Interleukin-6 promotes cervical tumor growth via a VEGF-dependent angiogenesis

LH Wei, MD, ML Kuo, PhD, CY Hsieh, MD

National Taiwan University Hospital, Taipei, Taiwan Taiwan

Interleukin-6 (IL-6), an important proinflammatory cytokine, is reported to be associated with cervical cancer. However, its role in the development of cervical cancer remains unclear. In this study, we investigated the effect of IL-6 over-expression on human cervical cancer cell line C33A to uncover the role of IL-6 for tumorigenesis in cervical cancer. Our results demonstrated that IL-6 promotes in vivo tumor growth and in vitro and in vivo angiogenesis of C33A cells but does not cause significant change in in vitro growth kinetics of C33A cells. The 6-day Matrigel plug assay confirmed the significant angiogenic effect induced by IL-6 over-expressing C33A cells as compared with the vector control cells. We next demonstrated that IL-6 was specifically associated with the expression of vascular endothelial growth factor (VEGF) among various angiogenic factors. The luciferase assay showed that IL-6 increases promoter activity of VEGF in C33A cells through a hypoxia-independent mechanism. Moreover, neutralizing anti-VEGF antibody abolished both in vitro and in vivo IL-6-induced, tumor-derived angiogenic effect. The results were consistent with the concomitant increased tumor expression of IL-6 and VEGF in cervical cancer patients. In summary, we conclude that IL-6 may activate hypoxia-independent, VEGF-mediated angiogenesis and promote cervical tumorigenesis.

KEY WORDS: angiogenesis, cervical cancer, cytokine, inflammation, interleukin-6, vascular endothelial growth factor.

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Paper presented at the International Symposium on Predictive Oncology and Intervention Strategies; Paris, France; February 9 - 12, 2002; in the section on Angiogenesis.