Interleukin-6, Secreted by Human Ovarian Carcinoma Cells, Is a Potent Proangiogenic Cytokine

Abstract

Angiogenesis, a key rate-limiting step in the growth and dissemination of malignant tumors, is regulated by the balance between positive and negative effectors. Recent studies indicate that the pleiotropic cytokine interleukin-6 (IL-6) may contribute to the vascularization of some tumors by disrupting the equilibrium between positive and negative angiogenic regulatory molecules. We determined whether IL-6 participates in the angiogenesis observed during the progression of ovarian carcinoma. We measured IL-6 production by human ovarian cancer cell lines in vitro and in vivo. Not all cell lines secreted IL-6 in vitro; however, when the cell lines were implanted into the peritoneal cavity of female nude mice, every line secreted IL-6. Most human ovarian carcinoma cell lines tested secreted significant levels of the soluble IL-6 receptor (sIL-6R). Endothelial cell lines established from the ovary and mesentery of female H-2Kb -tsA58 mice were tested for response to IL-6. Both endothelial cell lines expressed the IL-6R and their stimulation with the exogenous ligand significantly enhanced cell migration and activated the downstream signaling molecule signal transducers and activators of transcription 3. Dual immunohistochemical staining for IL-6R and CD31 revealed IL-6R expression on human endothelial cells within normal ovary and carcinoma specimens. Gelfoam sponges containing 0.4% agarose and IL-6 or basic fibroblast growth factor and implanted into the subcutis of BALB/c mice were vascularized to the same extent. Collectively, the data indicate that ovarian tumor cells secreted IL-6, a highly angiogenic cytokine that supports progression of disease. (Cancer Res 2005; 65(23): 10794-800)

CDDO-Me, a synthetic triterpenoid, inhibits expression of IL-6 and Stat3 phosphorylation in multi-drug resistant ovarian cancer cells

“…Several lines of evidence have demonstrated that IL-6 production and Stat3 activation may prevent cell death and lead to immunosuppression and drug resistance through upregulation of survival proteins in ovarian cancer [8,19,22,25]. Therefore, IL-6 and Stat3 proteins emerged as important targets for ovarian cancer therapy.…”

“…IL-6 is a progrowth, proangiogenic and anti-apoptotic cytokine that has been elevated in serum and ascites of patient with ovarian cancer as well as in culture supernatant of multi-drug resistant cell lines [8,[19][20][21]. In many tumors, elevated IL-6 levels in the serum is predictive of poor clinical outcome.…”

“…In many tumors, elevated IL-6 levels in the serum is predictive of poor clinical outcome. Recently, a study of a mouse model of ovarian cancer has demonstrated a pro-angiogenic role of this cytokine in ovarian cancer [19]. Oncostatin M, another member of IL-6 cytokine family, is constitutively expressed in ovarian cancer [23].…”

Neuroendocrine influences on cancer biology

“…Interleukin-6 (IL-6) is another important molecule in tumor progression and angiogenesis [48]. IL-6 has been shown to be secreted by ovarian cancer cells and to enhance tumor cell proliferation and migration in vitro [49,50].…”

“…IL-6 has been shown to be secreted by ovarian cancer cells and to enhance tumor cell proliferation and migration in vitro [49,50]. Furthermore, IL-6 is a potent angiogenic cytokine in vivo as evidenced by gelfoam sponge assays, showing a significant increase in microvessel density in the IL-6 impregnated sponges compared to control [48]. Clinically, individuals experiencing chronic stress have been shown to exhibit elevated circulating levels of IL-6 [51].…”