Cell death under epithelial–mesenchymal transition control in prostate cancer therapeutic response

Prostate cancer is a widespread problem among men, with >160 000 new cases in 2017 alone. Androgen deprivation therapy is commonly used in prostate cancer treatment to block androgens required for cancer growth, but disease relapse after androgen deprivation therapy is both common and severe. Changes in androgen receptor signaling from androgen deprivation therapy have been linked to therapeutic resistance and tumor progression. Resistant cells can become reprogrammed to undergo epithelial–mesenchymal transition, a phenotypic switch from benign, epithelial cells to a mobile cell with mesenchymal traits. In these cells, attachment to their epithelial cell layer is no longer required for survival. Anoikis is a form of cell death that occurs when detachment from other cells and the basement membrane occurs. Epithelial cells have been shown to undergo epithelial–mesenchymal transition, avoid anoikis induction and progress to a metastatic phenotype. In prostate cancer progression to advanced disease, epithelial–mesenchymal transition induction (characterized by loss of epithelial cellular attachment protein E-cadherin) correlates with a higher Gleason score, tumor progression, increased metastasis and higher biochemical recurrence. The concept of interfacing epithelial–mesenchymal transition with anoikis in the tumor microenvironment landscape will be discussed here, with focus on the significance of the functional exchange between the two processes in therapeutic targeting of advanced disease. The current evidence on the impact of loss of cell–cell contact, acquisition of chemoresistance, immune escape and metastatic spread in advanced tumors in response to transforming growth factor-β on prostate cancer metastasis will be also discussed. The signaling cross-talk between transforming growth factor-β and androgen receptor signaling will be interrogated as a new therapeutic platform for the development of combination strategies to impair prostate cancer metastasis.