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

• Published in: British journal of cancer Vol. 110; no. 2; pp. 469 - 478
• Main Authors: Nagasaki, T, Hara, M, Nakanishi, H, Takahashi, H, Sato, M, Takeyama, H
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 21.01.2014; Nature Publishing Group
• Subjects: 631/250/127/1213; 692/699/67/1504/1885/1393; 692/699/67/2328; 692/700/1750; Angiogenesis; Animals; Antibiotics; Antibodies - pharmacology; Biological and medical sciences; Biomedical and Life Sciences; Biomedicine; Cancer Research; Cell Line; Cell Line, Tumor; Cells; Colonic Neoplasms - blood supply; Colonic Neoplasms - drug therapy; Colonic Neoplasms - metabolism; Colorectal cancer; Cytokines; Drug Resistance; Epidemiology; Fibroblasts; Fibroblasts - drug effects; Fibroblasts - enzymology; Fibroblasts - metabolism; Fibroblasts - pathology; Gastroenterology. Liver. Pancreas. Abdomen; HT29 Cells; Humans; Inflammation - drug therapy; Inflammation - metabolism; Inflammation - pathology; Interleukin-6 - metabolism; Medical prognosis; Medical research; Medical sciences; Mice; Mice, Nude; Molecular Diagnostics; Molecular Medicine; Monoclonal antibodies; Multiple tumors. Solid tumors. Tumors in childhood (general aspects); Neovascularization, Pathologic - drug therapy; Neovascularization, Pathologic - metabolism; Neovascularization, Pathologic - pathology; Oncology; Receptors, Interleukin-6 - metabolism; Stomach. Duodenum. Small intestine. Colon. Rectum. Anus; Stromal Cells - drug effects; Stromal Cells - metabolism; Stromal Cells - pathology; Tumors; Vascular Endothelial Growth Factor A - metabolism; United States > US; Japan; cancer-stroma interaction (CSI); angiogenesis; VEGF; colon cancer; cancer-associated fibroblast (CAF); Interlerukin-6 (IL-6); Interleukin 6 receptor; Antibody; Cell antiviral factor; Cytokine; Stroma; Malignant tumor; Colonic disease; Interleukin 6; Angiogenesis; Colon cancer; Cancerology; Vascular endothelium growth factor; Digestive diseases; Intestinal disease; Inhibitor; Neovascularization; Fibroblast; Cancer
• ISSN: 0007-0920; 1532-1827
• DOI: 10.1038/bjc.2013.748

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.