Stromal Contribution to the Development of Resistance to New-Generation Drugs by Castration-Resistant Prostate Cancer.

摘要

The project will test the hypothesis that benign tumor support (stromal) cells have a significant role in acquired resistance of a prostate tumor to hormone therapies. Based upon our preliminary data showing that primary prostate stromal cells (PrSCs) acquire a steroidogenic phenotype under the influence of a paracrine Hedgehog (Hh) signaling microenvironment, we will test whether human bone marrow stromal cells (BMSCs) likewise convert to an androgen secreting phenotype under paracrine Hh stimulation. Aim 2 will test whether Hh-primed steroiodogenic BMSCs or PrSCs can adapt to acute or chronic abiraterone treatment by further increasing their expressions of steroidogenic genes and by further increasing their outputs of T and DHT. Finally, in Aim 3, I will attempt to demonstrate in cell co-culture models that Sonic Hh produced from PCa cells activates steroidogenesis in BMCs and PrSCs and test whether the addition of abiraterone to this model co-culture system further boosts production of androgen from the co-cultured stromal cells. Collectively, this work will significantly impact on our understanding of the mechanistic process leading to CRPC by showing that benign tumor support (stromal) cells within a bone metastasis have a supportive role in the development of CRPC through their ability to synthesize T and DHT upon Hh stimulation from metastatic PCa cells, and whether this adaptation can increase resistance to new generation therapies, which may lead to more productive combined therapies not only targeting steroidogenesis, but the supporting hedgehog pathway.