Abstract 3206: SPARC in tumor microenvironment induces dormancy of prostate cancer in bone

Despite significant advancement in early detection and treatment of prostate cancer, approximately 35% of patients who had surgically resected primary tumor experience recurrent disease after years of the treatment, suggesting that tumor cells disseminated before surgery remain dormant in patients for a period of time and awaken as recurrent disease. Prostate cancer is known to frequently recur in the bone; however, how dormant cells switch its phenotype leading to recurrent tumor remains poorly understood. We have isolated two syngeneic cell lines (Indolent and Aggressive), derived from in vivo selection after injection of PC3mm stem-like cells as a model system, which recapitulates dormancy and recurrence in bone microenvironment. We found that Indolent cells retained dormant phenotype whereas Aggressive cells grew rapidly in the tibial bone in vivo while the growth rates of both cells in culture were similar, 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. Furthermore, SPARC secreted by Indolent cells was found to stimulate BMP7 and DKK1 in microenvironmental cells (bone stromal cells and bone mesenchymal stem cells, respectively) that in turn kept cancer cells in dormant state. We previously showed that BMP7 secreted by bone stromal cells induced senescence in prostate cancer stem-like cells leading to dormancy of tumor cells. On the other hand, DKK1, an inhibitor of the Wnt pathway, suppressed Wnt-induced growth and decreased self-renewal of prostate cancer stem-like cells. We also found that DKK1 inhibited prostate cancer growth by inducing G1 cell cycle arrest. In addition, Wnt was found to up-regulate Noggin expression which might be a possible switch toward recurrence. Importantly, we observed elevated expression of a DNA methylase gene, DNMT3B, in Aggressive cells. Treatment of Aggressive cells with 5-Azacytidine reversed the SPARC gene expression in vitro, suggesting that the SPARC gene is epigenetically controlled by microenvironment via downregulation of the DNMT3B methylase gene. Furthermore, when Aggressive cells were cultured in the conditioned medium (CM) prepared from Indolent CM-treated bone mesenchymal cells, cell proliferation was found to be significantly reduced. Therefore, Wnt potentially serves as a recurrent factor in the bone microenvironment by upregulating Noggin and by inhibiting the effect of BMP7 on cancer stem-like cells. These findings suggest that SPARC plays a key role in maintaining dormancy of prostate cancer cells in bone microenvironment. Citation Format: Sambad Sharma, Fei Xing, Yin Liu, Kerui Wu, Aya Kobayashi, Kounosuke Watabe. SPARC in tumor microenvironment induces dormancy of prostate cancer in bone. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3206. doi:10.1158/1538-7445.AM2015-3206