Cancers

29 pages, 1267 KiB

Open AccessEditor’s ChoiceReview

Targeting HIF-2α in the Tumor Microenvironment: Redefining the Role of HIF-2α for Solid Cancer Therapy

by Leah Davis, Matthias Recktenwald, Evan Hutt, Schuyler Fuller, Madison Briggs, Arnav Goel and Nichole Daringer

Cancers 2022, 14(5), 1259; https://doi.org/10.3390/cancers14051259 - 28 Feb 2022

Cited by 28 | Viewed by 6426

Abstract

Inadequate oxygen supply, or hypoxia, is characteristic of the tumor microenvironment and correlates with poor prognosis and therapeutic resistance. Hypoxia leads to the activation of the hypoxia-inducible factor (HIF) signaling pathway and stabilization of the HIF-α subunit, driving tumor progression. The homologous alpha [...] Read more.

Inadequate oxygen supply, or hypoxia, is characteristic of the tumor microenvironment and correlates with poor prognosis and therapeutic resistance. Hypoxia leads to the activation of the hypoxia-inducible factor (HIF) signaling pathway and stabilization of the HIF-α subunit, driving tumor progression. The homologous alpha subunits, HIF-1α and HIF-2α, are responsible for mediating the transcription of a multitude of critical proteins that control proliferation, angiogenic signaling, metastasis, and other oncogenic factors, both differentially and sequentially regulating the hypoxic response. Post-translational modifications of HIF play a central role in its behavior as a mediator of transcription, as well as the temporal transition from HIF-1α to HIF-2α that occurs in response to chronic hypoxia. While it is evident that HIF-α is highly dynamic, HIF-2α remains vastly under-considered. HIF-2α can intensify the behaviors of the most aggressive tumors by adapting the cell to oxidative stress, thereby promoting metastasis, tissue remodeling, angiogenesis, and upregulating cancer stem cell factors. The structure, function, hypoxic response, spatiotemporal dynamics, and roles in the progression and persistence of cancer of this HIF-2α molecule and its EPAS1 gene are highlighted in this review, alongside a discussion of current therapeutics and future directions. Full article

(This article belongs to the Special Issue Hypoxia and Cancer: From Bench to Bedside)

► Show Figures

Figure 1

29 pages, 2394 KiB

Open AccessEditor’s ChoiceReview

Cancer-Associated Fibroblasts: Mechanisms of Tumor Progression and Novel Therapeutic Targets

by Ralf-Peter Czekay, Dong-Joo Cheon, Rohan Samarakoon, Stacie M. Kutz and Paul J. Higgins

Cancers 2022, 14(5), 1231; https://doi.org/10.3390/cancers14051231 - 27 Feb 2022

Cited by 41 | Viewed by 5681

Abstract

Cancer-associated fibroblasts (CAFs) are a heterogenous population of stromal cells found in solid malignancies that coexist with the growing tumor mass and other immune/nonimmune cellular elements. In certain neoplasms (e.g., desmoplastic tumors), CAFs are the prominent mesenchymal cell type in the tumor microenvironment, [...] Read more.

Cancer-associated fibroblasts (CAFs) are a heterogenous population of stromal cells found in solid malignancies that coexist with the growing tumor mass and other immune/nonimmune cellular elements. In certain neoplasms (e.g., desmoplastic tumors), CAFs are the prominent mesenchymal cell type in the tumor microenvironment, where their presence and abundance signal a poor prognosis in multiple cancers. CAFs play a major role in the progression of various malignancies by remodeling the supporting stromal matrix into a dense, fibrotic structure while secreting factors that lead to the acquisition of cancer stem-like characteristics and promoting tumor cell survival, reduced sensitivity to chemotherapeutics, aggressive growth and metastasis. Tumors with high stromal fibrotic signatures are more likely to be associated with drug resistance and eventual relapse. Clarifying the molecular basis for such multidirectional crosstalk among the various normal and neoplastic cell types present in the tumor microenvironment may yield novel targets and new opportunities for therapeutic intervention. This review highlights the most recent concepts regarding the complexity of CAF biology including CAF heterogeneity, functionality in drug resistance, contribution to a progressively fibrotic tumor stroma, the involved signaling pathways and the participating genes. Full article

(This article belongs to the Special Issue Cancer-Associated Fibroblasts: Mechanisms of Tumor Progression and Novel Therapeutic Targets)

► Show Figures

Figure 1

26 pages, 3662 KiB

Open AccessEditor’s ChoiceReview

Emerging CAR T Cell Strategies for the Treatment of AML

by Paresh Vishwasrao, Gongbo Li, Justin C. Boucher, D. Lynne Smith and Susanta K. Hui

Cancers 2022, 14(5), 1241; https://doi.org/10.3390/cancers14051241 - 27 Feb 2022

Cited by 24 | Viewed by 6623

Abstract

Engineered T cells expressing chimeric antigen receptors (CARs) on their cell surface can redirect antigen specificity. This ability makes CARs one of the most promising cancer therapeutic agents. CAR-T cells for treating patients with B cell hematological malignancies have shown impressive results. Clinical [...] Read more.

Engineered T cells expressing chimeric antigen receptors (CARs) on their cell surface can redirect antigen specificity. This ability makes CARs one of the most promising cancer therapeutic agents. CAR-T cells for treating patients with B cell hematological malignancies have shown impressive results. Clinical manifestation has yielded several trials, so far five CAR-T cell therapies have received US Food and Drug Administration (FDA) approval. However, emerging clinical data and recent findings have identified some immune-related toxicities due to CAR-T cell therapy. Given the outcome and utilization of the same proof of concept, further investigation in other hematological malignancies, such as leukemias, is warranted. This review discusses the previous findings from the pre-clinical and human experience with CAR-T cell therapy. Additionally, we describe recent developments of novel targets for adoptive immunotherapy. Here we present some of the early findings from the pre-clinical studies of CAR-T cell modification through advances in genetic engineering, gene editing, cellular programming, and formats of synthetic biology, along with the ongoing efforts to restore the function of exhausted CAR-T cells through epigenetic remodeling. We aim to shed light on the new targets focusing on acute myeloid leukemia (AML). Full article

(This article belongs to the Special Issue Immune Therapies for Hematologic Malignancies)

► Show Figures

Figure 1

11 pages, 10534 KiB

Open AccessEditor’s ChoiceReview

Diverse Roles and Targets of miRNA in the Pathogenesis of Testicular Germ Cell Tumour

by Mrinal K. Das, Øyvind P. Haugen and Trine B. Haugen

Cancers 2022, 14(5), 1190; https://doi.org/10.3390/cancers14051190 - 25 Feb 2022

Cited by 9 | Viewed by 2372

Abstract

Testicular germ cell tumour (TGCT) is the most common cancer type among young adults in many parts of the world. Although the pathogenesis of TGCT is not well understood, the involvement of heritable components is evident, and the risk is polygenic. Genome-wide association [...] Read more.

Testicular germ cell tumour (TGCT) is the most common cancer type among young adults in many parts of the world. Although the pathogenesis of TGCT is not well understood, the involvement of heritable components is evident, and the risk is polygenic. Genome-wide association studies have so far found 78 susceptibility loci for TGCT, and many of the loci are in non-coding regions indicating the involvement of non-coding RNAs in TGCT pathogenesis. MicroRNAs (miRNAs), a class of non-coding RNAs, have emerged as important gene regulators at the post-transcriptional level. They are crucial in controlling many cellular processes, such as proliferation, differentiation, and apoptosis, and an aberrant miRNA expression may contribute to the pathogenesis of several cancers, including TGCT. In support of this notion, several studies reported differential expression of miRNAs in TGCTs. We previously demonstrated that miRNAs were the most common group of small non-coding RNAs in TGCTs, and several functional studies of miRNAs in TGCTs suggest that they may act as either oncogene or tumour suppressors. Moreover, individual miRNA targets and downstream pathways in the context of TGCT development have been explored. In this review, we will focus on the diverse roles and targets of miRNAs in TGCT pathogenesis. Full article

(This article belongs to the Special Issue Non-coding RNA in Cancer: A Focus on Mechanisms of Action, Biomarker Properties, and Treatment Options)

► Show Figures

Figure 1

33 pages, 2754 KiB

Open AccessEditor’s ChoiceReview

Actively Targeted Nanomedicines in Breast Cancer: From Pre-Clinal Investigation to Clinic

by Ana Isabel Fraguas-Sánchez, Irene Lozza and Ana Isabel Torres-Suárez

Cancers 2022, 14(5), 1198; https://doi.org/10.3390/cancers14051198 - 25 Feb 2022

Cited by 28 | Viewed by 5271

Abstract

Breast cancer is one of the most frequently diagnosed tumors and the second leading cause of cancer death in women worldwide. The use of nanosystems specifically targeted to tumor cells (active targeting) can be an excellent therapeutic tool to improve and optimize current [...] Read more.

