Abstract
Prostate cancers may reactivate a latent embryonic program called the epithelial–mesenchymal transition (EMT) during the development of metastatic disease. Through EMT, tumors can develop a mesenchymal phenotype similar to cancer stem cell traits that contributes to metastasis and variation in therapeutic responses. Some of the recurrent somatic mutations of prostate cancer affect EMT driver genes and effector transcription factors that induce the chromatin- and androgen-dependent epigenetic alterations that characterize castrate-resistant prostate cancer (CRPC). EMT regulators in prostate cancer comprise transcription factors (SNAI1/2, ZEB1, TWIST1, and ETS), tumor suppressor genes (RB1, PTEN, and TP53), and post-transcriptional regulators (miRNAs) that under the selective pressures of antiandrogen therapy can develop an androgen-independent metastatic phenotype. In prostate cancer mouse models of EMT, Slug expression, as well as WNT/β-Catenin and notch signaling pathways, have been shown to increase stemness potential. Recent single-cell transcriptomic studies also suggest that the stemness phenotype of advanced prostate cancer may be related to EMT. Other evidence correlates EMT and stemness with immune evasion, for example, activation of the polycomb repressor complex I, promoting EMT and stemness and cytokine secretion through RB1, TP53, and PRC1. These findings are helping clinical trials in CRPC that seek to understand how drugs and biomarkers related to the acquisition of EMT can improve drug response.
Highlights
Prostate cancer (PCa) is the second most common cancer in men and the fifth cause of cancer-related deaths worldwide [1,2]
Androgen deprivation monotherapy (ADT) is no longer the standard of care for men with metastatic hormone-sensitive PCa; today, ADT should be combined with second-generation antiandrogens or chemotherapy, ADT is a unique therapy that should indefinitely continue in all stages of metastatic disease [4]
We summarize our current understanding regarding the role of epithelial–mesenchymal transition (EMT) in PCa with a specific focus on the relationship of somatic mutations of PCa on cancer stem-cell-like (CSC) biology and the immune microenvironment
Summary
Prostate cancer (PCa) is the second most common cancer in men and the fifth cause of cancer-related deaths worldwide [1,2]. The hallmark mechanism of EMT in tumor progression is loss of cell–cell adhesion [18] Transcriptional regulators, such as TWIST, SNAI1, SNAI2, ZEB1, and ZEB2, repress E-cadherin expression, while others promote the expression of mesenchymal differentiation markers, such as Nand/or R-cadherin and vimentin, as well as the expression of cellular matrix and focal adhesion proteins [19]. Mechanism of EMT in tumor progression is loss of cell–cell adhesion [18] These two important cellular programs of PCa progression—the CSC phenotype and EMT—are strongly interconnected [32]
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