Targeting the tumor microenvironment: focus on angiogenesis.

Fan, Fengjuan; Schimming, Alexander; Jaeger, Dirk; Podar, Klaus "Journal of oncology"

Tumorigenesis is a complex multistep process involving not only genetic and epigenetic changes in the tumor cell but also selective supportive conditions of the deregulated tumor microenvironment. One key compartment of the microenvironment is the vascular niche. The role of angiogenesis in solid tumors but also in hematologic malignancies is now well established.

Research on angiogenesis in general, and vascular endothelial growth factor in particular, is a major focus in biomedicine and has led to the clinical approval of several antiangiogenic agents including thalidomide, bevacizumab, sorafenib, sunitinib, pazopanib, temesirolimus, and everolimus. Indeed, antiangiogenic agents have significantly changed treatment strategies in solid tumors (colorectal cancer, renal cell carcinoma, and breast cancer) and multiple myeloma. Here we illustrate important aspects in the interrelationship between tumor cells and the microenvironment leading to tumor progression, with focus on angiogenesis, and summarize derived targeted therapies.

Much progress and significant therapeutic changes have been made in the field of tumor therapy in the past decades. Besides chemotherapy and radiotherapy, a special focus was laid on targeted therapies such as small molecule tyrosine kinase inhibitors (TKIs) and other immunomodulatory drugs, which have become standard therapies and important combination partners in a variety of malignancies. In contrast to the widely established use of these often anti-angiogenic drugs, many functional molecular mechanisms are yet not completely understood. Recent analyses focused not only on their direct anti-tumor responses, but also on their influence on tumor microenvironment, as well as on their effects on malignant and healthy cells. Different anti-angiogenic compounds targeting the vascular endothelial growth factor (VEGF) or platelet-derived growth factor pathways seem to be capable of modulating immune responses, in a positive, as well as apparently harmful manner. For an optimal clinical anti-cancer treatment, a better understanding of these immunomodulatory effects is necessary. Here we summarize recent reports on the immunomodulatory function of lately introduced clinically applied anti-angiogenic compounds, such as the humanized monoclonal antibody against VEGF bevacizumab, the small molecule TKIs sunitinib, sorafenib, imatinib, dasatinib, nilotinib and the proteasome inhibitor bortezomib