aimed to investigate the most updated worldwide incidence and mortality, risk factors, and epidemiologic trend of ovarian cancer in different countries, regions, and age groups. The Global Cancer Observatory database was used for incidence and mortality rates of ovarian cancer in 2020. Data from Cancer Incidence in Five Continents and the WHO mortality database was accessed for trend analysis. Age-standardized rates (ASRs, per 100,000 persons) were calculated for incidence and mortality. The 10-year annual average percent change (AAPC) was estimated by Joinpoint regression analysis. There was an overall decreasing trend of ovarian cancer, yet its burden has been increasing in lower-income countries and among younger females in some countries. Intensive lifestyle modifications are warranted, especially for the populations at high risk for ovarian cancer, including smoking cessation, alcohol use reduction, physical activity, weight control, and treatment of metabolic diseases. Full article
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30 pages, 1812 KiB  
Review
Biomarkers of Response and Resistance to Immunotherapy in Microsatellite Stable Colorectal Cancer: Toward a New Personalized Medicine
by Nicolas Huyghe, Elena Benidovskaya, Philippe Stevens and Marc Van den Eynde
Cancers 2022, 14(9), 2241; https://doi.org/10.3390/cancers14092241 - 29 Apr 2022
Cited by 25 | Viewed by 4089
Abstract
Immune Checkpoint Inhibitors (ICIs) are well recognized as a major immune treatment modality for multiple types of solid cancers. However, for colorectal cancer (CRC), ICIs are only approved for the treatment of Mismatch-Repair-Deficient and Microsatellite Instability-High (dMMR/MSI-H) tumors. For the vast majority of [...] Read more.
Immune Checkpoint Inhibitors (ICIs) are well recognized as a major immune treatment modality for multiple types of solid cancers. However, for colorectal cancer (CRC), ICIs are only approved for the treatment of Mismatch-Repair-Deficient and Microsatellite Instability-High (dMMR/MSI-H) tumors. For the vast majority of CRC, that are not dMMR/MSI-H, ICIs alone provide limited to no clinical benefit. This discrepancy of response between CRC and other solid cancers suggests that CRC may be inherently resistant to ICIs alone. In translational research, efforts are underway to thoroughly characterize the immune microenvironment of CRC to better understand the mechanisms behind this resistance and to find new biomarkers of response. In the clinic, trials are being set up to study biomarkers along with treatments targeting newly discovered immune checkpoint molecules or treatments combining ICIs with other existing therapies to improve response in MSS CRC. In this review, we will focus on the characteristics of response and resistance to ICIs in CRC, and discuss promising biomarkers studied in recent clinical trials combining ICIs with other therapies. Full article
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24 pages, 3780 KiB  
Article
Spatial Characterization of Tumor-Infiltrating Lymphocytes and Breast Cancer Progression
by Danielle J. Fassler, Luke A. Torre-Healy, Rajarsi Gupta, Alina M. Hamilton, Soma Kobayashi, Sarah C. Van Alsten, Yuwei Zhang, Tahsin Kurc, Richard A. Moffitt, Melissa A. Troester, Katherine A. Hoadley and Joel Saltz
Cancers 2022, 14(9), 2148; https://doi.org/10.3390/cancers14092148 - 26 Apr 2022
Cited by 22 | Viewed by 5240
Abstract
Tumor-infiltrating lymphocytes (TILs) have been established as a robust prognostic biomarker in breast cancer, with emerging utility in predicting treatment response in the adjuvant and neoadjuvant settings. In this study, the role of TILs in predicting overall survival and progression-free interval was evaluated [...] Read more.