Breast cancer is one of the most frequently diagnosed tumors and the second leading cause of cancer death in women worldwide. The use of nanosystems specifically targeted to tumor cells (active targeting) can be an excellent therapeutic tool to improve and optimize current chemotherapy for this type of neoplasm, since they make it possible to reduce the toxicity and, in some cases, increase the efficacy of antineoplastic drugs. Currently, there are 14 nanomedicines that have reached the clinic for the treatment of breast cancer, 4 of which are already approved (Kadcyla^®, Enhertu^®, Trodelvy^®, and Abraxane^®). Most of these nanomedicines are antibody–drug conjugates. In the case of HER-2-positive breast cancer, these conjugates (Kadcyla^®, Enhertu^®, Trastuzumab-duocarmycin, RC48, and HT19-MMAF) target HER-2 receptors, and incorporate maytansinoid, deruxtecan, duocarmicyn, or auristatins as antineoplastics. In TNBC these conjugates (Trodelvy^®, Glembatumumab-Vedotin, Ladiratuzumab-vedotin, Cofetuzumab-pelidotin, and PF-06647263) are directed against various targets, in particular Trop-2 glycoprotein, NMB glycoprotein, Zinc transporter LIV-1, and Ephrin receptor-4, to achieve this selective accumulation, and include campthotecins, calicheamins, or auristatins as drugs. Apart from the antibody–drug conjugates, there are other active targeted nanosystems that have reached the clinic for the treatment of these tumors such as Abraxane^® and Nab-rapamicyn (albumin nanoparticles entrapping placlitaxel and rapamycin respectively) and various liposomes (MM-302, C225-ILS-Dox, and MM-310) loaded with doxorubicin or docetaxel and coated with ligands targeted to Ephrin A2, EPGF, or HER-2 receptors. In this work, all these active targeted nanomedicines are discussed, analyzing their advantages and disadvantages over conventional chemotherapy as well as the challenges involved in their lab to clinical translation. In addition, examples of formulations developed and evaluated at the preclinical level are also discussed. Full article

(This article belongs to the Special Issue Development of Innovative Formulations for Breast Cancer Chemotherapy)

► Show Figures

Figure 1

15 pages, 12400 KiB

Open AccessEditor’s ChoiceArticle

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

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

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

Cited by 23 | Viewed by 6661

Abstract

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

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

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

► Show Figures

Figure 1

15 pages, 5789 KiB

Open AccessEditor’s ChoiceArticle

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

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

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

Cited by 24 | Viewed by 3532

Abstract

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

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

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

► Show Figures

Figure 1

22 pages, 1555 KiB

Open AccessEditor’s ChoiceArticle

Immune Checkpoint Inhibitors—Associated Cardiotoxicity

by Chenghui Li, Sajjad A. Bhatti and Jun Ying

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

Cited by 24 | Viewed by 3681

Abstract

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

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

► Show Figures

Figure 1

21 pages, 803 KiB

Open AccessEditor’s ChoiceReview

The Role of TP53 Mutations in EGFR-Mutated Non-Small-Cell Lung Cancer: Clinical Significance and Implications for Therapy

by Matteo Canale, Kalliopi Andrikou, Ilaria Priano, Paola Cravero, Luigi Pasini, Milena Urbini, Angelo Delmonte, Lucio Crinò, Giuseppe Bronte and Paola Ulivi

Cancers 2022, 14(5), 1143; https://doi.org/10.3390/cancers14051143 - 23 Feb 2022

Cited by 22 | Viewed by 4412

Abstract

Non-Small-Cell Lung Cancer (NSCLC) is the primary cause of cancer-related death worldwide. Oncogene-addicted patients usually benefit from targeted therapy, but primary and acquired resistance mechanisms inevitably occur. Tumor protein 53 (TP53) gene is the most frequently mutated gene in cancer, including [...] Read more.

Non-Small-Cell Lung Cancer (NSCLC) is the primary cause of cancer-related death worldwide. Oncogene-addicted patients usually benefit from targeted therapy, but primary and acquired resistance mechanisms inevitably occur. Tumor protein 53 (TP53) gene is the most frequently mutated gene in cancer, including NSCLC. TP53 mutations are able to induce carcinogenesis, tumor development and resistance to therapy, influencing patient prognosis and responsiveness to therapy. TP53 mutants present in different forms, suggesting that different gene alterations confer specific acquired protein functions. In recent years, many associations between different TP53 mutations and responses to Epidermal Growth Factor Receptor (EGFR) targeted therapy in NSCLC patients have been found. In this review, we discuss the current landscape concerning the role of TP53 mutants to guide primary and acquired resistance to Tyrosine-Kinase Inhibitors (TKIs) EGFR-directed, investigating the possible mechanisms of TP53 mutants within the cellular compartments. We also discuss the role of the TP53 mutations in predicting the response to targeted therapy with EGFR-TKIs, as a possible biomarker to guide patient stratification for treatment. Full article

(This article belongs to the Special Issue Mechanisms of Resistance in EGFR-Mutated Non-Small Cell Lung Cancer)

► Show Figures

Figure 1

21 pages, 790 KiB

Open AccessEditor’s ChoiceReview

The Role of Purinergic P2X7 Receptor in Inflammation and Cancer: Novel Molecular Insights and Clinical Applications

by John Charles Rotondo, Chiara Mazziotta, Carmen Lanzillotti, Chiara Stefani, Giada Badiale, Giulia Campione, Fernanda Martini and Mauro Tognon

Cancers 2022, 14(5), 1116; https://doi.org/10.3390/cancers14051116 - 22 Feb 2022

Cited by 37 | Viewed by 6150

Abstract

The purinergic P2X7 receptor (P2X7R) is a transmembrane protein whose expression has been related to a variety of cellular processes, while its dysregulation has been linked to inflammation and cancer. P2X7R is expressed in cancer and immune system cell surfaces. ATP plays a [...] Read more.

The purinergic P2X7 receptor (P2X7R) is a transmembrane protein whose expression has been related to a variety of cellular processes, while its dysregulation has been linked to inflammation and cancer. P2X7R is expressed in cancer and immune system cell surfaces. ATP plays a key role in numerous metabolic processes due to its abundance in the tumour microenvironment. P2X7R plays an important role in cancer by interacting with ATP. The unusual property of P2X7R is that stimulation with low doses of ATP causes the opening of a permeable channel for sodium, potassium, and calcium ions, whereas sustained stimulation with high doses of ATP favours the formation of a non-selective pore. The latter effect induces a change in intracellular homeostasis that leads to cell death. This evidence suggests that P2X7R has both pro- and anti-tumour proprieties. P2X7R is increasingly recognised as a regulator of inflammation. In this review, we aimed to describe the most relevant characteristics of P2X7R function, activation, and its ligands, while also summarising the role of P2X7R activation in the context of inflammation and cancer. The currently used therapeutic approaches and clinical trials of P2X7R modulators are also described. Full article

(This article belongs to the Special Issue Crosstalk between Inflammation and Carcinogenesis)

► Show Figures

Figure 1

13 pages, 2514 KiB

Open AccessEditor’s ChoiceReview

Update on Epidemiology, Diagnosis, and Biomarkers in Gastroenteropancreatic Neuroendocrine Neoplasms

by Daisuke Takayanagi, Hourin Cho, Erika Machida, Atsushi Kawamura, Atsuo Takashima, Satoshi Wada, Takuya Tsunoda, Takashi Kohno and Kouya Shiraishi

Cancers 2022, 14(5), 1119; https://doi.org/10.3390/cancers14051119 - 22 Feb 2022

Cited by 26 | Viewed by 3336

Abstract

Gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs) are a heterogeneous group of malignancies that originate from the diffuse neuroendocrine cell system of the pancreas and gastrointestinal tract and have increasingly increased in number over the decades. GEP-NENs are roughly classified into well-differentiated neuroendocrine tumors and poorly [...] Read more.

Gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs) are a heterogeneous group of malignancies that originate from the diffuse neuroendocrine cell system of the pancreas and gastrointestinal tract and have increasingly increased in number over the decades. GEP-NENs are roughly classified into well-differentiated neuroendocrine tumors and poorly differentiated neuroendocrine carcinomas; it is essential to understand the pathological classification according to the mitotic count and Ki67 proliferation index. In addition, with the advent of molecular-targeted drugs and somatostatin analogs and advances in endoscopic and surgical treatments, the multidisciplinary treatment of GEP-NENs has made great progress. In the management of GEP-NENs, accurate diagnosis is key for the proper selection among these diversified treatment methods. The evaluation of hormone-producing ability, diagnostic imaging, and histological diagnosis is central. Advances in the study of the genetic landscape have led to deeper understanding of tumor biology; it has also become possible to identify druggable mutations and predict therapeutic effects. Liquid biopsy, based on blood mRNA expression for GEP-NENs, has been developed, and is useful not only for early detection but also for assessing minimal residual disease after surgery and prediction of therapeutic effects. This review outlines the updates and future prospects of the epidemiology, diagnosis, and management of GEP-NENs. Full article

(This article belongs to the Collection Neuroendocrine Tumors: Treatment and Management)

► Show Figures

Figure 1

16 pages, 4091 KiB

Open AccessEditor’s ChoiceReview

Targeting Protein Kinase C for Cancer Therapy

by Sijia He, Qi Li, Qian Huang and Jin Cheng

Cancers 2022, 14(5), 1104; https://doi.org/10.3390/cancers14051104 - 22 Feb 2022

Cited by 24 | Viewed by 3962

Abstract

Protein kinase C (PKC) isoforms, a group of serine-threonine kinases, are important regulators in carcinogenesis. Numerous studies have demonstrated that PKC isoforms exert both positive and negative effects on cancer cell demise. In this review, we systematically summarize the current findings on the [...] Read more.

