The tumor endothelium is a focus of major interest to deliver anti-angiogenic and anti-vascular targeted therapies for cancer treatment. However, the development of these therapeutic strategies has been hampered by the considerable lack of understanding of endothelial cell function in the tumor environment. Tumor endothelium marker 8 (TEM8) is a cell surface receptor selectively induced in tumor-associated vasculature. Because of this restricted expression pattern, TEM8 has been proposed as a targeting candidate for anti-vascular therapies. Interestingly, this molecule also mediates anthrax toxin delivery into cells. Central to this proposal is our finding that TEM8 holds signature features of an adhesion molecule. The purpose of this study is to evaluate the adhesive function of TEM8 and its role in tumor associated vasculature. The proposed specific aims are focused on the features that define TEM8 as an adhesion molecule: 1) to determine whether collagen I is an adhesive ligand for this receptor by performing cell binding and spreading assays. 2) To identify the cytosolic domain determinants necessary to mediate cell spreading and linkage to the actin cytoskeleton by constructing deletion mutants and isolating interacting proteins using the cytosolic domain in pull-down assays. 3) We will explore the role of TEM8 in normal or tumoral vasculature using the chicken chorioallantoic membrane as a model vascular system accessible to genetic manipulation through intravenous delivery of recombinant adenoviruses. In addition, TEM8 expression effects on normal development associated vasculogenesis, growth factor induced angiogenesis and vascularization of tumor grafts will be examined in this model. Given that the development of therapies to target the tumor-associated blood vessels constitutes a promising and novel approach to improve cancer treatment, gaining further understanding of how candidate target molecules, such as TEM8, function in the vasculature, will provide significant and timely insights to optimize these therapeutic interventions.
| Gu, Jingsheng; Faundez, Victor; Werner, Erica (2010) Endosomal recycling regulates Anthrax Toxin Receptor 1/Tumor Endothelial Marker 8-dependent cell spreading. Exp Cell Res 316:1946-57 |
