Goodman Cancer Centre Seminar

Axel A. Thomson, PhD
Principal Investigator Research Scientist
MRC Human Reproductive Sciences Unit
Edinburgh, UK

Title: Stromal-Epithelial interactions and the regulation of prostate development and cancer – using mesenchymal molecules to slow tumour growth

The role of the tumour microenvironment in cancer initiation and progression is increasingly recognized as critically important and yet is poorly understood at the mechanistic or molecular level. Tumour stroma (cancer associated fibroblasts, CAFs) stimulate prostate carcinogenesis and stromal histology is an independent predictor of prostate cancer patient prognosis. There is considerable interest in identifying pathways in tumour stroma that act as paracrine regulators of tumour epithelia, as these may become new therapeutics or diagnostics. Our studies have utilized the similarities between mesenchyme involved in directing prostate organogenesis and CAFs involved in tumourigenesis, since both involve stromal/epithelial interactions and paracrine signalling. We have used gene profiling to identify molecules expressed in developmental prostate mesenchyme and CAFs, and focussed upon those which are secreted or surface bound – since these may function as paracrine regulators of epithelia (and/or autocrine regulators of stroma). Furthermore, we have recently demonstrated that we can inhibit the pro-tumourigenic signalling of CAFs using the pathways that we identified and characterized in developmental prostatic mesenchyme. This is a novel approach to tumour control.

My approach in regard to studying stromal mechanisms in prostate cancer is almost unique, since the majority of research is focussed upon tumour epithelia. We have combined basic developmental biology with tumour studies and used developmental systems to identify and test pathways. These have also been tested in a primary human prostate tumour reconstitution system in which to examine effects upon tumourigenesis via CAFs. This has led us to propose a new paradigm in which developmental mesenchymal pathways can be used to regulate epithelial tumourigenesis by reducing CAF pro-tumourigenic signalling.