Protein kinase C (PKC) isoforms, a group of serine-threonine kinases, are important regulators in carcinogenesis. Numerous studies have demonstrated that PKC isoforms exert both positive and negative effects on cancer cell demise. In this review, we systematically summarize the current findings on the architecture, activity regulation and biological functions of PKCs, especially their relationship with anti-cancer therapy-induced cell death. Additionally, we elaborate on current knowledge of the effects of PKCs on tumor metabolism and microenvironment, which have gained increasing attention in oncology-related areas. Furthermore, we underscore the basic experimental and clinical implications of PKCs as a target for cancer therapy to evaluate their therapeutic benefits and potential applications. Full article

(This article belongs to the Special Issue AGC Kinases and Cancer)

► Show Figures

Figure 1

24 pages, 1557 KiB

Open AccessEditor’s ChoiceReview

The Roles of microRNAs in Cancer Multidrug Resistance

by Lucia Pavlíková, Mário Šereš, Albert Breier and Zdena Sulová

Cancers 2022, 14(4), 1090; https://doi.org/10.3390/cancers14041090 - 21 Feb 2022

Cited by 20 | Viewed by 3394

Abstract

Cancer chemotherapy may induce a multidrug resistance (MDR) phenotype. The development of MDR is based on various molecular causes, of which the following are very common: induction of ABC transporter expression; induction/activation of drug-metabolizing enzymes; alteration of the expression/function of apoptosis-related proteins; changes [...] Read more.

Cancer chemotherapy may induce a multidrug resistance (MDR) phenotype. The development of MDR is based on various molecular causes, of which the following are very common: induction of ABC transporter expression; induction/activation of drug-metabolizing enzymes; alteration of the expression/function of apoptosis-related proteins; changes in cell cycle checkpoints; elevated DNA repair mechanisms. Although these mechanisms of MDR are well described, information on their molecular interaction in overall multidrug resistance is still lacking. MicroRNA (miRNA) expression and subsequent RNA interference are candidates that could be important players in the interplay of MDR mechanisms. The regulation of post-transcriptional processes in the proteosynthetic pathway is considered to be a major function of miRNAs. Due to their complementarity, they are able to bind to target mRNAs, which prevents the mRNAs from interacting effectively with the ribosome, and subsequent degradation of the mRNAs can occur. The aim of this paper is to provide an overview of the possible role of miRNAs in the molecular mechanisms that lead to MDR. The possibility of considering miRNAs as either specific effectors or interesting targets for cancer therapy is also analyzed. Full article

(This article belongs to the Special Issue The Roles of microRNAs in Cancer Aggressiveness and Drug Resistance)

► Show Figures

Graphical abstract

24 pages, 1132 KiB

Open AccessEditor’s ChoiceReview

Knowns and Unknowns about CAR-T Cell Dysfunction

by Aleksei Titov, Yaroslav Kaminskiy, Irina Ganeeva, Ekaterina Zmievskaya, Aygul Valiullina, Aygul Rakhmatullina, Alexey Petukhov, Regina Miftakhova, Albert Rizvanov and Emil Bulatov

Cancers 2022, 14(4), 1078; https://doi.org/10.3390/cancers14041078 - 21 Feb 2022

Cited by 24 | Viewed by 5790

Abstract

Immunotherapy using chimeric antigen receptor (CAR) T cells is a promising option for cancer treatment. However, T cells and CAR-T cells frequently become dysfunctional in cancer, where numerous evasion mechanisms impair antitumor immunity. Cancer frequently exploits intrinsic T cell dysfunction mechanisms that evolved [...] Read more.

Immunotherapy using chimeric antigen receptor (CAR) T cells is a promising option for cancer treatment. However, T cells and CAR-T cells frequently become dysfunctional in cancer, where numerous evasion mechanisms impair antitumor immunity. Cancer frequently exploits intrinsic T cell dysfunction mechanisms that evolved for the purpose of defending against autoimmunity. T cell exhaustion is the most studied type of T cell dysfunction. It is characterized by impaired proliferation and cytokine secretion and is often misdefined solely by the expression of the inhibitory receptors. Another type of dysfunction is T cell senescence, which occurs when T cells permanently arrest their cell cycle and proliferation while retaining cytotoxic capability. The first section of this review provides a broad overview of T cell dysfunctional states, including exhaustion and senescence; the second section is focused on the impact of T cell dysfunction on the CAR-T therapeutic potential. Finally, we discuss the recent efforts to mitigate CAR-T cell exhaustion, with an emphasis on epigenetic and transcriptional modulation. Full article

(This article belongs to the Special Issue Current Advances in Chimeric Antigen Receptor Technology)

► Show Figures

Figure 1

15 pages, 589 KiB

Open AccessEditor’s ChoiceReview

The New Era of Immunotherapy in Gastric Cancer

by Shogo Takei, Akihito Kawazoe and Kohei Shitara

Cancers 2022, 14(4), 1054; https://doi.org/10.3390/cancers14041054 - 18 Feb 2022

Cited by 64 | Viewed by 10110

Abstract

Immune checkpoint inhibitors (ICIs) such as anti-programmed cell death-1 (PD-1) or programmed cell death ligand-1 (PD-L1) monoclonal antibodies have prolonged survival in various types of malignancies, including advanced gastric cancer (AGC). Nivolumab, a monoclonal anti-PD-1 antibody, showed an improvement in overall survival at [...] Read more.

Immune checkpoint inhibitors (ICIs) such as anti-programmed cell death-1 (PD-1) or programmed cell death ligand-1 (PD-L1) monoclonal antibodies have prolonged survival in various types of malignancies, including advanced gastric cancer (AGC). Nivolumab, a monoclonal anti-PD-1 antibody, showed an improvement in overall survival at a later-line therapy in unselected AGC patients in the ATTRACTION-2 study or in combination with chemotherapy as first-line therapy in the global CheckMate-649 study. Another monoclonal anti-PD-1 antibody, pembrolizumab, showed single agent activity in tumors with high microsatellite instability or high tumor mutational burden. Furthermore, a recent KEYNOTE-811 study demonstrated significant improvement in response rate with pembrolizumab combined with trastuzumab and chemotherapy for HER2-positive AGC. Based on these results, ICIs are now incorporated into standard treatment for AGC patients. As a result of pivotal clinical trials, three anti-PD-1 antibodies were approved for AGC: nivolumab combined with chemotherapy as first-line treatment or nivolumab monotherapy as third- or later-line treatment in Asian countries; pembrolizumab for previously treated microsatellite instability-high (MSI-H) or tumor mutational burden-high AGC, or pembrolizumab combined with trastuzumab and chemotherapy for HER2-positive AGC in the United States; and dostarlimab for previously treated MSI-H AGC in the United States. However, a substantial number of patients have showed resistance to ICIs, highlighting the importance of the better selection of patients or further combined immunotherapy. This review focused on molecular and immunological profiles, pivotal clinical trials of ICIs with related biomarkers, and investigational immunotherapy for AGC. Full article

(This article belongs to the Special Issue Contemporary Perspectives and Emerging Trends in the Management of Gastric Cancer)

► Show Figures

Figure 1

17 pages, 6811 KiB

Open AccessEditor’s ChoiceReview

Matrix Stiffness Contributes to Cancer Progression by Regulating Transcription Factors

by Seiichiro Ishihara and Hisashi Haga

Cancers 2022, 14(4), 1049; https://doi.org/10.3390/cancers14041049 - 18 Feb 2022

Cited by 50 | Viewed by 7417

Abstract

Matrix stiffness is critical for the progression of various types of cancers. In solid cancers such as mammary and pancreatic cancers, tumors often contain abnormally stiff tissues, mainly caused by stiff extracellular matrices due to accumulation, contraction, and crosslinking. Stiff extracellular matrices trigger [...] Read more.

Matrix stiffness is critical for the progression of various types of cancers. In solid cancers such as mammary and pancreatic cancers, tumors often contain abnormally stiff tissues, mainly caused by stiff extracellular matrices due to accumulation, contraction, and crosslinking. Stiff extracellular matrices trigger mechanotransduction, the conversion of mechanical cues such as stiffness of the matrix to biochemical signaling in the cells, and as a result determine the cellular phenotypes of cancer and stromal cells in tumors. Transcription factors are key molecules for these processes, as they respond to matrix stiffness and are crucial for cellular behaviors. The Yes-associated protein (YAP)/transcriptional coactivator with PDZ-binding motif (TAZ) is one of the most studied transcription factors that is regulated by matrix stiffness. The YAP/TAZ are activated by a stiff matrix and promotes malignant phenotypes in cancer and stromal cells, including cancer-associated fibroblasts. In addition, other transcription factors such as β-catenin and nuclear factor kappa B (NF-κB) also play key roles in mechanotransduction in cancer tissues. In this review, the mechanisms of stiffening cancer tissues are introduced, and the transcription factors regulated by matrix stiffness in cancer and stromal cells and their roles in cancer progression are shown. Full article

(This article belongs to the Special Issue Molecular Mechanism of the Interaction Between Cells and Extracellular Matrix in Cancer Progression)

► Show Figures

Figure 1

21 pages, 1236 KiB

Open AccessEditor’s ChoiceReview

Current Limitations and Novel Perspectives in Pancreatic Cancer Treatment

by Steve Robatel and Mirjam Schenk

Cancers 2022, 14(4), 985; https://doi.org/10.3390/cancers14040985 - 16 Feb 2022

Cited by 24 | Viewed by 4188

Abstract

Pancreatic cancer is one of the deadliest cancers worldwide, largely due to its aggressive development. Consequently, treatment options are often palliative, as only one-fifth of patients present with potentially curable tumors. The only available treatment with curative intent is surgery followed by adjuvant [...] Read more.

