Vascular endothelial growth factor and Notch are important in angiogenesis, but what has been largely overlooked is the role and therapeutic potential of endothelial cell (EC) metabolism. In Tuesday’s Fritz Koller Plenary Lecture, Peter Carmeliet, M.D., Ph.D. revealed his key research findings:
- ECs are able to use fatty acid carbons to synthesize deoxyribonucleotides during DNA synthesis when vessels are sprouting.
- When glycolysis and fatty acid are inhibited by targeted therapies, angiogenesis and subsequent tumor vasculature growth can be inhibited.
These findings are important because aspects of EC metabolism are novel targets for anti-angiogenesis therapy with potentially fewer side effects, and less influence on lymphangiogenesis.
For the past 40 years, angiogenesis research has focused on identifying genetic signals, such as vascular endothelial growth factor (VEGF) and Notch, which regulate vessel sprouting. Here, Carmeliet reports his findings that ECs are addicted to glycolysis, which is important because glycolysis was found to co-determine vessel sprouting downstream of VEGF and other pro-angiogenic signals.
In his presentation, Carmeliet revealed that ECs have a unique ability to utilize fatty acid-derived carbons for the de novo synthesis of deoxyribonucleotides for DNA synthesis during EC proliferation when vessels sprout. He also showed that targeting (or blocking) glycolysis and fatty acid oxidation inhibits pathological angiogenesis in tumors and induces tumor vessel normalization, thereby reducing metastasis and improving tumor response to chemotherapy. Carmeliet suggested that these metabolic pathways could be valuable new targets for anti-angiogenic drug development because they may not evoke systemic toxicities. He also pointed out that lymphatic ECs differ from other EC subtypes in their metabolic requirements for lymphangiogenesis and may therefore not be susceptible to the same inhibitors that target tumor angiogenesis.
Since many of these metabolic pathways are pharmacologically druggable, they represent new and promising targets for therapeutic anti-angiogenesis strategies.