Tumor-infiltrating lymphocytes (TILs) have been established as a robust prognostic biomarker in breast cancer, with emerging utility in predicting treatment response in the adjuvant and neoadjuvant settings. In this study, the role of TILs in predicting overall survival and progression-free interval was evaluated in two independent cohorts of breast cancer from the Cancer Genome Atlas (TCGA BRCA) and the Carolina Breast Cancer Study (UNC CBCS). We utilized machine learning and computer vision algorithms to characterize TIL infiltrates in digital whole-slide images (WSIs) of breast cancer stained with hematoxylin and eosin (H&E). Multiple parameters were used to characterize the global abundance and spatial features of TIL infiltrates. Univariate and multivariate analyses show that large aggregates of peritumoral and intratumoral TILs (forests) were associated with longer survival, whereas the absence of intratumoral TILs (deserts) is associated with increased risk of recurrence. Patients with two or more high-risk spatial features were associated with significantly shorter progression-free interval (PFI). This study demonstrates the practical utility of Pathomics in evaluating the clinical significance of the abundance and spatial patterns of distribution of TIL infiltrates as important biomarkers in breast cancer. Full article
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29 pages, 1944 KiB  
Review
Targeting Ribosome Biogenesis in Cancer: Lessons Learned and Way Forward
by Asimina Zisi, Jiri Bartek and Mikael S. Lindström
Cancers 2022, 14(9), 2126; https://doi.org/10.3390/cancers14092126 - 24 Apr 2022
Cited by 24 | Viewed by 5602
Abstract
Rapid growth and unrestrained proliferation is a hallmark of many cancers. To accomplish this, cancer cells re-wire and increase their biosynthetic and metabolic activities, including ribosome biogenesis (RiBi), a complex, highly energy-consuming process. Several chemotherapeutic agents used in the clinic impair this process [...] Read more.
Rapid growth and unrestrained proliferation is a hallmark of many cancers. To accomplish this, cancer cells re-wire and increase their biosynthetic and metabolic activities, including ribosome biogenesis (RiBi), a complex, highly energy-consuming process. Several chemotherapeutic agents used in the clinic impair this process by interfering with the transcription of ribosomal RNA (rRNA) in the nucleolus through the blockade of RNA polymerase I or by limiting the nucleotide building blocks of RNA, thereby ultimately preventing the synthesis of new ribosomes. Perturbations in RiBi activate nucleolar stress response pathways, including those controlled by p53. While compounds such as actinomycin D and oxaliplatin effectively disrupt RiBi, there is an ongoing effort to improve the specificity further and find new potent RiBi-targeting compounds with improved pharmacological characteristics. A few recently identified inhibitors have also become popular as research tools, facilitating our advances in understanding RiBi. Here we provide a comprehensive overview of the various compounds targeting RiBi, their mechanism of action, and potential use in cancer therapy. We discuss screening strategies, drug repurposing, and common problems with compound specificity and mechanisms of action. Finally, emerging paths to discovery and avenues for the development of potential biomarkers predictive of therapeutic outcomes across cancer subtypes are also presented. Full article
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23 pages, 38669 KiB  
Article
Efficient Small Extracellular Vesicles (EV) Isolation Method and Evaluation of EV-Associated DNA Role in Cell–Cell Communication in Cancer
by Venkatesh Kumar Chetty, Jamal Ghanam, Srishti Anchan, Katarina Reinhardt, Alexandra Brenzel, Márton Gelléri, Christoph Cremer, Elena Grueso-Navarro, Markus Schneider, Nils von Neuhoff, Dirk Reinhardt, Jadwiga Jablonska, Irina Nazarenko and Basant Kumar Thakur
Cancers 2022, 14(9), 2068; https://doi.org/10.3390/cancers14092068 - 20 Apr 2022
Cited by 6 | Viewed by 4765
Abstract
Small extracellular vesicles (sEVs) play essential roles in intercellular signaling both in normal and pathophysiological conditions. Comprehensive studies of dsDNA associated with sEVs are hampered by a lack of methods, allowing efficient separation of sEVs from free-circulating DNA and apoptotic bodies. In this [...] Read more.
