Role of Myeloid and Other Stromal Cell Types in Tumor Angiogenesis.

Abstract SCI-32

Role of myeloid and other stromal cell types in tumor angiogenesis Napoleone Ferrara Genentech, Inc, 1 DNA Way, South San Francisco, CA, 94080, USA. Vascular endothelial growth factor (VEGF)-A is an important angiogenic factor, involved in both physiological and pathological growth of blood vessels. An anti-VEGF-A monoclonal antibodies and two small molecule VEGF RTK inhibitors have been approved by the FDA for cancer therapy. We have been investigating the mechanisms of refractoriness/resistance to anti-VEGF therapies. Our analysis points to the mobilization and recruitment of CD11b+ Gr1+myeloid cells from the bone marrow in the tumor as key mechanisms for VEGF-independent angiogenesis, at least in mouse models. Tumors that are refractory to anti-VEGF treatment result in increased peripheral mobilization and tumor homing of of CD11b+Gr1+ cells compared to sensitive tumors. Addition of CD11b+Gr1+ cells from resistant tumors was able to sustain the growth of sensitive tumors in the presence of anti-VEGF antibodies. In subsequent studies, we identified the secreted protein Bv8 as a mediator of myeloid cell-dependent angiogenesis. Blocking Bv8 using neutralizing antibodies inhibited the growth of several tumor cell lines transplanted in nude mice and also reduced the angiogenic switch in the RIP-Tag, a transgenic model of insulinoma. The expression of Bv8 by CD11b+ Gr1+myeloid was regulated by hematopoietic growth factor, especially G-CSF. Other studies have implicated tumor-associated fibroblasts as a source of alternative pro-angiogenic factors following VEGF blockade. We identified PDGF-C as one of such mediators. In summary, multiple stromal cell types and signaling pathways may contribute to inherent refractoriness and, potentially, acquired resistance to anti-VEGF therapies in tumors.