The Warburg Effect in Endothelial Cells and its Potential as an Anti-angiogenic Target in Cancer

Gillian Fitzgerald, Inés Soro-Arnaiz, Katrien De Bock

Endothelial cells (ECs) make up the lining of our blood vessels and they ensure optimal nutrient and oxygen delivery to the parenchymal tissue. In response to oxygen and/or nutrient deprivation, ECs become activated and sprout into hypo-vascularized tissues forming new vascular networks in a process termed angiogenesis. New sprouts are led by migratory tip cells and extended through the proliferation of trailing stalk cells. Activated ECs rewire their metabolism to cope with the increased energetic and biosynthetic demands associated with migration and proliferation. Moreover, metabolic signaling pathways interact and integrate with angiogenic signaling events. These metabolic adaptations play essential roles in determining EC fate and function, and are perturbed during pathological angiogenesis, as occurs in cancer. The angiogenic switch, or the growth of new blood vessels into an expanding tumor, increases tumor growth and malignancy. Limiting tumor angiogenesis has therefore long been a goal for anticancer therapy but the traditional growth factor targeted anti-angiogenic treatments have met with limited success. In recent years however, it has become increasingly recognized that focusing on altered tumor EC metabolism provides an attractive alternative anti-angiogenic strategy. In this review, we will describe the EC metabolic signature and how changes in EC metabolism affect EC fate during physiological sprouting, as well as in the cancer setting. Then, we will discuss the potential of targeting EC metabolism as a promising approach to develop new anti-cancer therapies.