Small extracellular vesicles (sEVs) play essential roles in intercellular signaling both in normal and pathophysiological conditions. Comprehensive studies of dsDNA associated with sEVs are hampered by a lack of methods, allowing efficient separation of sEVs from free-circulating DNA and apoptotic bodies. In this work, using controlled culture conditions, we enriched the reproducible separation of sEVs from free-circulated components by combining tangential flow filtration, size-exclusion chromatography, and ultrafiltration (TSU). EV-enriched fractions (F2 and F3) obtained using TSU also contained more dsDNA derived from the host genome and mitochondria, predominantly localized inside the vesicles. Three-dimensional reconstruction of high-resolution imaging showed that the recipient cell membrane barrier restricts a portion of EV-DNA. Simultaneously, the remaining EV-DNA overcomes it and enters the cytoplasm and nucleus. In the cytoplasm, EV-DNA associates with dsDNA-inflammatory sensors (cGAS/STING) and endosomal proteins (Rab5/Rab7). Relevant to cancer, we found that EV-DNA isolated from leukemia cell lines communicates with mesenchymal stromal cells (MSCs), a critical component in the BM microenvironment. Furthermore, we illustrated the arrangement of sEVs and EV-DNA at a single vesicle level using super-resolution microscopy. Altogether, employing TSU isolation, we demonstrated EV-DNA distribution and a tool to evaluate the exact EV-DNA role of cell–cell communication in cancer. Full article
(This article belongs to the Special Issue Biogenesis and Function of Extracellular Vesicles in Cancers)
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33 pages, 5085 KiB  
Review
Current and Developing Liquid Biopsy Techniques for Breast Cancer
by Hsing-Ju Wu and Pei-Yi Chu
Cancers 2022, 14(9), 2052; https://doi.org/10.3390/cancers14092052 - 19 Apr 2022
Cited by 19 | Viewed by 5574
Abstract
Breast cancer is the most commonly diagnosed cancer and leading cause of cancer mortality among woman worldwide. The techniques of diagnosis, prognosis, and therapy monitoring of breast cancer are critical. Current diagnostic techniques are mammography and tissue biopsy; however, they have limitations. With [...] Read more.
Breast cancer is the most commonly diagnosed cancer and leading cause of cancer mortality among woman worldwide. The techniques of diagnosis, prognosis, and therapy monitoring of breast cancer are critical. Current diagnostic techniques are mammography and tissue biopsy; however, they have limitations. With the development of novel techniques, such as personalized medicine and genetic profiling, liquid biopsy is emerging as the less invasive tool for diagnosing and monitoring breast cancer. Liquid biopsy is performed by sampling biofluids and extracting tumor components, such as circulating tumor cells (CTCs), circulating tumor DNA (ctDNA), cell-free mRNA (cfRNA) and microRNA (miRNA), proteins, and extracellular vehicles (EVs). In this review, we summarize and focus on the recent discoveries of tumor components and biomarkers applied in liquid biopsy and novel development of detection techniques, such as surface-enhanced Raman spectroscopy (SERS) and microfluidic devices. Full article
(This article belongs to the Special Issue Clinical Perspective and Translational Oncology of Liquid Biopsy)
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15 pages, 303 KiB  
Review
Current Landscape of Immune Checkpoint Inhibitor Therapy for Hepatocellular Carcinoma
by Nikolaos Machairas, Diamantis I. Tsilimigras and Timothy M. Pawlik
Cancers 2022, 14(8), 2018; https://doi.org/10.3390/cancers14082018 - 16 Apr 2022
Cited by 15 | Viewed by 5286
Abstract
Hepatocellular carcinoma (HCC) is the most frequent primary liver tumor. As a result of advanced disease being often present at diagnosis, only a small percentage of patients are amenable to curative-intent treatment options such as surgical resection and liver transplantation. Systemic therapy consisting [...] Read more.
