The chemokine stromal derived factor (SDF-1) signals through CXCR4 receptors expressed on a variety of lymphohematopoietic cells. It is a potent chemotactic factor for monocytes and lymphocytes, and we and others have shown that it is chemotactic for megakaryocytes and immature CD34+ hematopoietic cells, including progenitor and stem cell populations. Receptor activation leads to rapid upregulation of cytoadhesion molecules on stem cells that facilitates adhesion to endothelium and transendothelial migration involving interaction with E-selectin. In collaboration with Dr. S. Rafii (Weill Medical College) we observed that prolonged in vitro culture of stem cells leads to downregulation of their CXCR4 with reduction in transendothelial chemotaxis and in vivo engraftment potential. We are evaluating cytokines that can upregulate or stabilize CXCR4 expression (IL-6, IL-11, TNF), and cytokines that downmodulate and impair chemotaxis (IL-3). Expression of CXCR4 on metastatic solid tumor cells has been reported and production of SDF-1 at sites of metastasis suggests the value of targeting the CXCR4/SDF-1 pathway as an anti-cancer therapy. We are working with a number of small molecule antagonists of this pathway in vitro and in vivo in metastatic tumor models.