Pancreatic cancer is one of the deadliest cancers worldwide, largely due to its aggressive development. Consequently, treatment options are often palliative, as only one-fifth of patients present with potentially curable tumors. The only available treatment with curative intent is surgery followed by adjuvant chemotherapy. However, even for patients that are eligible for surgery, the 5-year OS remains below 10%. Hence, there is an urgent need to find new therapeutic regimens. In the first part of this review, we discuss the tumor staging method and its impact on the corresponding current standard-of-care treatments for PDAC. We also consider the key clinical trials over the last 20 years that have improved patient survival. In the second part, we provide an overview of the major components and cell types involved in PDAC, as well as their respective roles and interactions with each other. A deeper knowledge of the interactions taking place in the TME may lead to the discovery of potential new therapeutic targets. Finally, we discuss promising treatment strategies targeting specific components of the TME and potential combinations thereof. Overall, this review provides an overview of the current challenges and future perspectives in the treatment of pancreatic cancer. Full article

(This article belongs to the Special Issue Molecular Mechanisms Underlying Resistance and New Therapeutic Approaches in Pancreatic Cancer)

► Show Figures

Figure 1

16 pages, 1034 KiB

Open AccessEditor’s ChoiceReview

PARP Inhibitors in Glioma: A Review of Therapeutic Opportunities

by Hao-Wen Sim, Evanthia Galanis and Mustafa Khasraw

Cancers 2022, 14(4), 1003; https://doi.org/10.3390/cancers14041003 - 16 Feb 2022

Cited by 18 | Viewed by 6574

Abstract

Gliomas are the most common malignant primary brain tumor in adults. Despite advances in multimodality therapy, incorporating surgery, radiotherapy, systemic therapy, tumor treating fields and supportive care, patient outcomes remain poor, especially in glioblastoma where median survival has remained static at around 15 [...] Read more.

Gliomas are the most common malignant primary brain tumor in adults. Despite advances in multimodality therapy, incorporating surgery, radiotherapy, systemic therapy, tumor treating fields and supportive care, patient outcomes remain poor, especially in glioblastoma where median survival has remained static at around 15 months, for decades. Low-grade gliomas typically harbor isocitrate dehydrogenase (IDH) mutations, grow more slowly and confer a better prognosis than glioblastoma. However, nearly all gliomas eventually recur and progress in a way similar to glioblastoma. One of the novel therapies being developed in this area are poly(ADP-Ribose) polymerase (PARP) inhibitors. PARP inhibitors belong to a class of drugs that target DNA damage repair pathways. This leads to synthetic lethality of cancer cells with coexisting homologous recombination deficiency. PARP inhibitors may also potentiate the cytotoxic effects of radiotherapy and chemotherapy, and prime the tumor microenvironment for immunotherapy. In this review, we examine the rationale and clinical evidence for PARP inhibitors in glioma and suggest therapeutic opportunities. Full article

(This article belongs to the Special Issue Clinical Use of PARP Inhibitors in Cancer – From Bench to Bedside and Back Again)

► Show Figures

Figure 1

16 pages, 2548 KiB

Open AccessEditor’s ChoiceArticle

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

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

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

Cited by 12 | Viewed by 2074

Abstract

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

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

► Show Figures

Figure 1

28 pages, 15719 KiB

Open AccessEditor’s ChoiceReview

Dissecting Tumor Growth: The Role of Cancer Stem Cells in Drug Resistance and Recurrence

by Beatrice Aramini, Valentina Masciale, Giulia Grisendi, Federica Bertolini, Michela Maur, Giorgia Guaitoli, Isca Chrystel, Uliano Morandi, Franco Stella, Massimo Dominici and Khawaja Husnain Haider

Cancers 2022, 14(4), 976; https://doi.org/10.3390/cancers14040976 - 15 Feb 2022

Cited by 42 | Viewed by 8383

Abstract

Emerging evidence suggests that a small subpopulation of cancer stem cells (CSCs) is responsible for initiation, progression, and metastasis cascade in tumors. CSCs share characteristics with normal stem cells, i.e., self-renewal and differentiation potential, suggesting that they can drive cancer progression. Consequently, targeting [...] Read more.

Emerging evidence suggests that a small subpopulation of cancer stem cells (CSCs) is responsible for initiation, progression, and metastasis cascade in tumors. CSCs share characteristics with normal stem cells, i.e., self-renewal and differentiation potential, suggesting that they can drive cancer progression. Consequently, targeting CSCs to prevent tumor growth or regrowth might offer a chance to lead the fight against cancer. CSCs create their niche, a specific area within tissue with a unique microenvironment that sustains their vital functions. Interactions between CSCs and their niches play a critical role in regulating CSCs’ self-renewal and tumorigenesis. Differences observed in the frequency of CSCs, due to the phenotypic plasticity of many cancer cells, remain a challenge in cancer therapeutics, since CSCs can modulate their transcriptional activities into a more stem-like state to protect themselves from destruction. This plasticity represents an essential step for future therapeutic approaches. Regarding self-renewal, CSCs are modulated by the same molecular pathways found in normal stem cells, such as Wnt/β-catenin signaling, Notch signaling, and Hedgehog signaling. Another key characteristic of CSCs is their resistance to standard chemotherapy and radiotherapy treatments, due to their capacity to rest in a quiescent state. This review will analyze the primary mechanisms involved in CSC tumorigenesis, with particular attention to the roles of CSCs in tumor progression in benign and malignant diseases; and will examine future perspectives on the identification of new markers to better control tumorigenesis, as well as dissecting the metastasis process. Full article

(This article belongs to the Special Issue Understanding Molecular Regulation of Cancer Progression and Metastasis)

► Show Figures

Figure 1

20 pages, 8036 KiB

Open AccessEditor’s ChoiceArticle

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

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

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

Cited by 13 | Viewed by 2936

Abstract

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

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

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

► Show Figures

Figure 1

17 pages, 867 KiB

Open AccessEditor’s ChoiceReview

Intrinsic and Extrinsic Factors Impacting Cancer Stemness and Tumor Progression

by Alexey Ponomarev, Zarema Gilazieva, Valeriya Solovyeva, Cinzia Allegrucci and Albert Rizvanov

Cancers 2022, 14(4), 970; https://doi.org/10.3390/cancers14040970 - 15 Feb 2022

Cited by 16 | Viewed by 5091

Abstract

Tumor heterogeneity represents an important limitation to the development of effective cancer therapies. The presence of cancer stem cells (CSCs) and their differentiation hierarchies contribute to cancer complexity and confer tumors the ability to grow, resist treatment, survive unfavorable conditions, and invade neighboring [...] Read more.

Tumor heterogeneity represents an important limitation to the development of effective cancer therapies. The presence of cancer stem cells (CSCs) and their differentiation hierarchies contribute to cancer complexity and confer tumors the ability to grow, resist treatment, survive unfavorable conditions, and invade neighboring and distant tissues. A large body of research is currently focusing on understanding the properties of CSCs, including their cellular and molecular origin, as well as their biological behavior in different tumor types. In turn, this knowledge informs strategies for targeting these tumor initiating cells and related cancer stemness. Cancer stemness is modulated by the tumor microenvironment, which influences CSC function and survival. Several advanced in vitro models are currently being developed to study cancer stemness in order to advance new knowledge of the key molecular pathways involved in CSC self-renewal and dormancy, as well as to mimic the complexity of patients’ tumors in pre-clinical drug testing. In this review, we discuss CSCs and the modulation of cancer stemness by the tumor microenvironment, stemness factors and signaling pathways. In addition, we introduce current models that allow the study of CSCs for the development of new targeted therapies. Full article

(This article belongs to the Special Issue Cancer Stem Cells (CSCs) in Drug Resistance and Their Therapeutic Implications in Cancer Treatment)

► Show Figures

Graphical abstract

22 pages, 894 KiB

Open AccessEditor’s ChoiceReview

Everything Comes with a Price: The Toxicity Profile of DNA-Damage Response Targeting Agents

by Federica Martorana, Leandro Apolinario Da Silva, Cristiana Sessa and Ilaria Colombo

Cancers 2022, 14(4), 953; https://doi.org/10.3390/cancers14040953 - 14 Feb 2022

Cited by 16 | Viewed by 4244

Abstract

Targeting the inherent vulnerability of cancer cells with an impaired DNA Damage Repair (DDR) machinery, Poly-ADP-Ribose-Polymerase (PARP) inhibitors have yielded significant results in several tumor types, eventually entering clinical practice for the treatment of ovarian, breast, pancreatic and prostate cancer. More recently, inhibitors [...] Read more.

Targeting the inherent vulnerability of cancer cells with an impaired DNA Damage Repair (DDR) machinery, Poly-ADP-Ribose-Polymerase (PARP) inhibitors have yielded significant results in several tumor types, eventually entering clinical practice for the treatment of ovarian, breast, pancreatic and prostate cancer. More recently, inhibitors of other key components of DNA repair, such as ATR, CHK1 and WEE1, have been developed and are currently under investigation in clinical trials. The inhibition of DDR inevitably induces on-target and off-target adverse events. Hematological and gastrointestinal toxicities as well as fatigue are common with all DDR-targeting agents, while other adverse events are drug specific, such as hypertension with niraparib and transaminase elevation with rucaparib. Cases of pneumonitis and secondary hematological malignancies have been reported with PARP inhibitors and, despite being overly rare, they deserve particular attention due to their severity. Safety also represents a crucial issue for the development of combination regimens incorporating DDR-targeting agents with other treatments, such as chemotherapy, anti-angiogenics or immunotherapy. As such, overlapping and cumulative toxicities should be considered, especially when more than two classes of drugs are combined. Here, we review the safety profile of DDR-targeting agents when used as single agents or in combination and we provide principles of toxicity management. Full article

(This article belongs to the Special Issue DNA Damage Response Targeting: Challenges and Opportunities)

► Show Figures

Figure 1

16 pages, 1261 KiB

Open AccessEditor’s ChoiceReview

The Impact of Estrogens and Their Receptors on Immunity and Inflammation during Infection

by Alfred T. Harding and Nicholas S. Heaton

Cancers 2022, 14(4), 909; https://doi.org/10.3390/cancers14040909 - 12 Feb 2022

Cited by 41 | Viewed by 6893

Abstract

Sex hormones, such as estrogen and testosterone, are steroid compounds with well-characterized effects on the coordination and development of vertebrate reproductive systems. Since their discovery, however, it has become clear that these “sex hormones” also regulate/influence a broad range of biological functions. In [...] Read more.

