Transforming growth factor-β suppresses metastasis in a subset of human colon carcinoma cells

Background: TGF beta signaling has typically been associated with suppression of tumor initiation while the role it plays in metastasis is generally associated with progression of malignancy. However, we present evidence here for an anti-metastatic role of TGF beta signaling. Methods: To test the importance of TGF beta signaling to cell survival and metastasis we compared human colon carcinoma cell lines that are either non-tumorigenic with TGF beta response (FET), or tumorigenic with TGF beta response (FET alpha) or tumorigenic with abrogated TGF beta response via introduction of dominant negative TGF beta RII (FET alpha/DN) and their ability to metastasize. Metastatic competency was assessed by orthotopic transplantation. Metastatic colony formation was assessed histologically and by imaging. Results: Abrogation of TGF beta signaling through introduction of a dominant negative TGF beta receptor II (TGF beta RII) in non-metastatic FET alpha human colon cancer cells permits metastasis to distal organs, but importantly does not reduce invasive behavior at the primary site. Loss of TGF beta signaling in FET alpha-DN cells generated enhanced cell survival capabilities in response to cellular stress in vitro. We show that enhanced cellular survival is associated with increased AKT phosphorylation and cytoplasmic expression of inhibitor of apoptosis (IAP) family members (survivin and XIAP) that elicit a cytoprotective effect through inhibition of caspases in response to stress. To confirm that TGF beta signaling is a metastasis suppressor, we rescued TGF beta signaling in CBS metastatic colon cancer cells that had lost TGF beta receptor expression due to epigenetic repression. Restoration of TGF beta signaling resulted in the inhibition of metastatic colony formation in distal organs by these cells. These results indicate that TGF beta signaling has an important role in the suppression of metastatic potential in tumors that have already progressed to the stage of an invasive carcinoma. Conclusions: The observations presented here indicate a metastasis suppressor role for TGF beta signaling in human colon cancer cells. This raises the concern that therapies targeting inhibition of TGF beta signaling may be imprudent in some patient populations with residual TGF beta tumor suppressor activity.