The role of PFKFB3 in tumor angiogenesis and vessel normalization

Endothelial cells (ECs) line blood vessels to supply oxygen and nutrients to tissues. Abnormal blood vessel growth (angiogenesis) promotes cancer growth and spread. Traditional anti-angiogenesis strategies rely on the inhibition of pro-angiogenic factors, primarily the growth factor vascular endothelial growth factor (VEGF). However, the efficacy of this treatment strategy is limited by intrinsic refractoriness. Those treatments attempt to reduce the tumor vascular supply by pruning tumor vessels, but their success is restricted by insufficient efficacy or development of resistance. Overcoming therapy resistance is one of the major challenges in the field and requires innovative strategies. Instead of blocking pro-angiogenic factors to prevent angiogenesis, I propose to target the engine of cells, namely the metabolism of blood vessel forming ECs. Since ECs need increased amounts of energy when proliferating and migrating, blocking their energy supply and depriving their “engine” from nutrients is an attractive yet unexplored strategy to inhibit angiogenesis. The host laboratory discovered that PFKFB3 (6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3), a key regulator of the glycolytic breakdown of glucose to produce energy, regulates angiogenesis in vitro by controlling EC migration and proliferation. Using a multidisciplinary approach, state-of-the-art techniques such as metabolic flux analysis and combining molecular and cellular biology with mouse genetics, I propose to investigate the role and functional relevance of PFKFB3 driven glycolysis in tumor angiogenesis, and explore the therapeutic potential of PFKFB3 blockade as novel anti-angiogenic strategy for anti-cancer treatment. When successful, my results promise to provide unprecedented insights that will be useful for the development of a novel anti-glycolytic anti-angiogenesis therapy of tumor angiogenesis and growth.nrpages: 156status: publishe