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) through in vivo selection by implanting PC3mm stem-like cells into the tibial bones. We found that Indolent cells retained dormant phenotype whereas Aggressive cells grew rapidly in the bone in vivo, while the growth rates of both cells in culture were similar, suggesting the role of tumor microenvironment in regulation of dormancy and recurrence. Indolent cell was found to secrete a high level of SPARC which significantly stimulated the expression of BMP7 in bone marrow stromal cells (BMSC). The secreted BMP7 then kept cancer cells in dormant state by inducing senescence, reducing stemness and activating dormancy-associated p38 MAPK signaling and p21 expression in cancer cells. Importantly, we found that SPARC was epigenetically silenced in Aggressive cells by promoter methylation, but the 5-Azacytidine treatment reactivated the expression. Furthermore, high SPARC promoter methylation negatively correlated with disease-free survival of prostate cancer patients. We also found that the COX2 inhibitor, NS398, downregulated DNMTs and increased expression of SPARC that led to tumor growth suppression in the bone in vivo. These findings suggest that SPARC plays a key role in maintaining dormancy of prostate cancer cells in bone microenvironment.
The Journal of biological chemistry. 2016 Jul 15 [Epub ahead of print]
Sambad Sharma, Fei Xing, Yin Liu, Kerui Wu, Neveen Said, Radhika Pochampally, Yusuke Shiozawa, Hui-Kuan Lin, K C Balaji, Kounosuke Watabe
Wake Forest University School of Medicine, United States;, Wake Forest University School of Medicine, United States;, Wake Forest University School of Medicine, United States;, Wake Forest University School of Medicine, United States;, Wake Forest University School of Medicine, United States;, University of Mississippi Medical Center, United States., Wake Forest University School of Medicine, United States;, Wake Forest University School of Medicine, United States;, Wake Forest University School of Medicine, United States;, Wake Forest University School of Medicine, United States; .