Type III TGF-β Receptor Enhances Colon Cancer Cell Migration and Anchorage-Independent Growth

The type III TGF-beta receptor (T beta RIII or betagylcan) is a TGF-beta superfamily coreceptor with emerging roles in regulating TGF-beta superfamily signaling and cancer progression. Alterations in TGF-beta superfamily signaling are common in colon cancer; however, the role of T beta RIII has not been examined. Although T beta RIII expression is frequently lost at the message and protein level in human cancers and suppresses cancer progression in these contexts, here we demonstrate that, in colon cancer, T beta RIII messenger RNA expression is not significantly altered and T beta RIII expression is more frequently increased at the protein level, suggesting a distinct role for T beta RIII in colon cancer. Increasing T beta RIII expression in colon cancer model systems enhanced ligand-mediated phosphorylation of p38 and the Smad proteins, while switching TGF-beta and BMP-2 from inhibitors to stimulators of colon cancer cell proliferation, inhibiting ligand-induced p21 and p27 expression. In addition, increasing T beta RIII expression increased ligand-stimulated anchorage-independent growth, a resistance to ligand-and chemotherapy-induced apoptosis, cell migration and modestly increased tumorigenicity in vivo. In a reciprocal manner, silencing endogenous T beta RIII expression decreased colon cancer cell migration. These data support a model whereby T beta RIII mediates TGF-beta superfamily ligand-induced colon cancer progression and support a context-dependent role for T beta RIII in regulating cancer progression.