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Cancers
Special Issues
Stromal-Epithelial Interactions in Cancer Progression and Therapy Response
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Stromal-Epithelial Interactions in Cancer Progression and Therapy Response

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

Deadline for manuscript submissions: closed (15 February 2022) | Viewed by 15321

Special Issue Editor

Prof. Neil A. Bhowmick

E-Mail Website
Guest Editor
Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, 90048, USA
Interests: prostate cancer; tumor microenvironment; paracrine signaling; TGF-ß signaling; drug resistance mechanisms

Special Issue Information

Dear Colleagues,

Tumorigenesis is a result of cell-intrinsic epigenomic and genomic changes and cell-extrinsic factors. Fibroblasts in the tumor microenvironment can contribute to paracrine-mediated tumor initiation, progression, and therapeutic resistance. The tumor-associated immune cells, vascular endothelia, and extracellular matrix can have similar and distinct effects on tumor progression. Traditionally, cytokines and growth factors derived from the tumor microenvironment have been recognized as tumorigenic mediators and accordingly targets for therapeutic intervention. However, more recently, metabolites, extracellular vesicles, and even nucleic acids (DNA and noncoding RNA) are reported to serve as communication between the tumor and surrounding cells. The paracrine and juxtacrine cross talk described contribute to the recognized coevolution of the tumor and its microenvironment. 

When chemotherapy or targeted therapy, respectively, inhibit proliferation or restrict oncogenic dependence of the cancer cell, the fibroblasts, extrasellar matrix, immune cells, and vasculature are also impacted. Often the changes elicited by the therapy or the tumor response to the therapy have been found to contribute to the eventual development of drug resistance. The strong clinical correlates of these findings have supported combination therapies that target both the tumor and its microenvironment. For this Special Issue of Cancers, we will welcome manuscripts describing novel data, methods, collaborative initiatives, editorials, and reviews related to these topics that contribute to improving therapies for solid tumors.

Prof. Neil A. Bhowmick
Guest Editor

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

  • fibroblast
  • paracrine signaling
  • juxtacrine signaling
  • extracellular matrix
  • perivascular niche
  • metastatic niche
  • drug resistance

Published Papers (6 papers)

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Editorial

Jump to: Research, Review

3 pages, 181 KiB  
Editorial
Stromal–Epithelial Interactions in Cancer Progression and Therapy Response
by Manish Thiruvalluvan and Neil A. Bhowmick
Cancers 2023, 15(11), 3014; https://doi.org/10.3390/cancers15113014 - 1 Jun 2023
Viewed by 882
Abstract
Tumorigenesis is a result of cell-intrinsic epigenomic and genomic changes as well as cell-extrinsic factors [...] Full article
(This article belongs to the Special Issue Stromal-Epithelial Interactions in Cancer Progression and Therapy Response)

