Abstract 1416: BMP 7 regulates dormancy and recurrence of prostate cancer stem cell in bone via P38/NDRG1/P21 signaling axis.

Bone is the most common metastatic site of prostate cancer, which affects approximately 70% of patients with advanced disease. Although patients with localized lesions can be cured by radical prostatectomy or radiotherapy, more than 90% of cancer deaths are attributed to metastatic disease. Growth of the tumor cells in the bone is generally slow and they often become dormant until an appropriate microenvironment is established for their recurrence. However, how these metastatic tumor cells become dormant and how they recur at the target organs is virtually unknown. To address this critical question, we have studied an interaction of prostate cancer cells (PC3mm) and bone stromal cells (HS5).The conditioned medium of HS5 induced growth arrest and senescence to prostate cancer cells. Our results of Western blot, qRT-PCR and reporter assay showed that this effect was mediated by induction of p38 MAP kinase, the tumor metastasis suppressor gene, N-myc downstream regulated gene 1 (NDRG1) and cell cycle inhibitors. We also found that this secretory factor is bone morphogenetic protein 7 (BMP7) and that BMP7 indeed induced NDRG1 and p21 through activation of p38. Importantly, BMP7 was able to induce senescence to PC3mm cell; however, the tumor cells regained their growth ability upon withdrawal of BMP7, suggesting that BMP7-induced senescence is reversible. Notably, our results of the existing database analysis indicate that the expression level of BMPR2, one of the BMP7 receptors, showed inverse correlation with bone metastasis and recurrence of prostate cancer. Furthermore, BMP7 significantly suppressed sphere forming ability of the cancer stem-like cells isolated from PC3mm and induced senescence followed by activation of NDRG1 and p21, and this effect was reversed by withdrawal of BMP7. To determine whether BMP7 secreted from bone stromal cells induces growth arrest of cancer stem-like cells in vivo, we co-injected the cancer stem-like cells with bone stromal cells which had either scrambled shRNA (control) or shRNA for BMP7 into the tibia of nude mice. We found that the control HS5 suppressed the growth of cancer stem-like cells, while HS5 with knocked-down BMP7 failed to inhibit cancer growth in the bone. Furthermore, direct injection of BMP7 after inoculation of cancer stem-like cells into mouse tibiae significantly suppressed the tumor growth. More importantly, we found that withdrawal of BMP7 treatment led the tumor to regrow in the bone, suggesting again that BMP7 plays a critical role in determining the fate of cancer stem-like cells for dormancy and recurrence in bone metastasis of prostate cancer. Our results revealed a novel mechanism of the BMP7-NDRG1axis which plays a critical role in the regulation of dormancy and recurrence of prostate tumor cells in bone metastasis. Citation Format: Fei Xing, Aya Kobayashi, Hiroshi Okuda, Puspa Pandey, Misako Watabe, Sudha K. Pai, Sambad Sharma, Kounosuke Watabe. BMP 7 regulates dormancy and recurrence of prostate cancer stem cell in bone via P38/NDRG1/P21 signaling axis. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1416. doi:10.1158/1538-7445.AM2013-1416