Induction of interleukin-8 preserves the angiogenic response in HIF-1|[alpha]||[ndash]|deficient colon cancer cells

doi:doi:10.1038/nm1294

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,^2,^3,⁴. It represents an attractive therapeutic target^5,⁶ in colon cancer, one of the few tumor types that shows a clinical response to antiangiogenic therapy⁷. 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-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-1 alpha may be most effective when IL-8 is simultaneously targeted.

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

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