Abstract 897: CEA induces colorectal cancer metastases by disrupting TGF-β signaling

Abstract

Abstract Introduction: Advanced colorectal cancer (CRC) remains the second most common cause of cancer mortality worldwide. Carcinoembryonic antigen (CEA) represents one of the few biomarkers approved by the U.S. Food and Drug Administration (FDA) as signifying metastatic CRC, potentially through activation of STAT3, stimulating production of IL-6, IL-10 and others. Yet until recently a clear functional role of CEA in tumorigenesis has remained elusive. Our study demonstrated that CEA inactivates the tumor suppressive arm of transforming growth factor-β (TGF-β) signaling, providing crucial new mechanistic information for CEA in promoting aggressive CRC. Moreover, we previously found that deletion of Smad3/4 adaptor β2SP results in loss of TGF-β signaling, with dramatic and spontaneous formation of CRC, presenting a strong mouse model of CRC. We hypothesized that the disruption of the TGF-β tumor suppressor pathway by CEA (through TGF-β receptor TαR1, β2SP, Smad3 and Smad4) leads to aggressive colorectal cancers. Methods & Results: We observed that CEA plays a role in CRC metastasis by interacting directly with the transforming growth factor-β (TGF-β) receptor 1 (TαR1) and inhibiting downstream TGF-β tumor suppressor signaling. Targeting CEA with either an anti-CEA specific antibody or siRNA- mediated CEA silencing restores the tumor suppressive properties of TGF-β signaling. Ectopic expression of CEA induces CRC metastases. In human CRC, increased CEA levels are associated with loss of TGF-β signaling. Detailed analysis of the interaction between CEA and TαR1 by generating deletion fragments of CEA further revealed that the N terminal domain of CEA containing Ig like domain 1 is responsible for binding with TαR1. Our data also demonstrate that this fragment can impede the growth inhibitory TGF-β signaling by inhibiting the phospho SMAD3 level upon TGF-β treatment. Immunohistochemical analysis of the CRC revealed induction of phospho STAT3 level compared to normal colon tissue and STAT3 inhibitor inhibited the proliferation of cells with impaired TGF-β signaling. A novel triterpenoid molecule RTA402 inhibits CRC cell proliferation both through inhibition of STAT3 and restoration of TGF-β pathway in cell lines with activated CEA. Conclusions: Our results demonstrate that CEA induces CRC metastasis through interacting with TαR1 and suppressing growth inhibitory TGF-β signaling pathway. Inhibiting the interaction of CEA and TαR1 using peptide inhibitors will be very useful in preventing CRC cell growth and proliferation. It will be interesting to see the tumor suppressive effect of these peptide inhibitors and/or RTA402 in the consistently aggressive mouse model of CRC with high CEA levels. Thus the study holds promise to generate novel therapeutic agents for the treatment of lethal metastatic CRC. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 897. doi:1538-7445.AM2012-897