Research

Jump to: Editorial, Review

16 pages, 4195 KiB  
Article
Antagonizing Glutamine Bioavailability Promotes Radiation Sensitivity in Prostate Cancer
by Manish Thiruvalluvan, Sandrine Billet and Neil A. Bhowmick
Cancers 2022, 14(10), 2491; https://doi.org/10.3390/cancers14102491 - 19 May 2022
Cited by 5 | Viewed by 2003
Abstract
Nearly half of localized prostate cancer (PCa) patients given radiation therapy develop recurrence. Here, we identified glutamine as a key player in mediating the radio-sensitivity of PCa. Glutamine transporters and glutaminase are upregulated by radiation therapy of PCa cells, but respective inhibitors were [...] Read more.
Nearly half of localized prostate cancer (PCa) patients given radiation therapy develop recurrence. Here, we identified glutamine as a key player in mediating the radio-sensitivity of PCa. Glutamine transporters and glutaminase are upregulated by radiation therapy of PCa cells, but respective inhibitors were ineffective in radio-sensitization. However, targeting glutamine bioavailability by L-asparaginase (L-ASP) led to a significant reduction in clonogenicity when combined with irradiation. L-ASP reduced extracellular asparagine and glutamine, but the sensitization effects were driven through its depletion of glutamine. L-ASP led to G2/M cell cycle checkpoint blockade. As evidence, there was a respective delay in DNA repair associated with RAD51 downregulation and upregulation of CHOP, contributing to radiation-induced cell death. A radio-resistant PCa cell line was developed, was found to bypass radiation-induced mitotic catastrophe, and was sensitive to L-ASP/radiation combination treatment. Previously, PCa-associated fibroblasts were reported as a glutamine source supporting tumor progression. As such, glutamine-free media were not effective in promoting radiation-induced PCa cell death when co-cultured with associated primary fibroblasts. However, the administration L-ASP catalyzed glutamine depletion with irradiated co-cultures and catalyzed tumor volume reduction in a mouse model. The clinical history of L-ASP for leukemia patients supports the viability for its repurposing as a radio-sensitizer for PCa patients. Full article
(This article belongs to the Special Issue Stromal-Epithelial Interactions in Cancer Progression and Therapy Response)
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19 pages, 6389 KiB  
Article
Ephrin B Activate Src Family Kinases in Fibroblasts Inducing Stromal Remodeling in Prostate Cancer
by Mamatha Kakarla, Sathyavathi ChallaSivaKanaka, Mary F. Dufficy, Victoria Gil, Yana Filipovich, Renee Vickman, Susan E. Crawford, Simon W. Hayward and Omar E. Franco
Cancers 2022, 14(9), 2336; https://doi.org/10.3390/cancers14092336 - 9 May 2022
Cited by 8 | Viewed by 2712
Abstract
Through stromal-epithelial interactions, carcinoma associated fibroblasts (CAF) play a critical role in tumor growth and progression. Activation of erythrophoyetin-producing human hepatocellular (Eph) receptors has been implicated in cancer. Eph receptor interactions with Ephrin ligands lead to bidirectional signals in the recipient and effector [...] Read more.
Through stromal-epithelial interactions, carcinoma associated fibroblasts (CAF) play a critical role in tumor growth and progression. Activation of erythrophoyetin-producing human hepatocellular (Eph) receptors has been implicated in cancer. Eph receptor interactions with Ephrin ligands lead to bidirectional signals in the recipient and effector cells. The consequences of continuous reverse Ephrin signaling activation in fibroblasts on prostate cancer (PCa) is unknown. When compared to benign prostate fibroblast, CAF displayed higher expression of Ephrin B1, B2, and B3 ligands (EFNB1, EFNB2, and EFNB3). In this study, we found that continuous activation of EFNB1 and EFNB3 in a benign human prostate stromal cell line (BHPrS1) increased the expression of CAF markers and induced a CAF phenotype. BHPrS1EFNB1 and BHPrS1EFNB3 displayed a pro-tumorigenic secretome with multiple effects on neovascularization, collagen deposition, and cancer cell proliferation, overall increasing tumorigenicity of a premalignant prostate epithelial cell line BPH1 and PCa cell line LNCaP, both in vitro and in vivo. Inhibition of Src family kinases (SFK) in BHPrS1EFNB1 and BHPrS1EFNB3 suppressed EFNB-induced ɑ-SMA (Alpha-smooth muscle actin) and TN-C (Tenascin-C) in vitro. Our study suggests that acquisition of CAF characteristics via SFK activation in response to increased EFNB ligands could promote carcinogenesis via modulation of TME in PCa. Full article
(This article belongs to the Special Issue Stromal-Epithelial Interactions in Cancer Progression and Therapy Response)
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Graphical abstract

18 pages, 42324 KiB  
Article
TBX2 Drives Neuroendocrine Prostate Cancer through Exosome-Mediated Repression of miR-200c-3p
by Girijesh Kumar Patel, Sayanika Dutta, Mosharaf Mahmud Syed, Sabarish Ramachandran, Monica Sharma, Venkatesh Rajamanickam, Vadivel Ganapathy, David J. DeGraff, Kevin Pruitt, Manisha Tripathi and Srinivas Nandana
Cancers 2021, 13(19), 5020; https://doi.org/10.3390/cancers13195020 - 7 Oct 2021
Cited by 8 | Viewed by 3283
Abstract
Deciphering the mechanisms that drive transdifferentiation to neuroendocrine prostate cancer (NEPC) is crucial to identifying novel therapeutic strategies against this lethal and aggressive subtype of advanced prostate cancer (PCa). Further, the role played by exosomal microRNAs (miRs) in mediating signaling mechanisms that propagate [...] Read more.
Deciphering the mechanisms that drive transdifferentiation to neuroendocrine prostate cancer (NEPC) is crucial to identifying novel therapeutic strategies against this lethal and aggressive subtype of advanced prostate cancer (PCa). Further, the role played by exosomal microRNAs (miRs) in mediating signaling mechanisms that propagate the NEPC phenotype remains largely elusive. The unbiased differential miR expression profiling of human PCa cells genetically modulated for TBX2 expression led to the identification of miR-200c-3p. Our findings have unraveled the TBX2/miR-200c-3p/SOX2/N-MYC signaling axis in NEPC transdifferentiation. Mechanistically, we found that: (1) TBX2 binds to the promoter and represses the expression of miR-200c-3p, a miR reported to be lost in castrate resistant prostate cancer (CRPC), and (2) the repression of miR-200c-3p results in the increased expression of its targets SOX2 and N-MYC. In addition, the rescue of mir-200c-3p in the context of TBX2 blockade revealed that miR-200c-3p is the critical intermediary effector in TBX2 regulation of SOX2 and N-MYC. Further, our studies show that in addition to the intracellular mode, TBX2/miR-200c-3p/SOX2/N-MYC signaling can promote NEPC transdifferentiation via exosome-mediated intercellular mechanism, an increasingly recognized and key mode of propagation of the NEPC phenotype. Full article
(This article belongs to the Special Issue Stromal-Epithelial Interactions in Cancer Progression and Therapy Response)
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Review

