Resident and Recruited Stroma Contribute to Castrate Resistant Prostate Cancer

Abstract

Progression to castrate resistant prostate cancer (CRPC) is associated with high morbidity. Disease recurrence and progression is influenced by the tumor microenvironment. Resident and recruited stroma contribute to cancer progression through paracrine signaling. A conditional stromal TGF-beta type II receptor knockout mouse model (Tgfbr2fspKO) was characterized to be a model for understanding CRPC progression. We demonstrated the resident stromal fibroblast responsiveness to TGF-beta mediated paracrine canonical Wnt signaling in the adjacent prostate epithelia in castrate resistance. Regrowth of the prostate was associated with recruitment of stromal cells from the bone marrow and a contributor to CRPC. We determined that a population of bone marrow derived cells, particularly the mesenchymal stem cells (MSCs), were recruited and fused to prostatic ductal epithelia. These MSCs were found to be a source of Wnt ligands that could contribute to castrate resistant prostatic epithelia. In summary, the tumor microenvironment composed of both resident and recruited stromal cells mediate CRPC through paracrine signaling.