Sex hormones, such as estrogen and testosterone, are steroid compounds with well-characterized effects on the coordination and development of vertebrate reproductive systems. Since their discovery, however, it has become clear that these “sex hormones” also regulate/influence a broad range of biological functions. In this review, we will summarize some current findings on how estrogens interact with and regulate inflammation and immunity. Specifically, we will focus on describing the mechanisms by which estrogens alter immune pathway activation, the impact of these changes during infection and the development of long-term immunity, and how different types of estrogens and their respective concentrations mediate these outcomes. Full article

(This article belongs to the Special Issue The Role of Natural and Environmental Estrogens in Metabolic Regulation, Inflammation and Advanced Cancer)

► Show Figures

Figure 1

19 pages, 1406 KiB

Open AccessEditor’s ChoiceReview

Glycans as Targets for Drug Delivery in Cancer

by Francisca Diniz, Pedro Coelho, Henrique O. Duarte, Bruno Sarmento, Celso A. Reis and Joana Gomes

Cancers 2022, 14(4), 911; https://doi.org/10.3390/cancers14040911 - 12 Feb 2022

Cited by 20 | Viewed by 4582

Abstract

Innovative strategies have been proposed to increase drug delivery to the tumor site and avoid cytotoxicity, improving the therapeutic efficacy of well-established anti-cancer drugs. Alterations in normal glycosylation processes are frequently observed in cancer cells and the resulting cell surface aberrant glycans can [...] Read more.

Innovative strategies have been proposed to increase drug delivery to the tumor site and avoid cytotoxicity, improving the therapeutic efficacy of well-established anti-cancer drugs. Alterations in normal glycosylation processes are frequently observed in cancer cells and the resulting cell surface aberrant glycans can be used as direct molecular targets for drug delivery. In the present review, we address the development of strategies, such as monoclonal antibodies, antibody–drug conjugates and nanoparticles that specific and selectively target cancer-associated glycans in tumor cells. The use of nanoparticles for drug delivery encompasses novel applications in cancer therapy, including vaccines encapsulated in synthetic nanoparticles and specific nanoparticles that target glycoproteins or glycan-binding proteins. Here, we highlight their potential to enhance targeting approaches and to optimize the delivery of clinically approved drugs to the tumor microenvironment, paving the way for improved personalized treatment approaches with major potential importance for the pharmaceutical and clinical sectors. Full article

(This article belongs to the Special Issue Advances in Tumor Glycans)

► Show Figures

Figure 1

22 pages, 9452 KiB

Open AccessEditor’s ChoiceReview

PARP Inhibitors and Radiometabolic Approaches in Metastatic Castration-Resistant Prostate Cancer: What’s Now, What’s New, and What’s Coming?

by Andrea Marchetti, Matteo Rosellini, Giacomo Nuvola, Elisa Tassinari, Veronica Mollica, Alessandro Rizzo, Matteo Santoni, Alessia Cimadamore, Andrea Farolfi, Rodolfo Montironi, Stefano Fanti and Francesco Massari

Cancers 2022, 14(4), 907; https://doi.org/10.3390/cancers14040907 - 11 Feb 2022

Cited by 8 | Viewed by 3588

Abstract

In recent years, the advances in the knowledge on the molecular characteristics of prostate cancer is allowing to explore novel treatment scenarios. Furthermore, technological discoveries are widening diagnostic and treatment weapons at the clinician disposal. Among these, great relevance is being gained by [...] Read more.

In recent years, the advances in the knowledge on the molecular characteristics of prostate cancer is allowing to explore novel treatment scenarios. Furthermore, technological discoveries are widening diagnostic and treatment weapons at the clinician disposal. Among these, great relevance is being gained by PARP inhibitors and radiometabolic approaches. The result is that DNA repair genes need to be altered in a high percentage of patients with metastatic prostate cancer, making these patients optimal candidates for PARP inhibitors. These compounds have already been proved to be active in pretreated patients and are currently being investigated in other settings. Radiometabolic approaches combine specific prostate cancer cell ligands to radioactive particles, thus allowing to deliver cytotoxic radiations in cancer cells. Among these, radium-223 and lutetium-177 have shown promising activity in metastatic pretreated prostate cancer patients and further studies are ongoing to expand the applications of this therapeutic approach. In addition, nuclear medicine techniques also have an important diagnostic role in prostate cancer. Herein, we report the state of the art on the knowledge on PARP inhibitors and radiometabolic approaches in advanced prostate cancer and present ongoing clinical trials that will hopefully expand these two treatment fields. Full article

(This article belongs to the Special Issue Clinical Use of PARP Inhibitors in Cancer – From Bench to Bedside and Back Again)

► Show Figures

Figure 1

12 pages, 1623 KiB

Open AccessEditor’s ChoiceArticle

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

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

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

Cited by 35 | Viewed by 3369

Abstract

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

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

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

► Show Figures

Figure 1

15 pages, 11700 KiB

Open AccessFeature PaperEditor’s ChoiceArticle

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

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

Cancers 2022, 14(4), 855; https://doi.org/10.3390/cancers14040855 - 09 Feb 2022

Cited by 22 | Viewed by 2655

Abstract

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

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

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

► Show Figures

Figure 1

22 pages, 1071 KiB

Open AccessEditor’s ChoiceReview

Regulation of B-Cell Receptor Signaling and Its Therapeutic Relevance in Aggressive B-Cell Lymphomas

by Núria Profitós-Pelejà, Juliana Carvalho Santos, Ana Marín-Niebla, Gaël Roué and Marcelo Lima Ribeiro

Cancers 2022, 14(4), 860; https://doi.org/10.3390/cancers14040860 - 09 Feb 2022

Cited by 19 | Viewed by 6017

Abstract

The proliferation and survival signals emanating from the B-cell receptor (BCR) constitute a crucial aspect of mature lymphocyte’s life. Dysregulated BCR signaling is considered a potent contributor to tumor survival in different subtypes of B-cell non-Hodgkin lymphomas (B-NHLs). In the last decade, the [...] Read more.

The proliferation and survival signals emanating from the B-cell receptor (BCR) constitute a crucial aspect of mature lymphocyte’s life. Dysregulated BCR signaling is considered a potent contributor to tumor survival in different subtypes of B-cell non-Hodgkin lymphomas (B-NHLs). In the last decade, the emergence of BCR-associated kinases as rational therapeutic targets has led to the development and approval of several small molecule inhibitors targeting either Bruton’s tyrosine kinase (BTK), spleen tyrosine kinase (SYK), or phosphatidylinositol 3 kinase (PI3K), offering alternative treatment options to standard chemoimmunotherapy, and making some of these drugs valuable assets in the anti-lymphoma armamentarium. Despite their initial effectiveness, these precision medicine strategies are limited by primary resistance in aggressive B-cell lymphoma such as diffuse large B-cell lymphoma (DLBCL) and mantle cell lymphoma (MCL), especially in the case of first generation BTK inhibitors. In these patients, BCR-targeting drugs often fail to produce durable responses, and nearly all cases eventually progress with a dismal outcome, due to secondary resistance. This review will discuss our current understanding of the role of antigen-dependent and antigen-independent BCR signaling in DLBCL and MCL and will cover both approved inhibitors and investigational molecules being evaluated in early preclinical studies. We will discuss how the mechanisms of action of these molecules, and their off/on-target effects can influence their effectiveness and lead to toxicity, and how our actual knowledge supports the development of more specific inhibitors and new, rationally based, combination therapies, for the management of MCL and DLBCL patients. Full article

(This article belongs to the Special Issue Advanced Therapies for Hematological Cancers)

► Show Figures

Figure 1

16 pages, 1818 KiB

Open AccessEditor’s ChoiceArticle

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

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

Cancers 2022, 14(3), 829; https://doi.org/10.3390/cancers14030829 - 06 Feb 2022

Cited by 12 | Viewed by 2567

Abstract

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

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

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

► Show Figures

Figure 1

22 pages, 1400 KiB

Open AccessEditor’s ChoiceReview

Telomerase in Cancer: Function, Regulation, and Clinical Translation

by Nathaniel J. Robinson and William P. Schiemann

Cancers 2022, 14(3), 808; https://doi.org/10.3390/cancers14030808 - 05 Feb 2022

Cited by 25 | Viewed by 7144

Abstract

During the process of malignant transformation, cells undergo a series of genetic, epigenetic, and phenotypic alterations, including the acquisition and propagation of genomic aberrations that impart survival and proliferative advantages. These changes are mediated in part by the induction of replicative immortality that [...] Read more.

