Hypoxia inducible factor-1 (HIF-1) is considered a crucial mediator of the cellular response to
hypoxia through its regulation of genes that control angiogenesis. It represents an attractive therapeutic target in
colon cancer, one of the few
tumor types that shows a clinical response to antiangiogenic
therapy. But it is unclear whether inhibition of HIF-1 alone is sufficient to block
tumor angiogenesis. In HIF-1alpha knockdown DLD-1
colon cancer cells (DLD-1(HIF-kd)), the hypoxic induction of
vascular endothelial growth factor (
VEGF) was only partially blocked. Xenografts remained highly vascularized with microvessel densities identical to DLD-1
tumors that had wild-type HIF-1alpha (DLD-1(HIF-wt)). In addition to the preserved expression of
VEGF, the proangiogenic
cytokine interleukin (IL)-8 was induced by
hypoxia in DLD-1(HIF-kd) but not DLD-1(HIF-wt) cells. This induction was mediated by the production of
hydrogen peroxide and subsequent activation of
NF-kappaB. Furthermore, the KRAS oncogene, which is commonly mutated in
colon cancer, enhanced the hypoxic induction of
IL-8. A
neutralizing antibody to
IL-8 substantially inhibited angiogenesis and
tumor growth in DLD-1(HIF-kd) but not DLD-1(HIF-wt) xenografts, verifying the functional significance of this
IL-8 response. Thus, compensatory pathways can be activated to preserve the
tumor angiogenic response, and strategies that inhibit HIF-1alpha may be most effective when
IL-8 is simultaneously targeted.