Abstract B57: Oncostatin M promotes progression of Pten-deficient prostate cancer

Abstract

Abstract Chronic inflammation has been proposed to play a crucial role in several cancers including gastric, pancreatic, colon and lung, with recent evidence suggesting involvement in prostate cancer. While both interleukin 6 (IL6) and the related cytokine oncostatin M (OSM) have been implicated in prostate cancer, there have been few studies using in vivo models. To address this issue, we employed a dissociated prostate tissue recombination system using epithelium derived from conditional Pten knockout mice. Loss of Pten is common in prostate cancer and generates an intermediate murine prostatic intraepithelial neoplasia (mPIN) lesion in our system, providing an ideal means to assess functional synergy. We hypothesize that increased expression of these cytokines in the prostate microenvironment will promote malignant progression of intermediate prostate cancer lesions. Paracrine expression of IL6 did not transform naïve prostate epithelium nor did it exhibit functional synergy with Pten null epithelium in our system. Grafts expressing OSM alone did not transform naïve tissue, though in contrast, presented dramatic functional synergy with loss of Pten in prostate epithelium. Loss of Pten combined with OSM exhibited progression to poorly differentiated adenocarcinoma with features of epithelial-to-mesenchymal transition (EMT). Transformed tissues displayed loss of cytokeratin expression with down-regulation and mis-localization of e-cadherin. These tumors exhibit activation of several pathways downstream of OSM signaling including STAT3 and Erk1/2 as seen by immunohistochemical analysis. Further, we interrogated the role of OSM in promoting hormone refractory prostate cancer by castrating host animals following tumor establishment. Loss of Pten alone failed to progress beyond mPIN lesions and eventually regressed at 6 months post castration. In dramatic contrast, grafts expressing the OSM ligand exhibited initial regression with castration resistant growth following a latency period, recapitulating events commonly observed in human disease. Our evidence suggests that in the context of Pten loss, IL6 does not appear to promote prostate malignancy in the murine system. Conversely, we have identified that OSM synergizes with loss of Pten to promote aggressive prostate malignancy. Paracrine expression of OSM results in activation of several pathways, providing a means to interrogate hierarchy within signaling modules in the context of prostate cancer progression. Our study further indicates that OSM could play a role in promoting castration resistance, allowing investigation of potential points for therapeutic intervention. Citation Format: Daniel A. Smith, Yang Zong, Atsushi Kiba, Owen N. Witte. Oncostatin M promotes progression of Pten-deficient prostate cancer [abstract]. In: Proceedings of the AACR Special Conference on Advances in Prostate Cancer Research; 2012 Feb 6-9; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2012;72(4 Suppl):Abstract nr B57.