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The tumor microenvironment in prostate cancer: elucidating molecular pathways for therapy development.

ABSTRACT: Mechanisms leading to the development of virulent prostate cancer are not confined to the cancer epithelial cell, but also involve the tumor microenvironment. Multiple signaling pathways exist between epithelial cells, stromal cells, and the extracellular matrix to support tumor progression from the primary site to regional lymph nodes and distant metastases. Prostate cancers preferentially metastasize to the skeleton, prompting considerable research effort into understanding the unique interaction between prostate cancer epithelial cells and the bone microenvironment. This effort has led to the discovery that signaling pathways involved in normal prostate and bone development become dysregulated in cancer. These pathways stimulate excessive cell growth and neovascularization, impart more invasive properties to epithelial cells, weaken antitumor immune surveillance, and promote the emergence of castrate-resistant disease. An improved understanding of the complex relationship between cancer epithelial cells and the organ-specific microenvironments with which they interact has created a powerful opportunity to develop novel therapies.

SUBMITTER: Corn PG

PROVIDER: S-EPMC3421469 | biostudies-other | 2012

REPOSITORIES: biostudies-other

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The tumor microenvironment in prostate cancer: elucidating molecular pathways for therapy development.

Corn Paul G PG

Cancer management and research 20120725

Mechanisms leading to the development of virulent prostate cancer are not confined to the cancer epithelial cell, but also involve the tumor microenvironment. Multiple signaling pathways exist between epithelial cells, stromal cells, and the extracellular matrix to support tumor progression from the primary site to regional lymph nodes and distant metastases. Prostate cancers preferentially metastasize to the skeleton, prompting considerable research effort into understanding the unique interact ...[more]

PMID: 22904640

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Project description:Introduction: Cancer is an intricate disorder/dysfunction of cells that can be defined as a genetic heterogeneity in human disease. Therefore, it is characterized by several adaptive complex hallmarks. Among them, the pH dysregulation appears as a symbol of aberrant functions within the tumor microenvironment (TME). In comparison with normal tissues, in the solid tumors, we face with an irregular acidification and alkalinization of the extracellular and intracellular fluids. Methods: In this study, we comprehensively discussed the most recent reports on the hallmarks of solid tumors to provide deep insights upon the molecular machineries involved in the pH dysregulation of solid tumors and their impacts on the initiation and progression of cancer. Results: The dysregulation of pH in solid tumors is fundamentally related to the Warburg effect and hypoxia, leading to expression of a number of molecular machineries, including: NHE1, H+ pump V-ATPase, CA-9, CA-12, MCT-1, GLUT-1. Activation of proton exchangers and transporters (PETs) gives rise to formation of TME. This condition favors the cancer cells to evade from the anoikis and apoptosis, granting them aggressive and metastasis phenotype, as well as resistance to chemotherapy and radiation therapy. This review aimed to discuss the key molecular changes of tumor cells in terms of bio-energetics and cancer metabolism in relation with pH dysregulation. During this phenomenon, the intra- and extracellular metabolites are altered and/or disrupted. Such molecular alterations provide molecular hallmarks for direct targeting of the PETs by potent relevant inhibitors in combination with conventional cancer therapies as ultimate therapy against solid tumors. Conclusion: Taken all, along with other treatment strategies, targeting the key molecular machineries related to intra- and extracellular metabolisms within the TME is proposed as a novel strategy to inhibit or block PETs that are involved in the pH dysregulation of solid tumors.

Project description:BACKGROUNDMolecular characterization of prostate cancer (PCa) has revealed distinct subclasses based on underlying genomic alterations occurring early in the natural history of the disease. However, how these early alterations influence subsequent molecular events and the course of the disease over its long natural history remains unclear.METHODSWe explored the molecular and clinical progression of different genomic subtypes of PCa using distinct tumor lineage models based on human genomic and transcriptomic data. We developed transcriptional classifiers, and defined "early" and "late" categories of molecular subclasses from 8,158 PCa patients. Molecular subclasses were correlated with clinical outcomes and pathologic characteristics using Kaplan-Meier and logistic regression analyses.RESULTSWe identified PTEN and CHD1 alterations as subtype-specific late progression events specifically in ERG-overexpressing (ERG+) and SPOP-mutant tumors, respectively, and 2 distinct progression models consisting of ERG/PTEN (normal to ERG+ to PTEN-deleted) and SPOP/CHD1 (normal to SPOP-mutated to CHD1-deleted) with shared early tumorigenesis but distinct pathways toward progression. We found that within ERG+ and SPOP-mutant subtypes, late events were associated with worse prognosis. Importantly, the clinical and pathologic features associated with distinct late events at radical prostatectomy were strikingly different; PTEN deletions were associated with increased locoregional stage, while CHD1 deletions were only associated with increased grade, despite equivalent metastatic potential.CONCLUSIONThese findings suggest a paradigm in which specific subtypes of PCa follow distinct pathways of progression, at both the molecular and clinical levels. Therefore, the interpretation of common clinical parameters such as locoregional tumor stage may be influenced by the underlying tumor lineage, and potentially influence management decisions.FUNDINGProstate Cancer Foundation, National Cancer Institute, Urology Care Foundation, Damon Runyon Cancer Research Foundation, US Department of Defense, and the AIRC Foundation.

Dataset Information

The tumor microenvironment in prostate cancer: elucidating molecular pathways for therapy development.

Publications

The tumor microenvironment in prostate cancer: elucidating molecular pathways for therapy development.

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