BMP Signaling Promotes the Growth of Primary Human Colon Carcinomas in vivo

Abstract

Human colon carcinomas (CCs) represent a growing worldwide problem. One of the pathways that has been negatively implicated in the genesis of CCs is triggered by bone morphogenetic protein (BMP) ligands, which activate BMP receptors leading to the function of SMAD proteins in the nucleus. BMP signaling is altered in familial human polyposis, and mice with compromised BMP signaling in the intestine develop tumors. Here, we have re-evaluated the presence and roles of BMP signaling in advanced sporadic human CCs, using both primary tumors and established cell lines, and directly modulating BMP pathway activity in a cell-autonomous manner using constitutively active and dominant-negative BMP receptor Ib forms. We find evidence for active endogenous BMP signaling in all primary CC samples and for its role in promoting primary CC tumor growth and CC cell survival and proliferation in vivo in xenografts. In vitro, we also document autonomous and non-autonomous effects of enhanced BMP receptor activity on gap closure in culture, suggesting possible roles in invasion. Caution should thus be exerted in trying to augment or restore its activity for therapeutic purposes. In contrast, we raise the possibility that blockade of BMP signaling might have beneficial effects against at least a subset of advanced colon cancers.