Abstract 5762: Role of BMP7 in dormancy and recurrence of prostatic tumor stem cell in the bone metastasis

Abstract

Abstract Prostate cancer is becoming a curable disease when it is diagnosed at an early stage. However, even those patients who have localized cancer and have been “successfully” treated with surgery often experience recurrent disease after many years of dormancy. In the case of prostate cancer, bone is the most common metastatic site which affects approximately 70% of patients with advanced disease. The growth of the tumor cells in the bone is generally slow and they often become dormant until an appropriate microenviroment is established for their re-growth. 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 cell (PC3mm) and bone stromal cell (HS5). Our data indicate that the conditioned medium of HS5 cells was able to induce growth arrest and senescence to prostate cancer cells through activation of p38 MAP kinase. Western blot, qRT-PCR and reporter assay showed that this effect was mediated by induction of the tumor metastasis suppressor gene, N-myc downstream regulated gene 1 (NDRG1). We found that this secretory factor is bone morphogenetic protein 7 (BMP7) and that a specific inhibitor of p38 significantly abrogated up-regulation of NDRG1 by BMP7, suggesting that BMP7 induces NDRG1 through activation of p38. We also found that BMP7 significantly activated p21 and that this effect was inhibited by siRNA to NDRG1. Importantly, our results indicate that BMP7 was able to induce senescence to PC3mm cell; however, this senescence was reversible and the tumor cells re-gained the ability of their growth 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, we isolated tumor stem population from PC3mm, and examined the effect of BMP7 on these cells. BMP7 indeed induced p38, NDRG1 and p21 in the prostate tumor stem cells. BMP7 also significantly suppressed sphere forming ability of the tumor stem cells followed by activation of NDRG1 and this effect was reversed by withdrawal of BMP7. These results suggest that the BMP7-NDRG1axis plays a critical role in the regulation of dormancy and recurrence of prostate tumor cells in bone metastasis. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 5762.