title: 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.
abstract: 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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Gastroenterological Surgery, Nagoya City University, 1 Kawasumi, Mizuho-cho, Mizuho-ku, Nagoya 467-8601, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Nagasaki
authors.affiliation: Department of Gastroenterological Surgery, Nagoya City University, 1 Kawasumi, Mizuho-cho, Mizuho-ku, Nagoya 467-8601, Japan.
authors.forename: M
authors.initials: M
authors.lastname: Hara
authors.affiliation: Division of Oncological Pathology, Aichi Cancer Center Institute, 1-1 Kanokoden, Chikusa-ku, Nagoya 464-8681, Japan.
authors.forename: H
authors.initials: H
authors.lastname: Nakanishi
authors.affiliation: Department of Gastroenterological Surgery, Nagoya City University, 1 Kawasumi, Mizuho-cho, Mizuho-ku, Nagoya 467-8601, Japan.
authors.forename: H
authors.initials: H
authors.lastname: Takahashi
authors.affiliation: Department of Gastroenterological Surgery, Nagoya City University, 1 Kawasumi, Mizuho-cho, Mizuho-ku, Nagoya 467-8601, Japan.
authors.forename: M
authors.initials: M
authors.lastname: Sato
authors.affiliation: Department of Gastroenterological Surgery, Nagoya City University, 1 Kawasumi, Mizuho-cho, Mizuho-ku, Nagoya 467-8601, Japan.
authors.forename: H
authors.initials: H
authors.lastname: Takeyama
mesh_terms: D000818:Animals; D000906:Antibodies / Q000494:pharmacology*; D002460:Cell Line; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms / Q000098:blood supply* / Q000188:drug therapy* / Q000378:metabolism; D005347:Fibroblasts / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D019073:HT29 Cells; D006801:Humans; D007249:Inflammation / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D015850:Interleukin-6 / Q000378:metabolism*; D051379:Mice; D008819:Mice, Nude; D009389:Neovascularization, Pathologic / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D019947:Receptors, Interleukin-6 / Q000378:metabolism*; D017154:Stromal Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
chemical_list: D000906:Antibodies; C508600:IL6 protein, human; D015850:Interleukin-6; D019947:Receptors, Interleukin-6; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A