The study of the role of bone morphogenetic proteins in prostate cancer progression

High expression of bone morphogenetic protein 7 (BMP7) in bone metastasis of the human prostate tumor and increased BMP7 expression with progression of prostatic adenocarcinoma in a mouse model imply a role for this protein in the advanced cancer. We examined the effect of BMP7 on various human prostatic cell lines to investigate its function on their oncologic properties in prostate cancer progression. The cancer cell lines presented various features of cancer progression such as anti-apoptotic activity or enhanced cell migration and invasion that were modulated by BMP7. We identified survivin as a key player in the anti-apoptotic protection in C4-2B prostatic cancer cell line. A master transcription factor of osteoblastic differentiation, Runx2, was found to regulate survivin expression and cell protection. BMP7 maintained the level of Runx2 as well as enhanced the association of Runx2 on survivin gene promoter. Moreover, Runx2 played an important role in avoiding cell death in normal culture conditions. Runx2 inhibition using either siRNA or AML1-ETO fusion protein, which suppressed Runx target gene expressions, significantly increased cancer cell apoptosis. The expression pattern of Runx2 was also correlated with the tumor growth in the mouse model of prostate cancer. It was noted that BMP7 induced phenotypic conversion similar to epithelial-mesenchymal transition (EMT) in PC-3 human prostate cancer cells. EMT is widely accepted as an important event of cancer metastasis, we pursued to identify the conversion. We characterized the major features of EMT in the cells; morphologic conversion, alteration in molecular expressions, increased cell invasion and migration, signal transduction of BMP and the expression of transcription factors that execute EMT. We also examined the effect of cancer microenvironment on EMT. Cancer-associated fibroblasts (CAFs), but not its normal counterparts, were able to induce morphologic change similar to that induced by BMP7. The results are consistent with the notion that cancer activated stroma play a role in metastatic progression. To sum up, this study confirms that BMP7 can enhance the malignant potential of prostate cancer cells via protection from apoptotic stress and induction of invasive properties.