Hepatocellular carcinoma (HCC) is the most frequent primary liver tumor. As a result of advanced disease being often present at diagnosis, only a small percentage of patients are amenable to curative-intent treatment options such as surgical resection and liver transplantation. Systemic therapy consisting of tyrosine kinase inhibitors such as sorafenib had been used for over a decade with limited efficacy. More recently, treatment with immune checkpoint inhibitors has revolutionized the treatment landscape of various malignant tumors. With this shifting paradigm, recent data have demonstrated encouraging outcomes among patients with HCC. In particular, several trials have investigated the safety and efficacy of various immune checkpoint inhibitors (ICI) either as monotherapy or in the form of combined treatments. We sought to provide an overview of recent clinical trials among patients with advanced HCC as well as to highlight predictors of response and immune-related adverse events and to review the evidence on perioperative administration of ICI in patients with resectable HCC. Full article
25 pages, 1591 KiB  
Review
Dissecting Tumor-Immune Microenvironment in Breast Cancer at a Spatial and Multiplex Resolution
by Evangelos Tzoras, Ioannis Zerdes, Nikos Tsiknakis, Georgios C. Manikis, Artur Mezheyeuski, Jonas Bergh, Alexios Matikas and Theodoros Foukakis
Cancers 2022, 14(8), 1999; https://doi.org/10.3390/cancers14081999 - 14 Apr 2022
Cited by 6 | Viewed by 4704
Abstract
The tumor immune microenvironment (TIME) is an important player in breast cancer pathophysiology. Surrogates for antitumor immune response have been explored as predictive biomarkers to immunotherapy, though with several limitations. Immunohistochemistry for programmed death ligand 1 suffers from analytical problems, immune signatures are [...] Read more.
The tumor immune microenvironment (TIME) is an important player in breast cancer pathophysiology. Surrogates for antitumor immune response have been explored as predictive biomarkers to immunotherapy, though with several limitations. Immunohistochemistry for programmed death ligand 1 suffers from analytical problems, immune signatures are devoid of spatial information and histopathological evaluation of tumor infiltrating lymphocytes exhibits interobserver variability. Towards improved understanding of the complex interactions in TIME, several emerging multiplex in situ methods are being developed and gaining much attention for protein detection. They enable the simultaneous evaluation of multiple targets in situ, detection of cell densities/subpopulations as well as estimations of functional states of immune infiltrate. Furthermore, they can characterize spatial organization of TIME—by cell-to-cell interaction analyses and the evaluation of distribution within different regions of interest and tissue compartments—while digital imaging and image analysis software allow for reproducibility of the various assays. In this review, we aim to provide an overview of the different multiplex in situ methods used in cancer research with special focus on breast cancer TIME at the neoadjuvant, adjuvant and metastatic setting. Spatial heterogeneity of TIME and importance of longitudinal evaluation of TIME changes under the pressure of therapy and metastatic progression are also addressed. Full article
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18 pages, 2344 KiB  
Article
T-Cells Expressing a Highly Potent PRAME-Specific T-Cell Receptor in Combination with a Chimeric PD1-41BB Co-Stimulatory Receptor Show a Favorable Preclinical Safety Profile and Strong Anti-Tumor Reactivity
by Nadja Sailer, Ina Fetzer, Melanie Salvermoser, Monika Braun, Doris Brechtefeld, Christian Krendl, Christiane Geiger, Kathrin Mutze, Elfriede Noessner, Dolores J. Schendel, Maja Bürdek, Susanne Wilde and Daniel Sommermeyer
Cancers 2022, 14(8), 1998; https://doi.org/10.3390/cancers14081998 - 14 Apr 2022
Cited by 9 | Viewed by 7206
Abstract
The hostile tumor microenvironment (TME) is a major challenge for the treatment of solid tumors with T-cell receptor (TCR)-modified T-cells (TCR-Ts), as it negatively influences T-cell efficacy, fitness, and persistence. These negative influences are caused, among others, by the inhibitory checkpoint PD-1/PD-L1 axis. [...] Read more.
