Induction of interleukin-8 preserves the angiogenic response in HIF-1α-deficient colon cancer cells

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(1-4). It represents an attractive therapeutic target(5,6) in colon cancer, one of the few tumor types that shows a clinical response to antiangiogenic therapy(7). But it is unclear whether inhibition of HIF- 1 alone is sufficient to block tumor angiogenesis(8,9). In HIF- 1 alpha 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- 1 alpha ( 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-kappa B. 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- 1HIF- 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- 1 alpha may be most effective when IL- 8 is simultaneously targeted.