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

ABSTRACT:

Background

TGF? 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? signaling.

Methods

To test the importance of TGF? signaling to cell survival and metastasis we compared human colon carcinoma cell lines that are either non-tumorigenic with TGF? response (FET), or tumorigenic with TGF? response (FET?) or tumorigenic with abrogated TGF? response via introduction of dominant negative TGF?RII (FET?/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? signaling through introduction of a dominant negative TGF? receptor II (TGF?RII) in non-metastatic FET? human colon cancer cells permits metastasis to distal organs, but importantly does not reduce invasive behavior at the primary site. Loss of TGF? signaling in FET?-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? signaling is a metastasis suppressor, we rescued TGF? signaling in CBS metastatic colon cancer cells that had lost TGF? receptor expression due to epigenetic repression. Restoration of TGF? signaling resulted in the inhibition of metastatic colony formation in distal organs by these cells. These results indicate that TGF? 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? signaling in human colon cancer cells. This raises the concern that therapies targeting inhibition of TGF? signaling may be imprudent in some patient populations with residual TGF? tumor suppressor activity.

SUBMITTER: Simms NA 

PROVIDER: S-EPMC3517326 | biostudies-literature | 2012 Jun

REPOSITORIES: biostudies-literature