Interleukin-6 signalling regulates vascular endothelial growth factor-C synthesis and lymphangiogenesis in human oral squamous cell carcinoma

J Pathol. 2011 Sep;225(1):142-50. doi: 10.1002/path.2935. Epub 2011 Jun 25.


Lymph node metastasis is associated with resistance to conventional therapy and poor survival of patients with oral squamous cell carcinoma (OSCC). Although lymphangiogenesis is well known to be associated with the occurrence of lymph node metastasis in various cancers, the precise mechanisms of lymphangiogenesis in OSCC are largely unknown. IL-6, a potent pro-inflammatory cytokine, has been shown to play active roles in various cancers, including OSCC. This study aimed to investigate the involvement of IL-6 signalling in lymphatic metastasis and to evaluate the efficacy of tocilizumab, a humanized anti-human IL-6 receptor antibody, as an anti-lymphangiogenic agent for OSCC. This investigation confirmed that levels of expression of IL-6 protein and VEGF-C mRNA in OSCC tissues were significantly correlated with lymph node metastasis in patients with OSCC, as assessed by immunohistochemical analysis and real-time quantitative RT-PCR. In vitro studies showed that IL-6 regulated VEGF-C mRNA expression in a human OSCC cell line, SAS cells, through the phosphoinositide 3-kinase-Akt pathway. In addition, treatment with tocilizumab led to markedly reduced VEGF-C mRNA expression and OSCC-related lymphangiogenesis in SAS xenografts. Together, these data suggest that tocilizumab acted as expected: it inhibited lymph node metastasis in OSCC by reducing tumour lymphangiogenesis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Animals
  • Antibodies, Monoclonal / pharmacology
  • Antibodies, Monoclonal / therapeutic use
  • Antibodies, Monoclonal, Humanized
  • Antineoplastic Agents / pharmacology
  • Antineoplastic Agents / therapeutic use
  • Carcinoma, Squamous Cell / drug therapy
  • Carcinoma, Squamous Cell / genetics
  • Carcinoma, Squamous Cell / physiopathology
  • Carcinoma, Squamous Cell / secondary*
  • Drug Evaluation, Preclinical / methods
  • Female
  • Gene Expression Regulation, Neoplastic / drug effects
  • Humans
  • Interleukin-6 / physiology*
  • Lymphangiogenesis / drug effects
  • Lymphangiogenesis / physiology*
  • Male
  • Mice
  • Mice, SCID
  • Middle Aged
  • Mouth Neoplasms / drug therapy
  • Mouth Neoplasms / genetics
  • Mouth Neoplasms / physiopathology*
  • Phosphatidylinositol 3-Kinases / physiology
  • Phosphorylation / drug effects
  • Proto-Oncogene Proteins c-akt / physiology
  • RNA, Messenger / genetics
  • RNA, Neoplasm / genetics
  • Signal Transduction / physiology
  • Tumor Cells, Cultured
  • Vascular Endothelial Growth Factor C / biosynthesis*
  • Vascular Endothelial Growth Factor C / genetics
  • Xenograft Model Antitumor Assays


  • Antibodies, Monoclonal
  • Antibodies, Monoclonal, Humanized
  • Antineoplastic Agents
  • Interleukin-6
  • RNA, Messenger
  • RNA, Neoplasm
  • VEGFC protein, human
  • Vascular Endothelial Growth Factor C
  • Phosphatidylinositol 3-Kinases
  • Proto-Oncogene Proteins c-akt
  • tocilizumab