The hostile tumor microenvironment (TME) is a major challenge for the treatment of solid tumors with T-cell receptor (TCR)-modified T-cells (TCR-Ts), as it negatively influences T-cell efficacy, fitness, and persistence. These negative influences are caused, among others, by the inhibitory checkpoint PD-1/PD-L1 axis. The Preferentially Expressed Antigen in Melanoma (PRAME) is a highly relevant cancer/testis antigen for TCR-T immunotherapy due to broad expression in multiple solid cancer indications. A TCR with high specificity and sensitivity for PRAME was isolated from non-tolerized T-cell repertoires and introduced into T-cells alongside a chimeric PD1-41BB receptor, consisting of the natural extracellular domain of PD-1 and the intracellular signaling domain of 4-1BB, turning an inhibitory pathway into a T-cell co-stimulatory pathway. The addition of PD1-41BB to CD8+ T-cells expressing the transgenic PRAME-TCR enhanced IFN-γ secretion, improved cytotoxic capacity, and prevented exhaustion upon repetitive re-challenge with tumor cells in vitro without altering the in vitro safety profile. Furthermore, a single dose of TCR-Ts co-expressing PD1-41BB was sufficient to clear a hard-to-treat melanoma xenograft in a mouse model, whereas TCR-Ts without PD1-41BB could not eradicate the PD-L1-positive tumors. This cutting-edge strategy supports development efforts to provide more effective TCR-T immunotherapies for the treatment of solid tumors. Full article
(This article belongs to the Special Issue Engineering the Tumor Immune Microenvironment)
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13 pages, 6512 KiB  
Article
Sarcopenia Predicts Major Complications after Resection for Primary Hepatocellular Carcinoma in Compensated Cirrhosis
by Giovanni Marasco, Elton Dajti, Matteo Serenari, Luigina Vanessa Alemanni, Federico Ravaioli, Matteo Ravaioli, Amanda Vestito, Giulio Vara, Davide Festi, Rita Golfieri, Matteo Cescon, Matteo Renzulli and Antonio Colecchia
Cancers 2022, 14(8), 1935; https://doi.org/10.3390/cancers14081935 - 12 Apr 2022
Cited by 13 | Viewed by 1801
Abstract
The burden of post-operative complications of patients undergoing liver resection for hepatocellular carcinoma (HCC) is a cause of morbidity and mortality. Recently, sarcopenia has been reported to influence the outcome of patients with cirrhosis. We aimed to assess factors associated with sarcopenia and [...] Read more.
The burden of post-operative complications of patients undergoing liver resection for hepatocellular carcinoma (HCC) is a cause of morbidity and mortality. Recently, sarcopenia has been reported to influence the outcome of patients with cirrhosis. We aimed to assess factors associated with sarcopenia and its prognostic role in liver surgery candidates. We included all patients with compensated advanced chronic liver disease (cACLD) undergoing liver resection for primary HCC consecutively referred to the University of Bologna from 2014 to 2019 with an available preoperative abdominal CT-scan performed within the previous three months. A total of 159 patients were included. The median age was 68 years, and 80.5% of the patients were male. Sarcopenia was present in 82 patients (51.6%). Age and body mass index (BMI) were associated with the presence of sarcopenia at multivariate analysis. Thirteen (8.2%) patients developed major complications and 14 (8.9%) presented PHLF grade B-C. The model for end-stage liver disease score was associated with the development of major complications, whereas cACLD presence, thrombocytopenia, portal hypertension (PH), Child-Pugh score and Albumin-Bilirubin score were found to be predictors of clinically significative PHLF. The rate of major complications was 11.8% in sarcopenic patients with cACLD compared with no complications (0%) in patients without sarcopenia and cACLD (p = 0.032). The rate of major complications was significantly higher in patients with (16.3%) vs. patients without (0%) sarcopenia (p = 0.012) in patients with PH. In conclusion, sarcopenia, which is associated with age and BMI, may improve the risk stratification of post-hepatectomy major complications in patients with cACLD and PH. Full article
(This article belongs to the Section Cancer Therapy)
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32 pages, 1387 KiB  
Review
Monoclonal Antibodies in the Treatment of Diffuse Large B-Cell Lymphoma: Moving beyond Rituximab
by Sotirios G. Papageorgiou, Thomas P. Thomopoulos, Athanasios Liaskas and Theodoros P. Vassilakopoulos
Cancers 2022, 14(8), 1917; https://doi.org/10.3390/cancers14081917 - 10 Apr 2022
Cited by 10 | Viewed by 7085
Abstract
Although rituximab has revolutionized the treatment of diffuse large B-cell lymphoma (DLBCL), a significant proportion of patients experience refractory disease or relapse early after the end of treatment. The lack of effective treatment options in the relapsed/refractory (R/R) setting had made the prognosis [...] Read more.
