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7.4
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Cancers
Special Issues
Targeting Tumor Niches for Cancer Chemoprevention and Treatment
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Targeting Tumor Niches for Cancer Chemoprevention and Treatment

A special issue of Cancers (ISSN 2072-6694).

Deadline for manuscript submissions: closed (30 June 2023) | Viewed by 6590

Special Issue Editors

Prof. Dr. Vinata B.L. Lokeshwar

E-Mail Website
Guest Editor
Departments of Biochemistry and Molecular Biology, Medical College of Georgia, Augusta University, 1410 Laney Walker Blvd., Augusta, GA 30912, USA
Interests: urology; biomarkers; therapeutics
Prof. Dr. Balakrishna (Bal) L. Lokeshwar

E-Mail Website
Guest Editor
Georgia Cancer Center, Medical College of Georgia, Augusta University, Augusta, GA 30912, USA
Interests: urogenital cancers; cancer metastasis; diet and cancer chemoprevention; inflammation in cancer; chemokines and cytokines; invasion and metastasis
Dr. Thangaraju Muthusamy

E-Mail Website
Guest Editor
Department of Biochemistry & Molecular Biology, Medical College of Georgia, Augusta University, Augusta, GA, USA
Interests: breast cancer stem cells; breast cancer

Special Issue Information

Dear Colleagues,

Tumor niches are microanatomical compartments within the tumor microenvironment (TME) that regulate metabolic needs, immune surveillance, survival, tumor invasion, and cancer stem cell (CSC) maintenance. Although significant advances have been made in understanding the role of tumor niches and/or TME in tumor growth and metastasis, the application of cancer chemoprevention to control the tumor niches and/or TME during the early stages of carcinogenesis as well as targeted therapy response and prognosis have not received concerted attention.   

Tumor niches and TME in general also contribute to tumor heterogeneity, lineage plasticity, and response to therapy. While most preventive and treatment efforts are directed at controlling cancer cell dysfunction, the contribution of the TME to malignant behaviors, treatment response, and metastasis is an area of active research. New chemopreventive and treatment strategies directed at both the tumor microenvironment and the cancer epithelium are needed to effectively target carcinogenesis, and advanced cancers for cancer prevention and treatment.

We are pleased to invite you to contribute to this Special Issue; original research articles and reviews are welcome.

This Special Issue aims to highlight the role of tumor niches and TME in cancer chemoprevention and therapy response, covering both basic and clinical aspects, including diet-induced chemoprevention, chemotherapy and radiation therapy response, and any related biomarkers in different types of cancers.

We look forward to receiving your contributions.

Prof. Dr. Vinata B.L. Lokeshwar
Prof. Dr. Balakrishna (Bal) L. Lokeshwar
Dr. Thangaraju Muthusamy
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

  • tumor niches
  • tumor microenvironment
  • tumor heterogeneity
  • lineage plasticity
  • carcinogenesis
  • cancer chemoprevention
  • cancer treatment
  • targeted treatment
  • cancer biomarkers

Published Papers (3 papers)

