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Oncology Abstracts (2019) 1 P039 | DOI: 10.1530/oncolabs.1.P039

Vancouver Prostate Centre, Vancouver, Canada.

The exquisite dependency of PCa on androgens for growth and survival was first recognized in the 1940’s when Huggins and Hodges demonstrated the antitumour activity of hormonal manipulation in the treatment of PCa. Since then, androgen deprivation therapy has been the standard of care in the treatment of metastatic and locally advanced PCa. Drugs targeting the androgen/androgen receptor (AR) axis have been well-validated clinically and remain without a doubt the most effective class of therapies for treatment of advanced PCa. Despite the central role of AR pathway in PCa biology, the nature of these androgen-regulated genes that drive PCa growth/survival has been poorly elucidated. A first clue regarding the nature of androgen-regulated factors that mediate growth and survival came from the Cunha laboratory in the early 1970’s who showed from tissue recombination studies that prostate development was dependent on reciprocal interactions between the epithelium and the mesenchyme of the urogenital sinus. Their discovery that hormonal effects on the epithelium were mediated by soluble secreted paracrine factors induced by androgens in mesenchymal/stromal cells naturally spawned the ‘andromedin hypothesis’ that the paracrine mediators may be secreted soluble androgen-mediated growth factors called andromedins. Andromedins are thought to diffuse from the stroma into the epithelial layers and orchestrate growth and differentiation of the prostate by binding to cognate epithelial receptors. Over the years, a number of growth factors have been implicated as andromedins such as FGF7, FGF10, and IGF1. However, since none of these are androgen-regulated, a true andromedin has remained elusive. In early 2000’s, seminal work by Issacs found that the malignant transformation of normal prostatic epithelial cells is associated with a switch from a paracrine to an autocrine mechanism in androgen-stimulated growth. We have recently found that SEMA3C drives cancer growth by transactivating multiple receptor tyrosine kinases including EGFR, HER2 and MET via Plexin B1. Notably, we found that SEMA3C is a secreted, soluble autocrine growth factor in PCa and importantly combined with our findings that SEMA3C is transcriptionally induced by AR in a GATA2-dependent manner, these data together makes SEMA3C the first bona fide PCa andromedin to be identified. The identification of SEMA3C as an androgen-induced autocrine growth factor in PCa makes SEMA3C a promising new target for treatment of mCRPC.

Volume 1

7th International Pacific Rim (PacRim) Breast and Prostate Cancer Meeting

17 Mar 2019 - 20 Mar 2019

PacRim Breast and Prostate Cancer Group 

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