During the process of malignant transformation, cells undergo a series of genetic, epigenetic, and phenotypic alterations, including the acquisition and propagation of genomic aberrations that impart survival and proliferative advantages. These changes are mediated in part by the induction of replicative immortality that is accompanied by active telomere elongation. Indeed, telomeres undergo dynamic changes to their lengths and higher-order structures throughout tumor formation and progression, processes overseen in most cancers by telomerase. Telomerase is a multimeric enzyme whose function is exquisitely regulated through diverse transcriptional, post-transcriptional, and post-translational mechanisms to facilitate telomere extension. In turn, telomerase function depends not only on its core components, but also on a suite of binding partners, transcription factors, and intra- and extracellular signaling effectors. Additionally, telomerase exhibits telomere-independent regulation of cancer cell growth by participating directly in cellular metabolism, signal transduction, and the regulation of gene expression in ways that are critical for tumorigenesis. In this review, we summarize the complex mechanisms underlying telomere maintenance, with a particular focus on both the telomeric and extratelomeric functions of telomerase. We also explore the clinical utility of telomeres and telomerase in the diagnosis, prognosis, and development of targeted therapies for primary, metastatic, and recurrent cancers. Full article

(This article belongs to the Special Issue The Dual Roles of Telomeres and Telomerase in Aging and Cancer)

► Show Figures

Figure 1

12 pages, 569 KiB

Open AccessEditor’s ChoiceSystematic Review

Systematic Review of Single-Fraction Stereotactic Body Radiation Therapy for Early Stage Non-Small-Cell Lung Cancer and Lung Oligometastases: How to Stop Worrying and Love One and Done

by Austin J. Bartl, Mary Mahoney, Mark W. Hennon, Sai Yendamuri, Gregory M. M. Videtic, Kevin L. Stephans, Shankar Siva, Mark K. Farrugia, Sung Jun Ma and Anurag K. Singh

Cancers 2022, 14(3), 790; https://doi.org/10.3390/cancers14030790 - 03 Feb 2022

Cited by 24 | Viewed by 3102

Abstract

Adoption of single-fraction lung stereotactic body radiation therapy (SBRT) for patients with medically inoperable early stage non-small-cell lung cancer (NSCLC) or oligometastatic lung disease, even during the coronavirus disease 2019 (COVID-19) pandemic, was limited despite encouraging phase II trial results. Barriers to using [...] Read more.

Adoption of single-fraction lung stereotactic body radiation therapy (SBRT) for patients with medically inoperable early stage non-small-cell lung cancer (NSCLC) or oligometastatic lung disease, even during the coronavirus disease 2019 (COVID-19) pandemic, was limited despite encouraging phase II trial results. Barriers to using single-fraction SBRT may include lack of familiarity with the regimen and lack of clarity about the expected toxicity. To address these concerns, we performed a systematic review of prospective literature on single-fraction SBRT for definitive treatment of early stage and oligometastatic lung cancer. A PubMed search of prospective studies in English on single-fraction lung SBRT was conducted. A systematic review was performed of the studies that reported clinical outcomes of single-fraction SBRT in the treatment of early stage non-small-cell lung cancer and lung oligometastases. The current prospective literature including nine trials supports the use of single-fraction SBRT in the definitive treatment of early stage peripheral NSCLC and lung oligometastases. Most studies cite local control rates of >90%, mild toxicity profiles, and favorable survival outcomes. Most toxicities reported were grade 1–2, with grade ≥3 toxicity in 0–17% of patients. Prospective trial results suggest potential consideration of utilizing single-fraction SBRT beyond the COVID-19 pandemic. Full article

(This article belongs to the Special Issue Radiation Therapy in Thoracic Tumors: Recent Trends and Current Issues)

► Show Figures

Figure 1

30 pages, 908 KiB

Open AccessEditor’s ChoiceReview

The Role of Bruton’s Kinase Inhibitors in Chronic Lymphocytic Leukemia: Current Status and Future Directions

by Tadeusz Robak, Magda Witkowska and Piotr Smolewski

Cancers 2022, 14(3), 771; https://doi.org/10.3390/cancers14030771 - 02 Feb 2022

Cited by 35 | Viewed by 5848

Abstract

The use of Bruton’s tyrosine kinase (BTK) inhibitors has changed the management and clinical history of patients with chronic lymphocytic leukemia (CLL). BTK is a critical molecule that interconnects B-cell antigen receptor (BCR) signaling. BTKis are classified into two categories: irreversible (covalent) inhibitors [...] Read more.

The use of Bruton’s tyrosine kinase (BTK) inhibitors has changed the management and clinical history of patients with chronic lymphocytic leukemia (CLL). BTK is a critical molecule that interconnects B-cell antigen receptor (BCR) signaling. BTKis are classified into two categories: irreversible (covalent) inhibitors and reversible (non-covalent) inhibitors. Ibrutinib was the first irreversible BTK inhibitor approved by the U.S. Food and Drug Administration in 2013 as a breakthrough therapy in CLL patients. Subsequently, several studies have evaluated the efficacy and safety of new agents with reduced toxicity when compared with ibrutinib. Two other irreversible, second-generation BTK inhibitors, acalabrutinib and zanubrutinib, were developed to reduce ibrutinib-mediated adverse effects. Additionally, new reversible BTK inhibitors are currently under development in early-phase studies to improve their activity and to diminish adverse effects. This review summarizes the pharmacology, clinical efficacy, safety, dosing, and drug–drug interactions associated with the treatment of CLL with BTK inhibitors and examines their further implications. Full article

(This article belongs to the Special Issue Non-Hodgkin Lymphomas)

► Show Figures

Figure 1

24 pages, 14975 KiB

Open AccessEditor’s ChoiceSystematic Review

Molecular Systems Architecture of Interactome in the Acute Myeloid Leukemia Microenvironment

by V. A. Shiva Ayyadurai, Prabhakar Deonikar, Kevin G. McLure and Kathleen M. Sakamoto

Cancers 2022, 14(3), 756; https://doi.org/10.3390/cancers14030756 - 01 Feb 2022

Cited by 7 | Viewed by 3917

Abstract

A molecular systems architecture is presented for acute myeloid leukemia (AML) to provide a framework for organizing the complexity of biomolecular interactions. AML is a multifactorial disease resulting from impaired differentiation and increased proliferation of hematopoietic precursor cells involving genetic mutations, signaling pathways [...] Read more.

A molecular systems architecture is presented for acute myeloid leukemia (AML) to provide a framework for organizing the complexity of biomolecular interactions. AML is a multifactorial disease resulting from impaired differentiation and increased proliferation of hematopoietic precursor cells involving genetic mutations, signaling pathways related to the cancer cell genetics, and molecular interactions between the cancer cell and the tumor microenvironment, including endothelial cells, fibroblasts, myeloid-derived suppressor cells, bone marrow stromal cells, and immune cells (e.g., T-regs, T-helper 1 cells, T-helper 17 cells, T-effector cells, natural killer cells, and dendritic cells). This molecular systems architecture provides a layered understanding of intra- and inter-cellular interactions in the AML cancer cell and the cells in the stromal microenvironment. The molecular systems architecture may be utilized for target identification and the discovery of single and combination therapeutics and strategies to treat AML. Full article

(This article belongs to the Section Systematic Review or Meta-Analysis in Cancer Research)

► Show Figures

Figure 1

17 pages, 3623 KiB

Open AccessEditor’s ChoiceArticle

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

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

Cancers 2022, 14(3), 758; https://doi.org/10.3390/cancers14030758 - 01 Feb 2022

Cited by 10 | Viewed by 3737

Abstract

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

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

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

► Show Figures

Graphical abstract

13 pages, 1638 KiB

Open AccessEditor’s ChoiceArticle

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

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

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

Cited by 4 | Viewed by 4023

Abstract

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

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

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

► Show Figures

Figure 1

24 pages, 5669 KiB

Open AccessEditor’s ChoiceReview

Utility of Cell-Free DNA Detection in Transplant Oncology

by Tejaswini Reddy, Abdullah Esmail, Jenny C. Chang, Rafik Mark Ghobrial and Maen Abdelrahim

Cancers 2022, 14(3), 743; https://doi.org/10.3390/cancers14030743 - 31 Jan 2022

Cited by 12 | Viewed by 4408

Abstract

Transplant oncology is an emerging field in cancer treatment that applies transplant medicine, surgery, and oncology to improve cancer patient survival and quality of life. A critical concept that must be addressed to ensure the successful application of transplant oncology to patient care [...] Read more.

Transplant oncology is an emerging field in cancer treatment that applies transplant medicine, surgery, and oncology to improve cancer patient survival and quality of life. A critical concept that must be addressed to ensure the successful application of transplant oncology to patient care is efficient monitoring of tumor burden pre-and post-transplant and transplant rejection. Cell-free DNA (cfDNA) detection has emerged as a vital tool in revolutionizing the management of cancer patients who undergo organ transplantation. The advances in cfDNA technology have provided options to perform a pre-transplant evaluation of minimal residual disease (MRD) and post-transplant evaluation of cancer recurrence and transplant rejection. This review aims to provide a comprehensive overview of the history and emergence of cfDNA technology, its applications to specifically monitor tumor burden at pre-and post-transplant stages, and evaluate transplant rejection. Full article

(This article belongs to the Special Issue Precision Medicine in Gastrointestinal Oncology)

► Show Figures

Figure 1

35 pages, 6290 KiB

Open AccessEditor’s ChoiceReview

Exosomal Proteins and Lipids as Potential Biomarkers for Lung Cancer Diagnosis, Prognosis, and Treatment

by Ming-Tsung Hsu, Yu-Ke Wang and Yufeng Jane Tseng

Cancers 2022, 14(3), 732; https://doi.org/10.3390/cancers14030732 - 30 Jan 2022

Cited by 38 | Viewed by 5919

Abstract

Exosomes participate in cell–cell communication by transferring molecular components between cells. Previous studies have shown that exosomal molecules derived from cancer cells and liquid biopsies can serve as biomarkers for cancer diagnosis and prognosis. The exploration of the molecules transferred by lung cancer-derived [...] Read more.

