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Unravelling Cancer Mechanism and Developing Novel Therapeutics: An Urgent Need to Treat Cancer

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A special issue of Cancers (ISSN 2072-6694). This special issue belongs to the section "Cancer Therapy".

Deadline for manuscript submissions: closed (31 October 2023) | Viewed by 21256

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Special Issue Editors

Dr. Rajesh Singh

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Guest Editor

1. Department of Microbiology, Immunology, and Biochemistry, Morehouse School of Medicine, Atlanta, GA 30310, USA
2. Cancer Health Equity Institute, Morehouse School of Medicine, Atlanta, GA 30310, USA
Interests: targeted therapy; nano-therapy; nano-delivery; chemokine; combination therapy; prostate cancer; pancreatic cancer; liver cancer; ovarian cancer; breast cancer
Special Issues, Collections and Topics in MDPI journals

Dr. Santosh Kumar Singh

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Guest Editor

Department of Microbiology, Biochemistry & Immunology, Morehouse School of Medicine, Atlanta, GA 30310, USA
Interests: cancer; drug resistance; natural compound, chemotherapeutics; targeted therapy; drug delivery; nano therapy; 3D model; hypoxia; apoptosis; cell cycle; EMT
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Over several decades, cancer has been a rapidly growing health concern throughout the world. Many cancer screening programs are widely being implemented in high-and middle-income countries to reduce cancer incidence and mortality. However, the yearly rise in cases is disappointing considering the extensive use of various therapeutic approaches today. Emerging evidence suggests that drug resistance and relapse also represent significant issues during treatment. Therefore, no single breakthrough can cure cancer; in lieu, cumulative knowledge of complex underlying mechanisms could reduce many related deaths. Thus, understanding signaling pathways and developing novel targeted techniques, including molecular, biochemical, immunological, and nanotherapy, may give hope to clinicians searching for new targets for treatment.

To address these challenges, this Special Issue aims to present novel targeted therapies and their underlying cancer mechanism, including but not limited to natural compound combination therapy, chemotherapy, Immunotherapy, and nanotherapy. We welcome you to submit the original research and review articles on the latest progress in these topics.

Dr. Rajesh Singh
Dr. Santosh Kumar Singh
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Cancers is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2900 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

cancer
anticancer therapy
combination therapy
natural compound
nanotherapy
exosome therapy
targeted therapy
immunotherapy
chemokines
cytokines
antibodies
drug resistance

Published Papers (7 papers)

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Research

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15 pages, 3282 KiB

Open AccessArticle

Higher Expression of Annexin A2 in Metastatic Bladder Urothelial Carcinoma Promotes Migration and Invasion

by Christina Guo, Rucha Trivedi, Amit K. Tripathi, Rajesh R. Nandy, Diana C. Wagner, Kalyani Narra and Pankaj Chaudhary

Cancers 2022, 14(22), 5664; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers14225664 - 18 Nov 2022

Cited by 2 | Viewed by 1579

Abstract

In this study, we aim to evaluate the significance of AnxA2 in BLCA and establish its metastatic role in bladder cancer cells. Analysis of TCGA data showed that AnxA2 mRNA expression was significantly higher in BLCA tumors than in normal bladder tissues. High mRNA expression of AnxA2 in BLCA was significantly associated with high pathological grades and stages, non-papillary tumor histology, and poor overall survival (OS), progression-free survival (PFS), and diseases specific survival (DSS). Similarly, we found that AnxA2 expression was higher in bladder cancer cells derived from high-grade metastatic carcinoma than in cells derived from low-grade urothelial carcinoma. AnxA2 expression significantly mobilized to the surface of highly metastatic bladder cancer cells compared to cells derived from low-grade tumors and associated with high plasmin generation and AnxA2 secretion. In addition, the downregulation of AnxA2 cells significantly inhibited the proliferation, migration, and invasion in bladder cancer along with the reduction in proangiogenic factors and cytokines such as PDGF-BB, ANGPT1, ANGPT2, Tie-2, bFGF, GRO, IL-6, IL-8, and MMP-9. These findings suggest that AnxA2 could be a promising biomarker and therapeutic target for high-grade BLCA. Full article

(This article belongs to the Special Issue Unravelling Cancer Mechanism and Developing Novel Therapeutics: An Urgent Need to Treat Cancer)

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16 pages, 3995 KiB

Open AccessArticle

Histone Deacetylase 3 Governs β-Estradiol-ERα-Involved Endometrial Tumorigenesis via Inhibition of STING Transcription

by Guofang Chen, Qiang Yan, Lin Liu, Xinyue Wen, Hongliang Zeng and Shasha Yin

Cancers 2022, 14(19), 4718; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers14194718 - 28 Sep 2022

