Fig. 5

Physiological and pathological roles of endothelial SCUBE2 in modulating VEGF signaling during angiogenesis and potential immunotherapy approach. VEGF-stimulated VEGFR2 signaling is essential for angiogenesis and vasculogenesis under physiological conditions, such as during embryonic development (left panel). However, under pathological circumstances (e.g., intratumor hypoxia), hypoxia-inducible HIF-1 upregulates SCUBE2. The SCUBE2 protein localizes on the tumor EC cell surface, where it functions as a coreceptor with VEGFR2 to facilitate VEGF binding and enhance its downstream signaling. Thus, SCUBE2 promotes VEGF-induced tumor angiogenesis [23] (middle panel). SCUBE2 is internalized into the endosome-lysosomal protein degradation pathway when SP.B1 mAb attaches to EC-surface SCUBE2. This internalization decreases the VEGF-VEGFR2 association and prevents tumor angiogenesis (right panel). EC, endothelial cell. VEGF vascular endothelial growth factor; VEGFR2 VEGF receptor 2