Interleukin-6 released by colon cancer-associated fibroblasts is critical for tumour angiogenesis: anti-interleukin-6 receptor antibody suppressed angiogenesis and inhibited tumour-stroma interaction

Br J Cancer. 2014 Jan 21;110(2):469-78. doi: 10.1038/bjc.2013.748. Epub 2013 Dec 17.


Background: Interleukin-6 (IL-6) has an important role in cancer progression, and high levels of plasma IL-6 are correlated with a poor prognosis in a variety of cancers. It has also been reported that tumour stromal fibroblasts are necessary for steps in cancer progression, such as angiogenesis. There have been few reports of a correlation between fibroblast actions and IL-6 levels. In this study, we examined the correlation between cancer stromal fibroblasts and IL-6 and the utility of IL-6 as a therapeutic target in human colon cancer.

Methods: The expression levels of IL-6 and VEGF of fibroblasts and cancer cell lines were evaluated using real-time PCR and ELISA. The anti-angiogenic effect of inhibiting IL-6 signalling was measured in an angiogenesis model and animal experiment.

Results: We demonstrate that stromal fibroblasts isolated from colon cancer produced significant amounts of IL-6 and that colon cancer cells enhanced IL-6 production by stromal fibroblasts. Moreover, IL-6 enhanced VEGF production by fibroblasts, thereby inducing angiogenesis. In vivo, anti-IL6 receptor antibody targeting stromal tissue showed greater anti-tumour activity than did anti-IL6 receptor antibody targeting xenografted cancer cells.

Conclusion: Cancer stromal fibroblasts were an important source of IL-6 in colon cancer. IL-6 produced by activated fibroblasts induced tumour angiogenesis by stimulating adjacent stromal fibroblasts. The relationship between IL-6 and stromal fibroblasts offers new approaches to cancer therapy.

MeSH terms

  • Animals
  • Antibodies / pharmacology*
  • Cell Line
  • Cell Line, Tumor
  • Colonic Neoplasms / blood supply*
  • Colonic Neoplasms / drug therapy*
  • Colonic Neoplasms / metabolism
  • Fibroblasts / drug effects
  • Fibroblasts / enzymology
  • Fibroblasts / metabolism*
  • Fibroblasts / pathology
  • HT29 Cells
  • Humans
  • Inflammation / drug therapy
  • Inflammation / metabolism
  • Inflammation / pathology
  • Interleukin-6 / metabolism*
  • Mice
  • Mice, Nude
  • Neovascularization, Pathologic / drug therapy
  • Neovascularization, Pathologic / metabolism
  • Neovascularization, Pathologic / pathology
  • Receptors, Interleukin-6 / metabolism*
  • Stromal Cells / drug effects*
  • Stromal Cells / metabolism
  • Stromal Cells / pathology
  • Vascular Endothelial Growth Factor A / metabolism


  • Antibodies
  • IL6 protein, human
  • Interleukin-6
  • Receptors, Interleukin-6
  • VEGFA protein, human
  • Vascular Endothelial Growth Factor A