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

BMC Cancer

Research Article

Elizabeth A Sharratt¹  Ashwani Rajput²  Melanie Ongchin³  Neka A K Simms⁴  Carol A Teggart⁴  Michael G Brattain⁴  Jing Wang⁴ 

[1] Department of Pharmacology and Therapeutics, Roswell Park Cancer Institute, Buffalo, USA;Department of Surgery, Division of Surgical Oncology, University of New Mexico, Albuquerque, USA;Department of Surgery, University at Buffalo, Buffalo, USA;Eppley Institute for Research in Cancer and Allied Diseases, University at Nebraska Medical Center, Omaha, USA;

关键词: Green Fluorescent Protein Fluorescence;    Human Colon Carcinoma Cell Line;    Orthotopic Implantation;    XIAP Expression;    Nuclear Survivin;   

DOI  :  10.1186/1471-2407-12-221

 received in 2012-02-20, accepted in 2012-05-18,  发布年份 2012

来源: Springer

【 摘 要 】

BackgroundTGFβ 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 TGFβ signaling.MethodsTo test the importance of TGFβ signaling to cell survival and metastasis we compared human colon carcinoma cell lines that are either non-tumorigenic with TGFβ response (FET), or tumorigenic with TGFβ response (FETα) or tumorigenic with abrogated TGFβ response via introduction of dominant negative TGFβRII (FETα/DN) and their ability to metastasize. Metastatic competency was assessed by orthotopic transplantation. Metastatic colony formation was assessed histologically and by imaging.ResultsAbrogation of TGFβ signaling through introduction of a dominant negative TGFβ receptor II (TGFβRII) in non-metastatic FETα human colon cancer cells permits metastasis to distal organs, but importantly does not reduce invasive behavior at the primary site. Loss of TGFβ signaling in FETα-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 TGFβ signaling is a metastasis suppressor, we rescued TGFβ signaling in CBS metastatic colon cancer cells that had lost TGFβ receptor expression due to epigenetic repression. Restoration of TGFβ signaling resulted in the inhibition of metastatic colony formation in distal organs by these cells. These results indicate that TGFβ signaling has an important role in the suppression of metastatic potential in tumors that have already progressed to the stage of an invasive carcinoma.ConclusionsThe observations presented here indicate a metastasis suppressor role for TGFβ signaling in human colon cancer cells. This raises the concern that therapies targeting inhibition of TGFβ signaling may be imprudent in some patient populations with residual TGFβ tumor suppressor activity.

【 授权许可】

Unknown   
© Simms et al.; licensee BioMed Central Ltd; licensee BioMed Central Ltd. 2012. This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.