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Letter
Nature Medicine 11, 992 - 997 (2005)
Published online: 28 August 2005 | doi:10.1038/nm1294
There is a Corrigendum (February 2006) associated with this Letter.
Induction of interleukin-8 preserves the angiogenic response in HIF-1
–deficient colon cancer cells
Yusuke Mizukami1, Won-Seok Jo1, Eva-Maria Duerr1, Manish Gala1, Jingnan Li1, Xiaobo Zhang1, Michael A Zimmer2, Othon Iliopoulos2, Lawrence R Zukerberg3, Yutaka Kohgo4, Maureen P Lynch5, Bo R Rueda5 & Daniel C Chung1
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-1
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-1
(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-
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-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-1
may be most effective when IL-8 is simultaneously targeted.
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