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). Ectopic expression of CEA induces CRC metastases, potentially indirectly through activation of STAT3, stimulating production of IL-6, IL-10 and others. Yet until recently a clear mechanism 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 CEA interacts through a specific site targeting the TGF-β pathway potentially TGF-βRI leading to aggressive colorectal cancers. Impeding this interaction by using specific antibodies or peptide inhibitors may be used as a therapeutic agent to treat advanced CRC.
Methods & Results: We observed that CEA interacts directly with the transforming growth factor-β (TGF-β) receptor 1 (TGF-βR1) and causes inhibition of 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. Detailed analysis of this interaction revealed the D7 fragment of CEA responsible for binding with TGF-β receptor I and capable of inhibiting tumor suppressor function of TGF-β signaling as evident by the ability of D7 fragment to reduce phospho -Smad3 level upon TGF-β stimulation. In human CRC, increased CEA levels are associated with loss of TGF-β signaling. Immunohistochemical analysis of the CRC revealed induction of phospho STAT3 level compared to normal colon tissue. To impede the CEA mediated suppression of growth inhibitory TGF-β signaling we are currently using antibodies which block this interaction and reinforce tumor suppressor TGF-β signaling.
Conclusions: Our results demonstrate that CEA induces CRC metastasis through interacting with TGF-βR1 and suppressing growth inhibitory TGF-β signaling pathway which is mediated by the D7 fragment of CEA. Inhibiting the interaction of CEA and TGF-βR1 using peptide inhibitors/antibodies /small molecule inhibitors will be very useful in preventing CRC cell growth and proliferation. Thus the study holds promise to generate novel therapeutic agents for the treatment of lethal metastatic CRC.
Citation Format: Avijit Majumdar, Ying Li, Sue-Hwa Lin, Lopa Mishra. CEA: A therapeutic target for the treatment of advanced colorectal cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4335. doi:10.1158/1538-7445.AM2013-4335