Abstract PR3: Myofibroblasts activated upon tissue injury and hypoxia promote development of castration-resistant prostate cancer.

Abstract Background: Prostate cancer (PCa) progresses from prostatic intraepithelial neoplasia through locally invasive adenocarcinoma to castration resistant (CR) metastatic carcinoma. Although radical prostatectomy, radiation and androgen ablation are effective therapies for androgen-dependent (AD) PCa, metastatic CR-PCa is a major complication with high mortality. Cancer associated fibroblasts (CAFs) are a heterogeneous cell population of the tumor microenvironment that play important enabling roles in cancer development and progression. The mechanism resonsible for myofibroblast activation within the tumor microenvironment are not entirely clear and can be cancer-specific and heterogeneous. Methods: We used the Myc-CaP translpantable model of AD-PCa and the spontaneous mouse PCa model, TRAMP and we examinated how androgen ablation leads to induction of CXCL13 expression, which is critical for recruitment of B cells into tumor remnants and accellerate evolution of CR-PCa. We confirmed our data using human specimens of PCa. Results: Following castration, many myofibroblasts were present within the tumors remnants, which expressed CXCL13. Ablation of myofibroblasts led to a marked reduction in the infiltration of T, B and dendritic cells into the tumor remnants after the castration, reduced the expression of several chemokines, including CXCL13 and also delayed the re-growth of CR-PCa. We also found that androgen ablation led to increased expression of TGF-β in the tumor remnants. Inhibition of TGF-β signaling prevented activation of myofibroblasts, infiltration of B cells, induction of CXCL13 expressing myofibroblasts and also delayed the re-growth of CR-PCa. The main source of TGF-β in PCa tumors after castration appeared to be the fibroblast fraction. After castration, hypoxic areas appeared along with nuclear translocation of HIF-1α. Exposure of inactivated fibroblasts isolated from PCa tumors of non-castrated mice under hypoxic condition induced the expression of CTGF and TGF-β, which was HIF-1α dependent, and converted the fibroblasts into myofibroblasts. Conclusions: Our data show for the first time that androgen ablation led to hypoxia-induced myofibroblast activation, which is the cell type in the tumor stroma that recruits tumor-infiltrating B cells that allow the re-growth of CR-PCa through the production of lymphotoxin and IKKα nuclear translocation in the prostate epithelial cells. This abstract is also presented as Poster A75. Citation Format: Massimo Ammirante, Youngjin Kang, Michael Karin. Myofibroblasts activated upon tissue injury and hypoxia promote development of castration-resistant prostate cancer. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology: Multidisciplinary Science Driving Basic and Clinical Advances; Dec 2-5, 2012; Miami, FL. Philadelphia (PA): AACR; Cancer Res 2013;73(1 Suppl):Abstract nr PR3.