Induction of interleukin-8 preserves the angiogenic response in HIF-1α-deficient colon cancer cells
Induction of interleukin-8 preserves the angiogenic response in HIF-1α-deficient colon cancer cells
复制标题
DOI：
10.1038/nm1294
复制
发表时间：
2005-09-01
期刊：
影响因子：
82.9
通讯作者：
Chung, DC
中科院分区：
文献类型：
--
作者：
Mizukami, Y;Jo, WS;Chung, DC
低氧诱导因子-1(HIF-1)被认为是细胞对低氧反应的重要介质，它通过调节控制血管生成的基因(1-4)。它代表了结肠癌一个有吸引力的治疗靶点(5，6)，结肠癌是少数几种对抗血管生成治疗有临床反应的肿瘤类型之一(7)。但目前尚不清楚仅抑制HIF-1是否足以阻止肿瘤血管生成(8，9)。在HIF-1α基因敲除的DLD-1结肠癌细胞(DLD-1(HIF-kd))中，低氧诱导的血管内皮生长因子(VEGF)仅被部分阻断。异种移植血管高度血管化，微血管密度与携带野生型HIF-1α的DLD-1肿瘤相同(DLD-1(HIF-wt))。低氧可诱导DLD-1(HIF-kd)细胞表达促血管生成细胞因子IL-8，但不能诱导DLD-1(HIF-wt)细胞产生促血管生成因子IL-8。此外，在结肠癌中常见的KRAS癌基因突变增强了IL-8的低氧诱导。IL-8的中和抗体显著抑制了DLD-1HIF-kd移植瘤的血管生成和肿瘤生长，但不能抑制DLD-1(HIF-)(Wt)移植瘤的生长，证实了这种IL-8反应的功能意义。因此，可以激活代偿通路以保护肿瘤血管生成反应，当IL-8同时被靶向时，抑制HIF-1α的策略可能是最有效的。
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.