Although rituximab has revolutionized the treatment of diffuse large B-cell lymphoma (DLBCL), a significant proportion of patients experience refractory disease or relapse early after the end of treatment. The lack of effective treatment options in the relapsed/refractory (R/R) setting had made the prognosis of these patients dismal. The initial enthusiasm for novel anti-CD20 antibodies had been short-lived as they failed to prove their superiority to rituximab. Therefore, research has focused on developing novel agents with a unique mechanism of action. Among them, two antibody-drug conjugates, namely polatuzumab vedotin (PolaV) and loncastuximab tesirine, along with tafasitamab, an anti-CD19 bioengineered antibody, have been approved for the treatment of R/R DLBCL. Whereas PolaV has been FDA and EMA approved, EMA has not approved loncastuximab tesirine and tafasitamab yet. Results from randomized trials, as well as real-life data for PolaV have been promising. Novel agents as bispecific antibodies bridging CD3 on T-cells to CD20 have shown very promising results in clinical trials and are expected to gain approval for treatment of R/R DLBCL soon. As the therapeutic armamentarium against DLBCL is expanding, an improvement in survival of patients with R/R and higher cure rates might soon become evident. Full article
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17 pages, 1253 KiB  
Review
Regulation of ZEB1 Function and Molecular Associations in Tumor Progression and Metastasis
by Mabel Perez-Oquendo and Don L. Gibbons
Cancers 2022, 14(8), 1864; https://doi.org/10.3390/cancers14081864 - 07 Apr 2022
Cited by 21 | Viewed by 4804
Abstract
Zinc finger E-box binding homeobox 1 (ZEB1) is a pleiotropic transcription factor frequently expressed in carcinomas. ZEB1 orchestrates the transcription of genes in the control of several key developmental processes and tumor metastasis via the epithelial-to-mesenchymal transition (EMT). The biological function of ZEB1 [...] Read more.
Zinc finger E-box binding homeobox 1 (ZEB1) is a pleiotropic transcription factor frequently expressed in carcinomas. ZEB1 orchestrates the transcription of genes in the control of several key developmental processes and tumor metastasis via the epithelial-to-mesenchymal transition (EMT). The biological function of ZEB1 is regulated through pathways that influence its transcription and post-transcriptional mechanisms. Diverse signaling pathways converge to induce ZEB1 activity; however, only a few studies have focused on the molecular associations or functional changes of ZEB1 by post-translational modifications (PTMs). Due to the robust effect of ZEB1 as a transcription repressor of epithelial genes during EMT, the contribution of PTMs in the regulation of ZEB1-targeted gene expression is an active area of investigation. Herein, we review the pivotal roles that phosphorylation, acetylation, ubiquitination, sumoylation, and other modifications have in regulating the molecular associations and behavior of ZEB1. We also outline several questions regarding the PTM-mediated regulation of ZEB1 that remain unanswered. The areas of research covered in this review are contributing to new treatment strategies for cancer by improving our mechanistic understanding of ZEB1-mediated EMT. Full article
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30 pages, 2934 KiB  
Review
Melanin and Melanin-Functionalized Nanoparticles as Promising Tools in Cancer Research—A Review
by Iasmina Marcovici, Dorina Coricovac, Iulia Pinzaru, Ioana Gabriela Macasoi, Roxana Popescu, Raul Chioibas, Istvan Zupko and Cristina Adriana Dehelean
Cancers 2022, 14(7), 1838; https://doi.org/10.3390/cancers14071838 - 06 Apr 2022
Cited by 23 | Viewed by 4549
Abstract
Cancer poses an ongoing global challenge, despite the substantial progress made in the prevention, diagnosis, and treatment of the disease. The existing therapeutic methods remain limited by undesirable outcomes such as systemic toxicity and lack of specificity or long-term efficacy, although innovative alternatives [...] Read more.
