Abstract
Genomic changes that drive cancer initiation and progression contribute to the co-evolution of the adjacent stroma. The nature of the stromal reprogramming involves differential DNA methylation patterns and levels that change in response to the tumor and systemic therapeutic intervention. Epigenetic reprogramming in carcinoma-associated fibroblasts are robust biomarkers for cancer progression and have a transcriptional impact that support cancer epithelial progression in a paracrine manner. For prostate cancer, promoter hypermethylation and silencing of the RasGAP, RASAL3 that resulted in the activation of Ras signaling in carcinoma-associated fibroblasts. Stromal Ras activity initiated a process of macropinocytosis that provided prostate cancer epithelia with abundant glutamine for metabolic conversion to fuel its proliferation and a signal to transdifferentiate into a neuroendocrine phenotype. This epigenetic oncogenic metabolic/signaling axis seemed to be further potentiated by androgen receptor signaling antagonists and contributed to therapeutic resistance. Intervention of stromal signaling may complement conventional therapies targeting the cancer cell.
Highlights
Cancer is a general term for a group of diseases that diverge with respect to its origin and is characterized by uncontrolled proliferation with the potential for metastatic progression (Hanahan & Weinberg 2000, Chaffer & Weinberg 2011, Hanahan & Weinberg 2011)
Chromatin structure is central for the regulation of gene expression either by organizing the structure of promoters and regulatory elements or by providing accessibility to transcription factor binding at regulatory elements (Tirosh & Barkai 2008)
Epigenetic coevolution of stromal fibroblastic cells in response to tumorigenesis It is established that carcinogenesis involves reciprocal interactions between cancer cells and components of the surrounding microenvironment consisting of extracellular matrix, fibroblasts, vasculatureassociated endothelia and pericytes, as well as immune cells and occasionally adipose cells (Plava et al 2019)
Summary
The primary role of GSTP1 is in the detoxification of carcinogens (Allocati et al 2018), it is not involved in the suppression of cancer cell growth and cannot be classified as a tumor suppressor gene (TSG); its aberrant silencing in CAFs may create a permissive microenvironment for tumorigenesis (Lee 2007). We have reported that the epigenetic silencing of the TGF-β type II receptor (Tgfbr2) in prostatic CAF can be causative for GSTP1 promoter methylation, as the knockout of the Tgfbr resulted in GSTP1 silencing in addition to a number of DNA damage repair genes (Banerjee et al 2014). Prostatic human CAF and mouse transgenic knockout of Tgfbr demonstrated elevated DNA methyltransferases I (DNMT1) activity and histone H3 lysine 9 trimethylation (H3K9me3) associated with greater promoter methylation. The epigenetic landscape of PCa CAF has diagnostic and grading capacity of PCa (Gordetsky & Epstein 2016, Pidsley et al 2018)
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