Mechanistically, their activity is sustained by a VEGFA–VEGFR2–ESM1 positive feedback loop (based on in vitro data): VEGFA - secreted by myeloid and epithelial cells - activates tip cell VEGFR2, promoting ESM1 release that subsequently upregulates VEGFA in tumor cells, sustaining angiogenesis and promoting tumor growth. The gene discussed is KDR; the disease is neoplasm.