Fig. 7.

Schematic diagram of systemic anti-VEGF treatment-induced drug resistance. Systemic administration of anti-VEGF drugs such as bevacizumab enters into the circulation to target both tumor and healthy vasculatures such as kidney blood vessels. Anti-VEGF–induced vessel regression in the kidney cortex leads to tissue hypoxia, which induces HIF-1α and HIF-2α expressions. HIF-1α and HIF-2α at transcription level target the Epo promoter for high production of EPO in peritubular interstitial cells in kidney cortex. Kidney-derived EPO enters the circulation to stimulate angiogenesis and eventually contributes to antiangiogenic drug resistance. These findings provide mechanistic insights of off-tumor targets of antiangiogenic drugs in the cancer patients for development of drug resistance.