Cited by 7 | Viewed by 1811

Abstract

Purpose: The stimulator of interferon genes (STING) pathway plays a crucial role in antitumor immunity, and it is strictly regulated by many types of post-translational modifications. However, the contribution of acetylation involved in the regulation of STING to endometrial tumorigenesis remains unclear. Methods: We attempted to identify the key role of STING in endometrial carcinoma (EC) tissue and cell lines and explore its epigenetic regulation mechanism by HDACs that are critically involved in EC. We used IHC and qRT-PCR to detect the protein level and mRNA level of STING expression in endometrial carcinoma tissues, then explored the potential role of STING in tumor proliferation and apoptosis by CCK8 and flow cytometry, and identified the STING effect in the tumorigenicity by a mouse xenograft assay. We explored the possible relationship of acetylation alteration in STING regulation by ChIP analysis and Co-IP, and we knocked out STING in ECC1 and Ishikawa cells using CRISPR-Cas9 to further confirm the critical role of STING restoration induced by HDAC3 inhibitor RGFP-966 in the proliferation and apoptosis. Results: We found that STING expression was largely decreased and worked as an important regulator of cell proliferation and apoptosis; either activated or overexpressed STING, with both pharmacological and genetic approaches, largely blocked cell proliferation and induced apoptosis in EC. Moreover, STING expression was deregulated by both β-estradiol and HDAC3. Mechanically, we determined that HDAC3 can interact with β-estradiol-ERα and induce deacetylation of histone 3 lysine 4 at the STING promoter, thereby decreasing STING expression. Inhibition of HDAC3 increased STING expression, thereby inhibiting tumorigenesis. Conclusion: This study reveals a novel molecular mechanism by which HDAC3 inhibits STING transcription via β-estradiol-ERα and provides a promising therapy (a combination of HDAC and STING) for combating endometrial cancer. Full article

(This article belongs to the Special Issue Unravelling Cancer Mechanism and Developing Novel Therapeutics: An Urgent Need to Treat Cancer)

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14 pages, 1740 KiB

Open AccessArticle

Influence of Malignant Pleural Fluid from Lung Adenocarcinoma Patients on Neutrophil Response

by Maria Mulet, Rubén Osuna-Gómez, Carlos Zamora, José M. Porcel, Juan C. Nieto, Lídia Perea, Virginia Pajares, Ana M. Muñoz-Fernandez, Nuria Calvo, Maria Alba Sorolla and Silvia Vidal

Cancers 2022, 14(10), 2529; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers14102529 - 20 May 2022

Cited by 1 | Viewed by 2182

Abstract

Malignant pleural effusion (MPE) is a common severe complication of advanced lung adenocarcinoma (LAC). Neutrophils, an essential component of tumor infiltrates, contribute to tumor progression and their counts in MPE have been associated with worse outcome in LAC. This study aimed to evaluate phenotypical and functional changes of neutrophils induced by MPE to determine the influence of MPE immunomodulatory factors in neutrophil response and to find a possible association between neutrophil functions and clinical outcomes. Pleural fluid samples were collected from 47 LAC and 25 heart failure (HF) patients. We measured neutrophil degranulation products by ELISA, oxidative burst capacity and apoptosis by flow cytometry, and NETosis by fluorescence. The concentration of degranulation products was higher in MPE-LAC than in PE-HF. Functionally, neutrophils cultured with MPE-LAC had enhanced survival and neutrophil extracellular trap (NET) formation but had reduced oxidative burst capacity. In MPE, NETosis was positively associated with MMP-9, P-selectin, and sPD-L1 and clinically related to a worse outcome. This is the first study associating NETs with a worse outcome in MPE. Neutrophils likely contribute to tumor progression through the release of NETs, suggesting that they are a potential therapeutic target in LAC. Full article

(This article belongs to the Special Issue Unravelling Cancer Mechanism and Developing Novel Therapeutics: An Urgent Need to Treat Cancer)

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Review

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21 pages, 3117 KiB

Open AccessReview

Is Insulin Receptor Substrate4 (IRS4) a Platform Involved in the Activation of Several Oncogenes?

by Luis G. Guijarro, Francisco Javier Justo Bermejo, Diego Liviu Boaru, Patricia De Castro-Martinez, Diego De Leon-Oliva, Oscar Fraile-Martínez, Cielo Garcia-Montero, Melchor Alvarez-Mon, María del Val Toledo-Lobo and Miguel A. Ortega

Cancers 2023, 15(18), 4651; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers15184651 - 20 Sep 2023

Cited by 1 | Viewed by 1459

Abstract

The IRS (insulin receptor substrate) family of scaffold proteins includes insulin receptor substrate-4 (IRS4), which is expressed only in a few cell lines, including human kidney, brain, liver, and thymus and some cell lines. Its N-terminus carries a phosphotyrosine-binding (PTB) domain and a pleckstrin homology domain (PH), which distinguishes it as a member of this family. In this paper, we collected data about the molecular mechanisms that explain the relevance of IRS4 in the development of cancer and identify IRS4 differences that distinguish it from IRS1 and IRS2. Search engines and different databases, such as PubMed, UniProt, ENSEMBL and SCANSITE 4.0, were used. We used the name of the protein that it encodes “(IRS-4 or IRS4)”, or the combination of these terms with the word “(cancer)” or “(human)”, for searches. Terms related to specific tumor pathologies (“breast”, “ovary”, “colon”, “lung”, “lymphoma”, etc.) were also used. Despite the lack of knowledge on IRS4, it has been reported that some cancers and benign tumors are characterized by high levels of IRS-4 expression. Specifically, the role of IRS-4 in different types of digestive tract neoplasms, gynecological tumors, lung cancers, melanomas, hematological tumors, and other less common types of cancers has been shown. IRS4 differs from IRS1 and IRS2 in that can activate several oncogenes that regulate the PI3K/Akt cascade, such as BRK and FER, which are characterized by tyrosine kinase-like activity without regulation via extracellular ligands. In addition, IRS4 can activate the CRKL oncogene, which is an adapter protein that regulates the MAP kinase cascade. Knowledge of the role played by IRS4 in cancers at the molecular level, specifically as a platform for oncogenes, may enable the identification and validation of new therapeutic targets. Full article

