Pharmacologic IL-6Rα inhibition in cholangiocarcinoma promotes cancer cell growth and survival

Biochim Biophys Acta Mol Basis Dis. 2019 Feb 1;1865(2):308-321. doi: 10.1016/j.bbadis.2018.11.006. Epub 2018 Nov 9.

Abstract

Biliary tract cancer (BTC) represents a malignant tumor of the biliary tract including cholangiocarcinoma (CCA) and the carcinoma of the gallbladder (GBC) with a 5-year survival rate between 5 and 18% due to late diagnosis and rapid disease progression. Chronic inflammation is one of the main risk factors for CCA and GBC in particular. IL-6, as a mediator of inflammation, can act through a membrane-bound receptor alpha-chain (mIL-6R, "IL-6 classic signaling") or via soluble forms (sIL-6R, "IL-6 trans-signaling"). However, little is known about the impact on cellular responses of IL-6 trans-signaling on BTC. We analyzed primary tumors as whole sections and as tissue microarrays, and also searched The Cancer Genome Atlas database. Compared to non-neoplastic, non-inflamed gallbladder tissue, IL-6Rα was downregulated in GBC, and this correlated with the patients' overall survival. Furthermore, different CCA cell lines and compounds for activation (IL-6 and Hyper-IL-6) or inhibition (Tocilizumab and sgp130Fc) of IL-6 classic signaling and trans-signaling were used to determine their effects on cellular processes between the two modes of IL-6 signaling. Inhibition of IL-6 trans-signaling by sgp130Fc reduced CCA cell line viability and apoptosis, whereas migration and proliferation were increased. We conclude that IL-6Rα expression is a good prognostic marker for GBC, and that the blocking of IL-6 trans-signaling and activation of IL-6 classic signaling have tumor promoting activity. These findings warrant the exclusion of patients with GBC or other malignancies associated with bile metabolism from IL-6R inhibitor therapy.

Keywords: Cholangiocarcinoma; Gallbladder cancer; IL-6 receptor signaling; IL-6 trans-signaling; STAT3.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Antibodies, Monoclonal, Humanized / pharmacology
  • Apoptosis / drug effects
  • Bile Duct Neoplasms / metabolism*
  • Bile Duct Neoplasms / pathology*
  • Cell Line, Tumor
  • Cell Movement / drug effects
  • Cell Proliferation / drug effects
  • Cell Survival / drug effects
  • Cholangiocarcinoma / metabolism*
  • Cholangiocarcinoma / pathology*
  • Down-Regulation / drug effects
  • Down-Regulation / genetics
  • Female
  • G2 Phase / drug effects
  • Gallbladder / metabolism
  • Gallbladder / pathology
  • Humans
  • Interleukin-6 / metabolism
  • Male
  • Middle Aged
  • Mitosis / drug effects
  • Models, Biological
  • Phosphorylation / drug effects
  • Phosphotyrosine / metabolism
  • Receptors, Interleukin-6 / antagonists & inhibitors*
  • Receptors, Interleukin-6 / metabolism
  • Recombinant Fusion Proteins / pharmacology
  • STAT3 Transcription Factor / metabolism
  • Signal Transduction / drug effects
  • Survival Analysis

Substances

  • Antibodies, Monoclonal, Humanized
  • Interleukin-6
  • Receptors, Interleukin-6
  • Recombinant Fusion Proteins
  • STAT3 Transcription Factor
  • Sgp130Fc protein
  • Phosphotyrosine
  • tocilizumab