The Role of ephinB2 in Metastatic Angiogenesis - Young Investigator Award Final Report
Kenneth Cohen, M.D.
Assistant Professor, Department of Medicine, University of Chicago
2008 Young Investigator Award - 2010 Final Report
Tumor growth requires the development of new blood vessels through a process known as angiogenesis. One potential anti-angiogenic target is a protein called ephrinB2, a critical regulator of vessel organization in developing embryos. Based on preliminary observations using tumors grown in skin, we investigated several facets of the relationship between ephrinB2 and metastatic tumor vessels, including whether metastatic tumor vessels produce ephrinB2, recruit blood cells that already make ephrinB2, or induce the production of ephrinB2. Furthermore, we are also studying if tumor growth might be reduced by inhibiting the function of ephrinB2.
Models were established in the laboratory to study B16 melanoma, LLC lung cancer, and EL4 T-cell lymphomas in vivo in mice. While we were unable to reproducibly generate B-cell lymphomas by intravenous injection, we were able to evaluate the vasculature of a spontaneous lymphoproliferative disorder, a condition in which lymphocytes are produced in excessive quantities. By analyzing metastatic tumors using these models, several observations were made. First, blood vessels in metastatic tumors make ephrinB2. Second, within each tumor, local areas vary in the degree of ephrinB2 production, which might affect therapies that target ephrinB2.
Mice were also treated with an inhibitor of ephrinB2 known as soluble EphB4 (sEphB4) to determine if this compound would reduce the growth of metastases and their blood vessels. There was some difficulty in assessing the effect of ephrinB2 inhibition on metastatic tumors due to setbacks in demonstrating reproducible tumor engraftment in metastatic models. Our studies therefore chose to focus on the mechanisms involved in ephrinB2 mediated growth inhibition. Data demonstrated that ephrinB2 inhibition impaired tumor growth and vessel development and unexpectedly led to increased numbers of immune cells in tumors. Taken together, this suggests that ephrinB2 is a therapeutic target in both primary and metastatic tumors. Moreover, ephrinB2 inhibition has the potential to affect other cells in the tumor microenvironment to make it less permissive to tumor growth. The possibility of enhancing the entry of immune cells into tumors increases the possibility of using ephrinB2 inhibition to enhance immune therapies.
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