(This article belongs to the Special Issue Unravelling Cancer Mechanism and Developing Novel Therapeutics: An Urgent Need to Treat Cancer)

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25 pages, 3981 KiB

Open AccessReview

Targeted Therapy and Mechanisms of Drug Resistance in Breast Cancer

by Briana Kinnel, Santosh Kumar Singh, Gabriela Oprea-Ilies and Rajesh Singh

Cancers 2023, 15(4), 1320; https://doi.org/10.3390/cancers15041320 - 19 Feb 2023

Cited by 14 | Viewed by 6959

Abstract

Breast cancer is the most common cause of cancer-related death in women worldwide. Multidrug resistance (MDR) has been a large hurdle in reducing BC death rates. The drug resistance mechanisms include increased drug efflux, enhanced DNA repair, senescence escape, epigenetic alterations, tumor heterogeneity, tumor microenvironment (TME), and the epithelial-to-mesenchymal transition (EMT), which make it challenging to overcome. This review aims to explain the mechanisms of resistance in BC further, identify viable drug targets, and elucidate how those targets relate to the progression of BC and drug resistance. Full article

(This article belongs to the Special Issue Unravelling Cancer Mechanism and Developing Novel Therapeutics: An Urgent Need to Treat Cancer)

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23 pages, 649 KiB

Open AccessReview

Therapeutic Strategies Targeting Urokinase and Its Receptor in Cancer

by Maria Teresa Masucci, Michele Minopoli, Gioconda Di Carluccio, Maria Letizia Motti and Maria Vincenza Carriero

Cancers 2022, 14(3), 498; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers14030498 - 19 Jan 2022

Cited by 19 | Viewed by 2683

Abstract

Several studies have ascertained that uPA and uPAR do participate in tumor progression and metastasis and are involved in cell adhesion, migration, invasion and survival, as well as angiogenesis. Increased levels of uPA and uPAR in tumor tissues, stroma and biological fluids correlate with adverse clinic–pathologic features and poor patient outcomes. After binding to uPAR, uPA activates plasminogen to plasmin, a broad-spectrum matrix- and fibrin-degrading enzyme able to facilitate tumor cell invasion and dissemination to distant sites. Moreover, uPAR activated by uPA regulates most cancer cell activities by interacting with a broad range of cell membrane receptors. These findings make uPA and uPAR not only promising diagnostic and prognostic markers but also attractive targets for developing anticancer therapies. In this review, we debate the uPA/uPAR structure–function relationship as well as give an update on the molecules that interfere with or inhibit uPA/uPAR functions. Additionally, the possible clinical development of these compounds is discussed. Full article

(This article belongs to the Special Issue Unravelling Cancer Mechanism and Developing Novel Therapeutics: An Urgent Need to Treat Cancer)

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19 pages, 996 KiB

Open AccessReview

Nano-Based Drug Delivery and Targeting to Overcome Drug Resistance of Ovarian Cancers

by Melayshia McFadden, Santosh Kumar Singh, Gabriela Oprea-Ilies and Rajesh Singh

Cancers 2021, 13(21), 5480; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13215480 - 31 Oct 2021

Cited by 15 | Viewed by 3469

Abstract

Ovarian cancer (OvCa) is a destructive malignancy due to difficulties in early detection and late advanced-stage diagnoses, leading to high morbidity and mortality rates for women. Currently, the quality treatment for OvCa includes tumor debulking surgery and intravenous platinum-based chemotherapy. However, numerous patients either succumb to the disease or undergo relapse due to drug resistance, such as to platinum drugs. There are several mechanisms that cause cancer cells’ resistance to chemotherapy, such as inactivation of the drug, alteration of the drug targets, enhancement of DNA repair of drug-induced damage, and multidrug resistance (MDR). Some targeted therapies, such as nanoparticles, and some non-targeted therapies, such as natural products, reverse MDR. Nanoparticle targeting can lead to the reversal of MDR by allowing direct access for agents to specific tumor sites. Natural products have many anti-cancer properties that adversely regulate the factors contributing to MDR. The present review displays the current problems in OvCa treatments that lead to resistance and proposes using nanotechnology and natural products to overcome drug resistance. Full article

(This article belongs to the Special Issue Unravelling Cancer Mechanism and Developing Novel Therapeutics: An Urgent Need to Treat Cancer)

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