Exosomes participate in cell–cell communication by transferring molecular components between cells. Previous studies have shown that exosomal molecules derived from cancer cells and liquid biopsies can serve as biomarkers for cancer diagnosis and prognosis. The exploration of the molecules transferred by lung cancer-derived exosomes can advance the understanding of exosome-mediated signaling pathways and mechanisms. However, the molecular characterization and functional indications of exosomal proteins and lipids have not been comprehensively organized. This review thoroughly collected data concerning exosomal proteins and lipids from various lung cancer samples, including cancer cell lines and cancer patients. As potential diagnostic and prognostic biomarkers, exosomal proteins and lipids are available for clinical use in lung cancer. Potential therapeutic targets are mentioned for the future development of lung cancer therapy. Molecular functions implying their possible roles in exosome-mediated signaling are also discussed. Finally, we emphasized the importance and value of lung cancer stem cell-derived exosomes in lung cancer therapy. In summary, this review presents a comprehensive description of the protein and lipid composition and function of lung cancer-derived exosomes for lung cancer diagnosis, prognosis, and treatment. Full article

► Show Figures

Figure 1

18 pages, 6998 KiB

Open AccessEditor’s ChoiceArticle

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

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

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

Cited by 9 | Viewed by 3421

Abstract

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

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

(This article belongs to the Special Issue Tumor Heterogeneity)

► Show Figures

Figure 1

16 pages, 3181 KiB

Open AccessEditor’s ChoiceReview

Fecal Microbiota Transplant for Hematologic and Oncologic Diseases: Principle and Practice

by Maroun Bou Zerdan, Stephanie Niforatos, Sandy Nasr, Dayana Nasr, Mulham Ombada, Savio John, Dibyendu Dutta and Seah H. Lim

Cancers 2022, 14(3), 691; https://doi.org/10.3390/cancers14030691 - 29 Jan 2022

Cited by 10 | Viewed by 8658

Abstract

Understanding of the importance of the normal intestinal microbial community in regulating microbial homeostasis, host metabolism, adaptive immune responses, and gut barrier functions has opened up the possibility of manipulating the microbial composition to modulate the activity of various intestinal and systemic diseases [...] Read more.

Understanding of the importance of the normal intestinal microbial community in regulating microbial homeostasis, host metabolism, adaptive immune responses, and gut barrier functions has opened up the possibility of manipulating the microbial composition to modulate the activity of various intestinal and systemic diseases using fecal microbiota transplant (FMT). It is therefore not surprising that use of FMT, especially for treating relapsed/refractory Clostridioides difficile infections (CDI), has increased over the last decade. Due to the complexity associated with and treatment for these diseases, patients with hematologic and oncologic diseases are particularly susceptible to complications related to altered intestinal microbial composition. Therefore, they are an ideal population for exploring FMT as a therapeutic approach. However, there are inherent factors presenting as obstacles for the use of FMT in these patients. In this review paper, we discussed the principles and biologic effects of FMT, examined the factors rendering patients with hematologic and oncologic conditions to increased risks for relapsed/refractory CDI, explored ongoing FMT studies, and proposed novel uses for FMT in these groups of patients. Finally, we also addressed the challenges of applying FMT to these groups of patients and proposed ways to overcome these challenges. Full article

► Show Figures

Figure 1

23 pages, 14888 KiB

Open AccessEditor’s ChoiceReview

Cancer-on-a-Chip: Models for Studying Metastasis

by Xiaojun Zhang, Mazharul Karim, Md Mahedi Hasan, Jacob Hooper, Riajul Wahab, Sourav Roy and Taslim A. Al-Hilal

Cancers 2022, 14(3), 648; https://doi.org/10.3390/cancers14030648 - 27 Jan 2022

Cited by 24 | Viewed by 6895

Abstract

The microfluidic-based cancer-on-a-chip models work as a powerful tool to study the tumor microenvironment and its role in metastasis. The models recapitulate and systematically simplify the in vitro tumor microenvironment. This enables the study of a metastatic process in unprecedented detail. This review [...] Read more.

The microfluidic-based cancer-on-a-chip models work as a powerful tool to study the tumor microenvironment and its role in metastasis. The models recapitulate and systematically simplify the in vitro tumor microenvironment. This enables the study of a metastatic process in unprecedented detail. This review examines the development of cancer-on-a-chip microfluidic platforms at the invasion/intravasation, extravasation, and angiogenesis steps over the last three years. The on-chip modeling of mechanical cues involved in the metastasis cascade are also discussed. Finally, the popular design of microfluidic chip models for each step are discussed along with the challenges and perspectives of cancer-on-a-chip models. Full article

(This article belongs to the Special Issue Modeling Cancer in Microfluidic Chips)

► Show Figures

Figure 1

19 pages, 1643 KiB

Open AccessEditor’s ChoiceReview

Update on Management Recommendations for Advanced Cutaneous Squamous Cell Carcinoma

by Jesús García-Foncillas, Antonio Tejera-Vaquerizo, Onofre Sanmartín, Federico Rojo, Javier Mestre, Salvador Martín, Ignacio Azinovic and Ricard Mesía

Cancers 2022, 14(3), 629; https://doi.org/10.3390/cancers14030629 - 27 Jan 2022

Cited by 9 | Viewed by 9274

Abstract

Cutaneous squamous cell carcinoma (cSCC) is the second most common form of skin cancer, the incidence of which has risen over the last years. Although cSCC rarely metastasizes, early detection and treatment of primary tumours are critical to limit progression and local invasion. [...] Read more.

Cutaneous squamous cell carcinoma (cSCC) is the second most common form of skin cancer, the incidence of which has risen over the last years. Although cSCC rarely metastasizes, early detection and treatment of primary tumours are critical to limit progression and local invasion. Several prognostic factors related to patients’ clinicopathologic profile and tumour features have been identified as high-risk markers and included in the stratification scales, but their association with regional control or survival is uncertain. Therefore, decision-making on the diagnosis and management of cSCC should be made based on each individual patient’s characteristics. Recent advances in non-invasive imaging techniques and molecular testing have enhanced clinical diagnostic accuracy. Surgical excision is the mainstay of local treatment, whereas radiotherapy (RT) is recommended for patients with inoperable disease or in specific circumstances. Novel systemic treatments including immunotherapies and targeted therapies have changed the therapeutic landscape for cSCC. The anti-PD-1 agent cemiplimab is currently the only FDA/EMA-approved first-line therapy for patients with locally advanced or metastatic cSCC who are not candidates for curative surgery or RT. Given the likelihood of recurrence and the increased risk of developing multiple cSCC, close follow-up should be performed during the first years of treatment and continued long-term surveillance is warranted. Full article

(This article belongs to the Special Issue Prevention, Diagnosis and Treatment of Skin Cancer)

► Show Figures

Figure 1

42 pages, 5014 KiB

Open AccessEditor’s ChoiceReview

Targeting Tumor Glycans for Cancer Therapy: Successes, Limitations, and Perspectives

by Nora Berois, Alvaro Pittini and Eduardo Osinaga

Cancers 2022, 14(3), 645; https://doi.org/10.3390/cancers14030645 - 27 Jan 2022

Cited by 41 | Viewed by 8498

Abstract

Aberrant glycosylation is a hallmark of cancer and can lead to changes that influence tumor behavior. Glycans can serve as a source of novel clinical biomarker developments, providing a set of specific targets for therapeutic intervention. Different mechanisms of aberrant glycosylation lead to [...] Read more.

Aberrant glycosylation is a hallmark of cancer and can lead to changes that influence tumor behavior. Glycans can serve as a source of novel clinical biomarker developments, providing a set of specific targets for therapeutic intervention. Different mechanisms of aberrant glycosylation lead to the formation of tumor-associated carbohydrate antigens (TACAs) suitable for selective cancer-targeting therapy. The best characterized TACAs are truncated O-glycans (Tn, TF, and sialyl-Tn antigens), gangliosides (GD2, GD3, GM2, GM3, fucosyl-GM1), globo-serie glycans (Globo-H, SSEA-3, SSEA-4), Lewis antigens, and polysialic acid. In this review, we analyze strategies for cancer immunotherapy targeting TACAs, including different antibody developments, the production of vaccines, and the generation of CAR-T cells. Some approaches have been approved for clinical use, such as anti-GD2 antibodies. Moreover, in terms of the antitumor mechanisms against different TACAs, we show results of selected clinical trials, considering the horizons that have opened up as a result of recent developments in technologies used for cancer control. Full article

(This article belongs to the Special Issue Advances in Tumor Glycans)

► Show Figures

Figure 1

57 pages, 2143 KiB

Open AccessEditor’s ChoiceReview

Clinical Evidence for Thermometric Parameters to Guide Hyperthermia Treatment

by Adela Ademaj, Danai P. Veltsista, Pirus Ghadjar, Dietmar Marder, Eva Oberacker, Oliver J. Ott, Peter Wust, Emsad Puric, Roger A. Hälg, Susanne Rogers, Stephan Bodis, Rainer Fietkau, Hans Crezee and Oliver Riesterer

Cancers 2022, 14(3), 625; https://doi.org/10.3390/cancers14030625 - 26 Jan 2022

Cited by 16 | Viewed by 3768

Abstract

Hyperthermia (HT) is a cancer treatment modality which targets malignant tissues by heating to 40–43 °C. In addition to its direct antitumor effects, HT potently sensitizes the tumor to radiotherapy (RT) and chemotherapy (CT), thereby enabling complete eradication of some tumor entities as [...] Read more.

