Targeting inflammatory cells to improve anti-VEGF therapies in oncology.

Vascular endothelial growth factor A (VEGF-A) is a well-characterized regulator of physiological and pathological angiogenesis. Multiple therapeutic compounds interfering with VEGF-A-regulated signal transduction pathways are currently being developed for the treatment of neoplasias and other malignancies associated with pathological angiogenesis. A major challenge in developing anti-VEGF therapies are tumor intrinsic refractoriness and the emergence of treatment-induced resistance. A variety of molecular and cellular mechanisms contribute to tumor angiogenesis, including the recruitment of bone marrow (BM)-derived endothelial cell progenitors (EPCs) and inflammatory cells to the tumor mass. Among the latter, two types of tumor infiltrating, inflammatory cells were recently identified to mediate refractoriness to anti-VEGF treatment: CD11b + Gr1+ myeloid derived suppressor cells (MDSC) and tumor-associated macrophages (TAMs). In this chapter, we review some of the inflammatory components regulating tumor angiogenesis and their roles in mediating refractoriness toward anti-VEGF treatment. In addition, we discuss potential therapeutic strategies targeting angiogenic pathways regulated by inflammatory cells. A better understanding of the biological and molecular events involved in mediating refractoriness to anti-VEGF treatment may help to further improve therapeutic strategies targeting tumor angiogenesis.