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

¹  Gastrointestinal Unit, Massachusetts General Hospital and Harvard Medical School, 50 Blossom Street, Boston, Massachusetts 02114, USA.

²  Oncology Unit, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, 50 Blossom Street, Boston, Massachusetts 02114, USA.

³  Department of Pathology, Massachusetts General Hospital and Harvard Medical School, 50 Blossom Street, Boston, Massachusetts 02114, USA.

⁴  Third Department of Internal Medicine, Asahikawa Medical College, 2-1 Midorigaoka-Higashi, Asahikawa, 078-8510 Japan.

⁵  Vincent Center for Reproductive Biology, Department of Obstetrics and Gynecology, Massachusetts General Hospital and Harvard Medical School, 50 Blossom Street Boston, Massachusetts 02114, USA.

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 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 (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-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 may be most effective when IL-8 is simultaneously targeted.

	Top