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

Abstract

Hypoxia inducible factor-1 (HIF-1) is considered a crucial mediator of the cellular response to hypoxia through its regulation of genes that control angiogenesis1,2,3,4. It represents an attractive therapeutic target5,6 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 angiogenesis8,9. In HIF-1α knockdown DLD-1 colon cancer cells (DLD-1HIF-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-1α (DLD-1HIF-wt). In addition to the preserved expression of VEGF, the proangiogenic cytokine interleukin (IL)-8 was induced by hypoxia in DLD-1HIF-kd but not DLD-1HIF-wt cells. This induction was mediated by the production of hydrogen peroxide and subsequent activation of NF-κB. 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-1HIF-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-1α may be most effective when IL-8 is simultaneously targeted.

Cite this article

Mizukami, Y., Jo, WS., Duerr, EM. et al. Induction of interleukin-8 preserves the angiogenic response in HIF-1α–deficient colon cancer cells. Nat Med 11, 992–997 (2005). https://doi.org/10.1038/nm1294

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