Suppression of tumorigenesis and activation of Wnt signaling by bone morphogenetic protein 4 in human cancer cells

Abstract

Aberrations in BMP signaling have recently been implicated as a cause of human cancer. Here we demonstrate and define the tumor suppressive properties of BMP4. Consistent with its potential role in a tumor suppressor pathway, BMP4 treatment eliminated the tumorigenic potential of an undifferentiated human cancer cell line. This loss of tumorigenicity was accompanied by an increase in apoptosis, alterations in cell cycle profile, and an increase in cell size. Interestingly, human colon cancer cells were resistant to the growth-suppressive properties of BMP4. To identify putative downstream mediators of BMP4-mediated tumor suppression, Affymetrix Genechips were employed to identify BMP4-regulated genes. The human BMP4 transcriptome was characterized by the modulation of many genes well known to play important roles in differentiation and development, including the induction of numerous genes involved in Wnt signaling. Modulation of Wnt gene expression by BMP4 had several functional consequences - BMP4 treatment led to activation of TCF reporters; complete activation of at least one BMP4-responsive gene required TCF sites; and treatment with a Wnt ligand was sufficient to mimic several of the phenotypic effects of BMP4 treatment. These data demonstrate the tumor suppressive properties of BMP4 signaling, show that colon cancer cells are resistant to BMP4-induced differentiation and growth suppression, further define the BMP4 transcriptome, and raise the intriguing possibility that interactions between the Wnt and BMP signaling pathways may play an important role in differentiation and tumor suppression.