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

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 C33 A, 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 22 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. (C) 2001 Academic Press