Drugs that target the
tumor vasculature and inhibit angiogenesis are widely used for
cancer treatment. Individual
tumors show large differences in vascularity, but it is uncertain how these differences affect responsiveness to antiangiogenesis. We investigated this question using two closely related
prostate cancer models that differ markedly in
tumor vascularity: PC3, which has very low vascularity, and the PC3-derived
cancer stem-like cell holoclone PC3/2G7, which forms
tumors with high microvessel density, high
tumor blood flow, and low
hypoxia compared with parental PC3
tumors. Three
angiogenesis inhibitors (
axitinib,
sorafenib, and DC101) all induced significantly greater decreases in
tumor blood flow and microvessel density in PC3/2G7
tumors compared with PC3
tumors, as well as significantly greater decreases in
tumor cell proliferation and cell viability and a greater increase in apoptosis. The increased sensitivity of PC3/2G7
tumors to antiangiogenesis indicates they are less tolerant of low vascularity and suggests they become addicted to their
oxygen- and nutrient-rich environment. PC3/2G7
tumors showed strong upregulation of the proangiogenic factors
chemokine ligand 2 (CCL2) and VEGFA compared with PC3
tumors, which may contribute to their increased vascularity, and they have significantly lower endothelial cell pericyte coverage, which may contribute to their greater sensitivity to antiangiogenesis. Interestingly, high levels of
VEGF receptor-2 were expressed on PC3 but not PC3/2G7
tumor cells, which may contribute to the growth static response of PC3
tumors to
VEGF-targeted antiangiogenesis. Finally, prolonged antiangiogenic treatment led to resumption of PC3/2G7
tumor growth and neovascularization, indicating these
cancer stem-like cell-derived
tumors can adapt and escape from antiangiogenesis.