The importance of angiogenesis in supporting and promoting tumor growth in solid tumors has been established for many years. But angiogenesis was until recently not thought to play a role in leukemias. Several studies have now shown increased vascularity in the bone marrow and increased VEGF plasma levels in patients with leukemia and VEGF receptors in leukemia cells. Clinically, elevated cellular levels of VEGF are associated with a poor prognosis in AML.
We are now starting to understand the biologic effects of angiogenesis in leukemia. It has been shown that VEGF can stimulate leukemia cell growth in vitro. Schuch et al (page 4622) now show the role of VEGF in promoting leukemia growth in vivo with 2 animal models. The first is a SCID mouse model injected subcutaneously with M1 cells that develop chloromas. Using a novel delivery system for release of VEGF or its antagonist, they demonstrate significant growth of the tumors with a rich capillary network promoted by VEGF. They use as a VEGF antagonist a soluble version of the extracellular portion of neuropilin-1 (NRP-1) that can bind circulating VEGF. sNRP-1 inhibited the growth of chloromas. The second model is a systemic leukemia model in SCID mice injected intravenously with M1 cells. Again, VEGF promoted and sNRP-1 inhibited leukemia progression.
These findings are significant in many ways. First, they demonstrate quite convincingly in vivo the opposing effects of VEGF and anti-VEGF in leukemia progression. An interesting observation in this study is that these results come from a model that uses a cell line (M1) that does not directly respond to VEGF. This suggests that the effect is not through direct stimulation of leukemia cell growth by VEGF, but rather that angiogenesis itself plays a role in leukemia growth. The exact mechanism by which angiogenesis supports leukemia progression remains to be determined. Second, it shows the potential of sNRP-1 as an antiangiogenic strategy that should be investigated further. Other antiangiogenic agents are already in clinical trials, including anti-VEGF monoclonal antibodies and VEGF-receptor inhibitors. These molecules may have a role in the management of AML. One major challenge will be the proper design and evaluation of clinical trials that would incorporate these agents. Finally, the microencapsulation technology used in this study may offer a new way to investigate similar peptides in the future.