Hyperthermia (HT) is a cancer treatment modality which targets malignant tissues by heating to 40–43 °C. In addition to its direct antitumor effects, HT potently sensitizes the tumor to radiotherapy (RT) and chemotherapy (CT), thereby enabling complete eradication of some tumor entities as shown in randomized clinical trials. Despite the proven efficacy of HT in combination with classic cancer treatments, there are limited international standards for the delivery of HT in the clinical setting. Consequently, there is a large variability in reported data on thermometric parameters, including the temperature obtained from multiple reference points, heating duration, thermal dose, time interval, and sequence between HT and other treatment modalities. Evidence from some clinical trials indicates that thermal dose, which correlates with heating time and temperature achieved, could be used as a predictive marker for treatment efficacy in future studies. Similarly, other thermometric parameters when chosen optimally are associated with increased antitumor efficacy. This review summarizes the existing clinical evidence for the prognostic and predictive role of the most important thermometric parameters to guide the combined treatment of RT and CT with HT. In conclusion, we call for the standardization of thermometric parameters and stress the importance for their validation in future prospective clinical studies. Full article

(This article belongs to the Special Issue Oncologic Thermoradiotherapy: Need for Evidence, Harmonisation, and Innovation)

► Show Figures

Figure 1

27 pages, 12636 KiB

Open AccessEditor’s ChoiceReview

Chemotherapy Side-Effects: Not All DNA Damage Is Equal

by Winnie M. C. van den Boogaard, Daphne S. J. Komninos and Wilbert P. Vermeij

Cancers 2022, 14(3), 627; https://doi.org/10.3390/cancers14030627 - 26 Jan 2022

Cited by 89 | Viewed by 13382

Abstract

Recent advances have increased survival rates of children and adults suffering from cancer thanks to effective anti-cancer therapy, such as chemotherapy. However, during treatment and later in life they are frequently confronted with the severe negative side-effects of their life-saving treatment. The occurrence [...] Read more.

Recent advances have increased survival rates of children and adults suffering from cancer thanks to effective anti-cancer therapy, such as chemotherapy. However, during treatment and later in life they are frequently confronted with the severe negative side-effects of their life-saving treatment. The occurrence of numerous features of accelerated aging, seriously affecting quality of life, has now become one of the most pressing problems associated with (pediatric) cancer treatment. Chemotherapies frequently target and damage the DNA, causing mutations or genome instability, a major hallmark of both cancer and aging. However, there are numerous types of chemotherapeutic drugs that are genotoxic and interfere with DNA metabolism in different ways, each with their own biodistribution, kinetics, and biological fate. Depending on the type of DNA lesion produced (e.g., interference with DNA replication or RNA transcription), the organ or cell type inflicted (e.g., cell cycle or differentiation status, metabolic state, activity of clearance and detoxification mechanisms, the cellular condition or micro-environment), and the degree of exposure, outcomes of cancer treatment can largely differ. These considerations provide a conceptual framework in which different classes of chemotherapeutics contribute to the development of toxicities and accelerated aging of different organ systems. Here, we summarize frequently observed side-effects in (pediatric) ex-cancer patients and discuss which types of DNA damage might be responsible. Full article

(This article belongs to the Special Issue Genomic Instability in Tumor Evolution and Therapy Response)

► Show Figures

Figure 1

16 pages, 862 KiB

Open AccessEditor’s ChoiceReview

Machine Learning and Deep Learning Applications in Multiple Myeloma Diagnosis, Prognosis, and Treatment Selection

by Alessandro Allegra, Alessandro Tonacci, Raffaele Sciaccotta, Sara Genovese, Caterina Musolino, Giovanni Pioggia and Sebastiano Gangemi

Cancers 2022, 14(3), 606; https://doi.org/10.3390/cancers14030606 - 25 Jan 2022

Cited by 26 | Viewed by 6065

Abstract

Artificial intelligence has recently modified the panorama of oncology investigation thanks to the use of machine learning algorithms and deep learning strategies. Machine learning is a branch of artificial intelligence that involves algorithms that analyse information, learn from that information, and then employ [...] Read more.

Artificial intelligence has recently modified the panorama of oncology investigation thanks to the use of machine learning algorithms and deep learning strategies. Machine learning is a branch of artificial intelligence that involves algorithms that analyse information, learn from that information, and then employ their discoveries to make abreast choice, while deep learning is a field of machine learning basically represented by algorithms inspired by the organization and function of the brain, named artificial neural networks. In this review, we examine the possibility of the artificial intelligence applications in multiple myeloma evaluation, and we report the most significant experimentations with respect to the machine and deep learning procedures in the relevant field. Multiple myeloma is one of the most common haematological malignancies in the world, and among them, it is one of the most difficult ones to cure due to the high occurrence of relapse and chemoresistance. Machine learning- and deep learning-based studies are expected to be among the future strategies to challenge this negative-prognosis tumour via the detection of new markers for their prompt discovery and therapy selection and by a better evaluation of its relapse and survival. Full article

(This article belongs to the Special Issue Applications of Machine Learning and Statistical Modeling in Precision Oncology)

► Show Figures

Figure 1

20 pages, 1950 KiB

Open AccessEditor’s ChoiceReview

Peptide Receptor Radionuclide Therapy with [¹⁷⁷Lu]Lu-DOTA-TATE in Patients with Advanced GEP NENS: Present and Future Directions

by Maria I. del Olmo-García, Stefan Prado-Wohlwend, Pilar Bello, Angel Segura and Juan F. Merino-Torres

Cancers 2022, 14(3), 584; https://doi.org/10.3390/cancers14030584 - 24 Jan 2022

Cited by 13 | Viewed by 4210

Abstract

This review article summarizes findings published in the last years on peptide receptor radionuclide therapy in GEP NENs, as well as potential future developments and directions. Unanswered questions remain, such as the following: Which is the correct dose and individual dosimetry? Which is [...] Read more.

This review article summarizes findings published in the last years on peptide receptor radionuclide therapy in GEP NENs, as well as potential future developments and directions. Unanswered questions remain, such as the following: Which is the correct dose and individual dosimetry? Which is the place for salvage PRRT-Lu? Whicht is the role of PRRT-Lu in the pediatric population? Which is the optimal sequencing of PRRT-Lu in advanced GEP NETs? Which is the place of PRRT-Lu in G3 NENs? These, and future developments such as inclusion new radiopharmaceuticals and combination therapy with different agents, such as radiosensitizers, will be discussed. Full article

(This article belongs to the Special Issue Molecular Targeting in Cancer: Imaging and Therapy)

► Show Figures

Figure 1

14 pages, 635 KiB

Open AccessEditor’s ChoiceReview

Strategies for Improving the Efficacy of CAR T Cells in Solid Cancers

by Jon Amund Kyte

Cancers 2022, 14(3), 571; https://doi.org/10.3390/cancers14030571 - 23 Jan 2022

Cited by 12 | Viewed by 4837

Abstract

Therapy with T cells equipped with chimeric antigen receptors (CARs) shows strong efficacy against leukaemia and lymphoma, but not yet against solid cancers. This has been attributed to insufficient T cell persistence, tumour heterogeneity and an immunosuppressive tumour microenvironment. The present article provides [...] Read more.

Therapy with T cells equipped with chimeric antigen receptors (CARs) shows strong efficacy against leukaemia and lymphoma, but not yet against solid cancers. This has been attributed to insufficient T cell persistence, tumour heterogeneity and an immunosuppressive tumour microenvironment. The present article provides an overview of key strategies that are currently investigated to overcome these hurdles. Basic aspects of CAR design are revisited, relevant for tuning the stimulatory signal to the requirements of solid tumours. Novel approaches for enhancing T cell persistence are highlighted, based on epigenetic or post-translational modifications. Further, the article describes CAR T strategies that are being developed for overcoming tumour heterogeneity and the escape of cancer stem cells, as well as for countering prevalent mechanisms of immune suppression in solid cancers. In general, personalised medicine is faced with a lack of drugs matching the patient’s profile. The advances and flexibility of modern gene engineering may allow for the filling of some of these gaps with tailored CAR T approaches addressing mechanisms identified as important in the individual patient. At this point, however, CAR T cell therapy remains unproved in solid cancers. The further progress of the field will depend on bringing novel strategies into clinical evaluation, while maintaining safety. Full article

(This article belongs to the Special Issue Current Advances in Chimeric Antigen Receptor Technology)

► Show Figures

Figure 1

19 pages, 4641 KiB

Open AccessEditor’s ChoiceArticle

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

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

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

Cited by 13 | Viewed by 6649

Abstract

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

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

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

► Show Figures

Figure 1

16 pages, 1064 KiB

Open AccessEditor’s ChoiceReview

Emerging Role of Epigenetic Alterations as Biomarkers and Novel Targets for Treatments in Pancreatic Ductal Adenocarcinoma

by Marcus T. T. Roalsø, Øyvind H. Hald, Marina Alexeeva and Kjetil Søreide

Cancers 2022, 14(3), 546; https://doi.org/10.3390/cancers14030546 - 21 Jan 2022

Cited by 5 | Viewed by 2797

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is a lethal disease with limited treatment options. Emerging evidence shows that epigenetic alterations are present in PDAC. The changes are potentially reversible and therefore promising therapeutic targets. Epigenetic aberrations also influence the tumor microenvironment with the potential to [...] Read more.

Pancreatic ductal adenocarcinoma (PDAC) is a lethal disease with limited treatment options. Emerging evidence shows that epigenetic alterations are present in PDAC. The changes are potentially reversible and therefore promising therapeutic targets. Epigenetic aberrations also influence the tumor microenvironment with the potential to modulate and possibly enhance immune-based treatments. Epigenetic marks can also serve as diagnostic screening tools, as epigenetic changes occur at early stages of the disease. Further, epigenetics can be used in prognostication. The field is evolving, and this review seeks to provide an updated overview of the emerging role of epigenetics in the diagnosis, treatment, and prognostication of PDAC. Full article

(This article belongs to the Special Issue Epigenetic Detection and Regulation of Cancer Biomarkers)

► Show Figures

Figure 1

Journal Menu

Journal Browser

Editor’s Choice Articles

Further Information

Guidelines

MDPI Initiatives

Follow MDPI