Interleukin-6 in Cervical Cancer: The Relationship with Vascular Endothelial Growth Factor

Abstract

Objective. Interleukin-6 (IL-6), a central proinflammatory cytokine, has been implicated in cervical cancer, though its role remains elusive. This study was an attempt to elucidate the role of IL-6 in the pathogenesis of cervical cancer, with particular emphasis on tumor angiogenesis.Methods. Cytosolic IL-6, vascular endothelial growth factor (VEGF), and platelet-derived growth factor (PDGF) levels were determined via enzyme immunoassay in 60 FIGO stage IB–IIA cervical cancer patients. Immunohistochemical staining in tissue sections was performed to analyze the distributions of IL-6 and IL-6 receptors. Meanwhile, human papillomavirus (HPV) DNA was detected by polymerase chain reaction-based survey. In vitro studies of two cervical cancer cell lines, C33A and SiHa, for the interaction between IL-6 and VEGF were also performed.Results. Consistently higher expression of IL-6 and VEGF was evident in cancerous tissues than in adjacent noncancer tissues in early-stage cervical cancer patients (P < 0.01). After recombinant human IL-6 was added, VEGF was induced in a time- and dose-dependent manner in cervical cancer cell line C33A. Correspondingly, interrupting the IL-6 autocrine machinery with either anti-IL-6 or anti-IL-6 receptor antibody markedly reduced the expression of VEGF at the transcriptional level in SiHa cells. Significantly higher levels of IL-6 in cancer tissues were observed in patients older than 45 (P < 0.01), patients with tumors >2 cm (P < 0.01), patients with oncogenic HPV-16 or -18 infections (P < 0.01), and patients with squamous cell carcinoma (P = 0.02). Patients with a deeper stromal invasion, vaginal invasion, lymphovascular emboli, or lymph node metastasis appeared to have higher intratumoral IL-6 levels, although the differences were statistically insignificant.Conclusions. Substantially high microenvironmental IL-6 levels promote tumor angiogenesis and the development of cervical cancer. Thus, inhibition of the biological activity of IL-6 may be potentially beneficial.