Abstract 2380: Carcinoembryonic antigen (CEA) directly activates endothelial cells, thereby inducing (tumor)-angiogenesis

Angiogenesis has become a major target in treatment of a varietly of cancers, whereby the major angiogenic growth factor VEGF is currently in focus for therapeutic interventions. Nevertheless, the use of VEGF-targeting drugs has been shown to be of limited efficacy, which might lie in the fact that tumor angiogenesis is not only induced by VEGF, but also by a variety of other factors. In this study, we report that the human carcinoembryonic antigen (CEA), a GPI-anchored cell surface adhesion molecule, which is shedded by 70% of human cancers, directly binds to endothelial cells, thereby inducing angiogenic endothelial cell behavior in vitro and in vivo: Overexpressing CEA in endogenous negative renal cell cancer (RCC) cell line or in the sarcoma cell line MethA led to an enhanced tumor angiogenesis and an increase in tumor growth in vivo, effects which were reverted by downregulation of the CEA receptor in endothelial cells via a lentiviral shRNA construct. Furthermore, targeting CEA by CEA mimotope immunized BALB/c mice, led to a breakdown In tumor vascularization, which was reflected by retarded tumor growth. We found that CEA, by binding to its receptor, led to an increase in integrin activation state, leading to enhanced endothelial cell adhesion, followed by amplified adhesion-induced signal transduction, which involved c-src-activation, focal adhesion kinase (FAK) and ERK phosphorylation, as well as PI3kinase/Akt activation. As a consequence, pro-angiogenic endothelial cell behavior, such as migration and invasion or proliferation were induced. Whenever integrin beta-3 were blocked, CEA was effect less in endothelial cells. These results show that the tumor marker CEA might bear hitherto undescribed biological significance in promoting tumor-angiogenesis. Thus, CEA-mediated signaling may offer a potential novel therapeutic target for the treatment of cancer. Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2380.