Interleukin-6/interleukin-6 Receptor Pathway as a New Therapy Target in Epithelial Ovarian Cancer

Eveline      M. Dijkgraaf; Marij      J.P. Welters; Johan      W.R. Nortier; Sjoerd      H. van der Burg; Judith      R. Kroep

doi:10.2174/138161212802002797

Abstract

Epithelial ovarian cancer is a major problem as about 75% of patients develop recurrence after initial primary treatment and tumors are often chemoresistant. This article reviews the role of the interleukin-6 (IL-6) in chemoresistance and suppression of tumor immunity in ovarian cancer and provides the rationale for modulating the IL-6/ IL-6 receptor (IL-6R) induced pathway as a potential new target for the treatment of ovarian cancer. IL-6 is elevated in serum and ascites of ovarian cancer patients and increased IL-6 levels correlate with chemoresistance and poor prognosis in these patients. IL-6 induced Jak/Stat3, Ras/MEK/ERK and PI3K/Ras signaling pathways lead to cell survival, proliferation, angiogenesis, and confers resistance to apoptosis induced by conventional therapies. Furthermore, IL-6 induces tumor-promoting macrophages which are known to foster tumor growth and suppress local immunity. However, direct proof of the clinical impact of IL-6 blocking on disease progression is missing necessiting further studies in which the IL-6(R) pathway is modulated and its clinical impact on (epithelial) ovarian cancer is tested.

Keywords: Ovarian cancer, interleukin-6, immunotherapy, Stat3, chemoresistance, tumor immunity, serum, ascites, cell survival, angiogenesis.