GDF15 at Cancer-Relevant Concentrations Promotes Angiogenesis

Abstract Growth Differentiation Factor 15 (GDF15) is a key molecule of cellular stress responses and an established biomarker in cancer, where elevated serum concentrations correlate with cachexia and poor prognosis. Although the metabolic actions of circulating GDF15 are primarily attributed to its interactions with the GDNF family receptor alpha (GFRAL) expressed in the hindbrain, GDF15 also exerts pleiotropic effects in multiple other tissues, indicating the presence of GFRAL-independent signaling pathways. Earlier studies reported pro-angiogenic effects of GDF15 on endothelial cells, but they predominantly employed higher concentrations of recombinant protein than common in health or disease. Here, we examined how GDF15 levels commonly observed in the serum of cancer patients influence the behavior of primary human endothelial cells. At these concentrations, GDF15 enhanced endothelial cell-cycle progression, proliferation, migration, tube formation and aerobic glycolysis. Notably, pharmacological blockade of GFRAL did not diminish these responses, supporting the existence of alternative receptor mechanisms mediating GDF15 activity in the vasculature. The results suggest that GDF15 at cancer-associated concentrations has a protective effect on endothelial cells.