Abstract 4098: SPARC expression stimulates paracrine inhibitory response from bone marrow stroma during dormancy of prostate cancer in the bone

Abstract

Abstract Recurrent disease is the most daunting aspect of cancer treatment; however, how tumor cells become dormant and later recur even years after “successful” treatment is poorly understood. However, studies to decipher mechanisms responsible for dormancy have been hampered due to lack of appropriate model. In this study, we isolated two syngeneic cell lines (Indolent and Aggressive), which recapitulates dormancy and recurrence of prostate cancer in the bone microenvironment. We found that Indolent cells retained dormant phenotype whereas Aggressive cells grew rapidly in the tibial bone in vivo whereas the in vitro cell proliferation, invasion, migration and self-renewal properties of both cells in culture were not altered, suggesting the role of microenvironment in regulation of dormancy and recurrence. The expression profile by our microarray analysis revealed that SPARC and Noggin (a known inhibitor of BMP7) were significantly upregulated in Indolent and Aggressive cells, respectively. SPARC secreted by Indolent cells was found to stimulate BMP7 expression in bone stromal cells that in turn inhibited cancer cells by activating the dormancy-associated p38 MAPK pathway and its downstream cell cycle inhibitors, p21 and p18. In addition, BMP7 increased senescence and diminished stem-cell phenotype of cancer cells, which was rescued by addition of recombinant Noggin. We also found that BMPR2 plays a crucial role in SPARC-induced paracrine inhibition of tumor cells residing in the bone. Accordingly, BMPR2 knockdown rescued the BMP7-mediated decrease in stemness. Importantly, the BMPR2 correlative signature was enriched in patients who did not experience recurrence for a long period of time, which further verified the role of BMPR2 downstream signaling in dormancy. When primary tumor samples were examined by immunohistochemistry, both SPARC and BMPR2 were found to be significantly downregulated in patients with bone metastasis. Moreover, patients who did not experience bone metastasis were found to express high level of both SPARC and BMPR2. Importantly, we also observed elevated expression of DNA methylase genes, DNMT1 and -3B in Aggressive cells. Treatment of Aggressive cells with NS398, a COX-2 inhibitor downregulated DNMTs and concomitantly augmented SPARC expression in vitro. Therefore, recurrence of cancer cells in the bone microenvironment involves epigenetic regulation of SPARC and disruption of inhibitory crosstalk of cancer cells with the stroma. These findings suggest that SPARC plays a critical role in maintaining dormancy of prostate cancer cells in bone microenvironment. Citation Format: Sambad Sharma, Fei Xing, Kerui Wu, Yin Liu, Kounosuke Watabe. SPARC expression stimulates paracrine inhibitory response from bone marrow stroma during dormancy of prostate cancer in the bone. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4098.