Recent data indicate that the
Bone Morphogenetic Protein BMP-7 exhibits mucosal protection against experimental
colitis in rats, suggesting that this
cytokine exerts direct actions in intestinal epithelial cells during
inflammatory bowel diseases and other precancerous lesions of the colon. In this study, we investigated the functional expression of
BMP-7 and its receptors in normal human colon crypts,
aberrant crypt foci (ACF) in sigmoiditis and
colorectal tumors, and their derived
cancer cell lines. Transcripts encoding
BMP-7 receptors type II (BMPRII, ActRII, ActRIIB) and type I (ALK-2) were clearly detected by RT-PCR in several premalignant and
carcinoma cell lines. The
cytokine was identified by immunohistochemistry in surface epithelial cells and crypts in the normal colon mucosa, ACF in sigmoiditis, sporadic high grade dysplastic
adenoma, and in 9 of 16 colon
carcinomas (56.2%). In addition, the
conditioned medium collected from the
adenoma PC/AA/C1 and
carcinoma HCT8/S11 and SW48 cell lines in culture contained significant levels of
BMP-7 ranging from 0.17 to 0.38 ng/ml. We found that
BMP-7 induced scattering and proinvasive responses (EC50=1 ng/ml) in kidney and
colon cancer cell lines through SMAD4 and src -independent pathways and signaling cascades using FAK phosphorylation at Y925 and activation of ERK1/2, Rac1 and JNK. This phosphorylation of FAK on Y925 was also induced by the proinvasive agent
EGF. Taken together, our findings suggest that
BMP-7 exerts divergent effects in the colon mucosa, one counteracting transient inflammatory situations and the other linked to pejorative functions during chronic ulcerative diseases and the neoplastic progression.