Cancer poses an ongoing global challenge, despite the substantial progress made in the prevention, diagnosis, and treatment of the disease. The existing therapeutic methods remain limited by undesirable outcomes such as systemic toxicity and lack of specificity or long-term efficacy, although innovative alternatives are being continuously investigated. By offering a means for the targeted delivery of therapeutics, nanotechnology (NT) has emerged as a state-of-the-art solution for augmenting the efficiency of currently available cancer therapies while combating their drawbacks. Melanin, a polymeric pigment of natural origin that is widely spread among many living organisms, became a promising candidate for NT-based cancer treatment owing to its unique physicochemical properties (e.g., high biocompatibility, redox behavior, light absorption, chelating ability) and innate antioxidant, photoprotective, anti-inflammatory, and antitumor effects. The latest research on melanin and melanin-like nanoparticles has extended considerably on many fronts, allowing not only efficient cancer treatments via both traditional and modern methods, but also early disease detection and diagnosis. The current paper provides an updated insight into the applicability of melanin in cancer therapy as antitumor agent, molecular target, and delivery nanoplatform. Full article
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28 pages, 1150 KiB  
Review
MMP9: A Tough Target for Targeted Therapy for Cancer
by Katarzyna Augoff, Anita Hryniewicz-Jankowska, Renata Tabola and Kamilla Stach
Cancers 2022, 14(7), 1847; https://doi.org/10.3390/cancers14071847 - 06 Apr 2022
Cited by 62 | Viewed by 6257
Abstract
Having the capability to proteolyze diverse structural and signaling proteins, matrix metalloproteinase 9 (MMP9), one of the best-studied secretory endopeptidases, has been identified as a crucial mediator of processes closely associated with tumorigenesis, such as the extracellular matrix reorganization, epithelial to mesenchymal transition, [...] Read more.
Having the capability to proteolyze diverse structural and signaling proteins, matrix metalloproteinase 9 (MMP9), one of the best-studied secretory endopeptidases, has been identified as a crucial mediator of processes closely associated with tumorigenesis, such as the extracellular matrix reorganization, epithelial to mesenchymal transition, cell migration, new blood vessel formation, and immune response. In this review, we present the current state of knowledge on MMP9 and its role in cancer growth in the context of cell adhesion/migration, cancer-related inflammation, and tumor microenvironment formation. We also summarize recent achievements in the development of selective MMP9 inhibitors and the limitations of using them as anticancer drugs. Full article
(This article belongs to the Section Cancer Therapy)
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19 pages, 2138 KiB  
Review
Impact of Lipid Metabolism on Antitumor Immune Response
by Nesrine Mabrouk, Baptiste Lecoeur, Ali Bettaieb, Catherine Paul and Frédérique Végran
Cancers 2022, 14(7), 1850; https://doi.org/10.3390/cancers14071850 - 06 Apr 2022
Cited by 18 | Viewed by 3105
Abstract
Over the past decade, metabolic reprogramming has been defined as a hallmark of cancer. More recently, a large number of studies have demonstrated that metabolic reprogramming can modulate the differentiation and functions of immune cells, and thus modify the antitumor response. Increasing evidence [...] Read more.
Over the past decade, metabolic reprogramming has been defined as a hallmark of cancer. More recently, a large number of studies have demonstrated that metabolic reprogramming can modulate the differentiation and functions of immune cells, and thus modify the antitumor response. Increasing evidence suggests that modified energy metabolism could be responsible for the failure of antitumor immunity. Indeed, tumor-infiltrating immune cells play a key role in cancer, and metabolic switching in these cells has been shown to help determine their phenotype: tumor suppressive or immune suppressive. Recent studies in the field of immunometabolism focus on metabolic reprogramming in the tumor microenvironment (TME) by targeting innate and adaptive immune cells and their associated anti- or protumor phenotypes. In this review, we discuss the lipid metabolism of immune cells in the TME as well as the effects of lipids; finally, we expose the link between therapies and lipid metabolism. Full article
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