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20 pages, 1504 KiB  
Review
Impact of the Tumor Microenvironment for Esophageal Tumor Development—An Opportunity for Prevention?
by Martin Borgmann and Michael Quante
Cancers 2022, 14(9), 2246; https://doi.org/10.3390/cancers14092246 - 30 Apr 2022
Cited by 5 | Viewed by 2480
Abstract
Despite therapeutical advancements, and in contrast to other malignancies, esophageal adenocarcinoma (EAC) prognosis remains dismal while the incidence has markedly increased worldwide over the past decades. EAC is a malignancy of the distal esophageal squamous epithelium at the squamocolumnar junction with gastric cells [...] Read more.
Despite therapeutical advancements, and in contrast to other malignancies, esophageal adenocarcinoma (EAC) prognosis remains dismal while the incidence has markedly increased worldwide over the past decades. EAC is a malignancy of the distal esophageal squamous epithelium at the squamocolumnar junction with gastric cells expanding into the esophagus. Most EAC patients have a history of Barret’s esophagus (BE), a metaplastic adaption to chronic reflux, initially causing an inflammatory microenvironment. Thus, the immune system is highly involved early on in disease development and progression. Normally, anti-tumor immunity could prevent carcinogenesis but in rare cases BE still progresses over a dysplastic intermediate state to EAC. The inflammatory milieu during the initial esophagitis phase changes to a tolerogenic immune environment in BE, and back to pro-inflammatory conditions in dysplasia and finally to an immune-suppressive tumor microenvironment in EAC. Consequently, there is a huge interest in understanding the underpinnings that lead to the inflammation driven stepwise progression of the disease. Since knowledge about the constellations of the various involved cells and signaling molecules is currently fragmentary, a comprehensive description of these changes is needed, allowing better preventative measures, diagnosis, and novel therapeutic targets. Full article
(This article belongs to the Special Issue Stromal-Epithelial Interactions in Cancer Progression and Therapy Response)
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26 pages, 398 KiB  
Review
Clinical Applications of Minimal Residual Disease Assessments by Tumor-Informed and Tumor-Uninformed Circulating Tumor DNA in Colorectal Cancer
by Jun Gong, Andrew Hendifar, Alexandra Gangi, Karen Zaghiyan, Katelyn Atkins, Yosef Nasseri, Zuri Murrell, Jane C. Figueiredo, Sarah Salvy, Robert Haile and Megan Hitchins
Cancers 2021, 13(18), 4547; https://doi.org/10.3390/cancers13184547 - 10 Sep 2021
Cited by 15 | Viewed by 2894
Abstract
Emerging data suggest that circulating tumor DNA (ctDNA) can detect colorectal cancer (CRC)-specific signals across both non-metastatic and metastatic settings. With the development of multiple platforms, including tumor-informed and tumor-agnostic ctDNA assays and demonstration of their provocative analytic performance to detect minimal residual [...] Read more.
Emerging data suggest that circulating tumor DNA (ctDNA) can detect colorectal cancer (CRC)-specific signals across both non-metastatic and metastatic settings. With the development of multiple platforms, including tumor-informed and tumor-agnostic ctDNA assays and demonstration of their provocative analytic performance to detect minimal residual disease, there are now ongoing, phase III randomized clinical trials to evaluate their role in the management paradigm of CRC. In this review, we highlight landmark studies that have formed the basis for ongoing studies on the clinically applicability of plasma ctDNA assays in resected, stage I–III CRC and metastatic CRC. We discuss clinical settings by which ctDNA may have the most immediate impact in routine clinical practice. These include the potential for ctDNA to (1) guide surveillance and intensification or de-intensification strategies of adjuvant therapy in resected, stage I–III CRC, (2) predict treatment response to neoadjuvant therapy in locally advanced rectal cancer inclusive of total neoadjuvant therapy (TNT), and (3) predict response to systemic and surgical therapies in metastatic disease. We end by considering clinical variables that can influence our ability to reliably interpret ctDNA dynamics in the clinic. Full article
(This article belongs to the Special Issue Stromal-Epithelial Interactions in Cancer Progression and Therapy Response)
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