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Research

14 pages, 3119 KiB  
Article
Antiandrogen-Equipped Histone Deacetylase Inhibitors Selectively Inhibit Androgen Receptor (AR) and AR-Splice Variant (AR-SV) in Castration-Resistant Prostate Cancer (CRPC)
by Balaji Chandrasekaran, Subhasish Tapadar, Bocheng Wu, Uttara Saran, Ashish Tyagi, Alexis Johnston, David A. Gaul, Adegboyega K. Oyelere and Chendil Damodaran
Cancers 2023, 15(6), 1769; https://doi.org/10.3390/cancers15061769 - 15 Mar 2023
Cited by 3 | Viewed by 1976
Abstract
Background: Epigenetic modification influences androgen receptor (AR) activation, often resulting in prostate cancer (PCa) development and progression. Silencing histone-modifying enzymes (histone deacetylases-HDACs) either genetically or pharmacologically suppresses PCa proliferation in preclinical models of PCa; however, results from clinical studies were not encouraging. Similarly, [...] Read more.
Background: Epigenetic modification influences androgen receptor (AR) activation, often resulting in prostate cancer (PCa) development and progression. Silencing histone-modifying enzymes (histone deacetylases-HDACs) either genetically or pharmacologically suppresses PCa proliferation in preclinical models of PCa; however, results from clinical studies were not encouraging. Similarly, PCa patients eventually become resistant to androgen ablation therapy (ADT). Our goal is to develop dual-acting small molecules comprising antiandrogen and HDAC-inhibiting moieties that may overcome the resistance of ADT and effectively suppress the growth of castration-resistant prostate cancer (CRPC). Methods: Several rationally designed antiandrogen-equipped HDAC inhibitors (HDACi) were synthesized, and their efficacy on CRPC growth was examined both in vitro and in vivo. Results: While screening our newly developed small molecules, we observed that SBI-46 significantly inhibited the proliferation of AR+ CRPC cells but not AR- CRPC and normal immortalized prostate epithelial cells (RWPE1) or normal kidney cells (HEK-293 and VERO). Molecular analysis confirmed that SBI-46 downregulated the expressions of both AR+ and AR-splice variants (AR-SVs) in CRPC cells. Further studies revealed the downregulation of AR downstream (PSA) events in CRPC cells. The oral administration of SBI-46 abrogated the growth of C4-2B and 22Rv1 CRPC xenograft tumors that express AR or both AR and AR-SV in xenotransplanted nude mice models. Further, immunohistochemical analysis confirmed that SBI-46 inhibits AR signaling in xenografted tumor tissues. Conclusion: These results demonstrate that SBI-46 is a potent agent that inhibits preclinical models of CRPC by downregulating the expressions of both AR and AR-SV. Furthermore, these results suggest that SBI-46 may be a potent compound for treating CRPC. Full article
(This article belongs to the Special Issue Targeting Tumor Niches for Cancer Chemoprevention and Treatment)
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13 pages, 2405 KiB  
Article
Pyruvate Dehydrogenase Kinase 4 Deficiency Increases Tumorigenesis in a Murine Model of Bladder Cancer
by Benjamin L. Woolbright, Ganeshkumar Rajendran, Erika Abbott, Austin Martin, Ryan Didde, Katie Dennis, Robert A. Harris and John A. Taylor III
Cancers 2023, 15(6), 1654; https://doi.org/10.3390/cancers15061654 - 08 Mar 2023
Viewed by 1449
Abstract
Pyruvate dehydrogenase kinase 4 (PDK4) is a mitochondrial isozyme in the PDK family (PDK1-4) partially responsible for phosphorylation of pyruvate dehydrogenase (PDH). Phosphorylation of PDH is thought to result in a pro-proliferative shift in metabolism that sustains growth of cancer cells. Previous data [...] Read more.
Pyruvate dehydrogenase kinase 4 (PDK4) is a mitochondrial isozyme in the PDK family (PDK1-4) partially responsible for phosphorylation of pyruvate dehydrogenase (PDH). Phosphorylation of PDH is thought to result in a pro-proliferative shift in metabolism that sustains growth of cancer cells. Previous data from our lab indicate the pan-PDK inhibitor dichloroacetate (DCA) or acute genetic knockdown of PDK4 blocks proliferation of bladder cancer (BCa) cells. The goal of this study was to determine the role of PDK4 in an in vivo BCa model, with the hypothesis that genetic depletion of PDK4 would impair formation of BCa. PDK4−/− or WT animals were exposed to N-Butyl-N-(4-hydroxybutyl) nitrosamine (BBN) for 16 weeks, and tumors were allowed to develop for up to 7 additional weeks. PDK4−/− mice had significantly larger tumors at later time points. When animals were treated with cisplatin, PDK4−/− animals still had larger tumors than WT mice. PDK4 expression was assessed in human tissue and in mice. WT mice lost expression of PDK4 as tumors became muscle-invasive. Similar results were observed in human samples, wherein tumors had less expression of PDK4 than benign tissue. In summary, PDK4 has a complex, multifunctional role in BCa and may represent an underrecognized tumor suppressor. Full article
(This article belongs to the Special Issue Targeting Tumor Niches for Cancer Chemoprevention and Treatment)
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19 pages, 2752 KiB  
Article
Viral Particle-Mediated SAMHD1 Depletion Sensitizes Refractory Glioblastoma to DNA-Damaging Therapeutics by Impairing Homologous Recombination
by Waaqo Daddacha, Dominique Monroe, Kristen Carver, Edidiong R. Usoro, Ahmet Alptekin, Hongyan Xu, Satoru Osuka, Ali S. Arbab and Daitoku Sakamuro
Cancers 2022, 14(18), 4490; https://doi.org/10.3390/cancers14184490 - 16 Sep 2022
Cited by 2 | Viewed by 2371
Abstract
The current standard-of-care treatment for glioblastoma includes DNA damaging agents, γ-irradiation (IR) and temozolomide (TMZ). These treatments fail frequently and there is limited alternative strategy. Therefore, identifying a new therapeutic target is urgently needed to develop a strategy that improves the efficacy of [...] Read more.
The current standard-of-care treatment for glioblastoma includes DNA damaging agents, γ-irradiation (IR) and temozolomide (TMZ). These treatments fail frequently and there is limited alternative strategy. Therefore, identifying a new therapeutic target is urgently needed to develop a strategy that improves the efficacy of the existing treatments. Here, we report that tumor samples from GBM patients express a high level of SAMHD1, emphasizing SAMHD1’s importance. The depletion of SAMHD1 using virus-like particles containing Vpx, VLP(+Vpx), sensitized two independent GBM cell lines (LN-229 and U-87) to veliparib, a well-established PARP inhibitor, and slowed cell growth in a dose-dependent manner. In the mouse GBM xenograft model, Vpx-mediated SAMHD1 depletion reduced tumor growth and SAMHD1 knockout (KO) improved survival. In combination with IR or TMZ, SAMHD1 KO and exposure to 50% growth inhibitory dose (gID50) of VLP(+Vpx) displayed a synergistic effect, resulting in impaired HR, and improved LN-229 cells’ sensitivity to TMZ and IR. In conclusion, our finding demonstrates that SAMHD1 promotes GBM resistance to treatment, and it is a plausible therapeutic target to improve the efficacy of TMZ and IR in GBM. Furthermore, we show that Vpx could be a potential therapeutic tool that can be utilized to deplete SAMHD1 in GBM. Full article
(This article belongs to the Special Issue Targeting Tumor Niches for Cancer Chemoprevention and Treatment)
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