Induction of interleukin-8 preserves the angiogenic response in HIF-1-deficient colon cancer cells (Nature Medicine, 11:992-997, September 2005)

報告日期: 2005/10/21
報告時間: 17:10/18:00
報告學生: 陳威宇
講評老師: 張文粲

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

Nature Medicine, 11:992-997

Speaker:      Wei-Yu Chen 陳威宇

Commentator:  Wen-Tsan Chang 張文粲

Time: 17:10 ~ 18:00

Room 602


Hypoxia inducible factor-1 (HIF-1), a heterodimeric protein that consists of alpha and beta subunits, is considered a crucial transcription factor 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. The authors investigated whether inhibition of HIF-1alpha alone is sufficient to block tumor angiogenesis using HIF-1alpha short interfering RNA knockdown in DLD-1 colon cancer cells (DLD-1HIF-kd). Surprisingly, they observed that when the HIF1alpha knockdown cells were transplanted into mice, the resulting tumors remained highly vascularized . Also, the hypoxic induction of vascular endothelial growth factor (VEGF) was only partially blocked. 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 and maintained tumor vascularity in DLD-1HIF-kd xenograft tumor. 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-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-1alpha or VEGF might therefore be most effective when IL-8 is simultaneously targeted. This article provids a mechanism by which cancer cells survive and induce angiogenesis in the absence of oxygen.


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