Induction of Ephs/Ephrins-Mediated Tumor Cells-Endothelial Cells Repulsion as an Anti-Cancer Therapeutic Approach
Abstract
Eph receptors constitute the largest family of receptor tyrosine kinases. They comprise 8 type A receptors and 6 type B receptors. Originally identified as neuronal path finding molecules, where they guide the migrating cells to specific tissue targets, they are an essential component in vascular assembly regulation, including during angiogenesis, and in embryonic development. Ephs interact with membrane-bound ligands, the Ephrins, of which 8 have been found to date (Ephrin-AI to 5 and Ephrin-BI to 3). We hypothesize that manipulating Eph/Ephrin interactions could prevent attraction and/or induce repulsion between tumor cells and endothelial cells. The goal is to take advantage of Ephs/Ephrins interactions to turn endothelial cells into a barrier to metastatic tumor cells entering the blood flow through vascular endothelial cells, or exiting the flow through bone marrow endothelial cells in the direction of their specific metastatic sites. To test our hypothesis, we first performed a profiling of breast cancer cells with regard to the expression and activation levels of various Ephs/Ephrins. We found that the EphB2 receptor is overexpressed in almost 50 % of the cancer cell lines. Similarly, the Ephrin-B2, which is a ligand to EphB2, is also strongly expressed in over 50 % of the cancer cell lines while not found in benign cell lines. Another EphB2 ligand, Ephrin-BI, is present in all normal cells but lost in 4 out of II cancer cell lines. We also found that EphB2 could be subject to defects in phosphorylation and response to the ligand. We are investigating attractive/repulsive behavior of tumor cells, with different expression levels of EphB2 and EphrinBs, towards endothelial cells and vice-versa. Next, we will study the invasive and metastatic potential of tumor cells with different expression levels of Ephs/Ephrins in vivo.
Document Details
- Document Type
- Technical Report
- Publication Date
- Sep 01, 2005
- Accession Number
- ADA445200
Entities
People
- Gerald Batist
Organizations
- Jewish General Hospital