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The VEGF angiogenic switch of fibroblasts is regulated by MMP-7 from cancer cells

Oncogene volume 26, pages 7194–7203 (2007)Cite this article

Abstract

Vascular endothelial growth factor (VEGF) production by stromal fibroblasts plays an important role in tumor angiogenesis. However, VEGF is also expressed by normal tissue fibroblasts, raising the question of how the VEGF activity of fibroblasts is regulated. Here we report that the latent VEGF angiogenic activity of fibroblasts is activated by cancer cells, resulting in tumor-selective utilization of fibroblast-derived VEGF. Through the production of VEGF, human VA-13 fibroblasts promote angiogenesis in and growth of human pancreas cancer Capan-1 xenograft tumors, whereas VA-13 fibroblasts alone do not show significant angiogenesis. Treatment of VA-13 fibroblast supernatant with matrix metalloproteinase-7 (MMP-7), an extracellular proteinase characteristically expressed by cancer cells, elicits endothelial tube formation. This effect is abrogated by anti-VEGF antibody or connective tissue growth factor (CTGF), which was previously reported to sequester VEGF and be degraded by MMP-7. Suppression of MMP-7 in Capan-1 cells abrogates the tumor angiogenic activity of VA-13 fibroblasts, which is restored by suppression of CTGF in VA-13 fibroblasts. We further show that these molecular mechanisms that trigger angiogenesis are effective in human primary fibroblasts and human colorectal tissue. These data suggest that fibroblasts may store VEGF in a latent state in the extracellular environment for urgent use in angiogenesis.

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Acknowledgements

We thank Y Okuhara, C Okumura, M Okumoto and Y Murata for histological preparation of tissues; T Sangai, M Emura, M Nakamura, K Tsuchihara, S Fujii, SC Zhang, S Mitsunaga and A Hoshino for helpful advice; S Miyamoto and Y Aoyagi for collecting tissue samples; and K Harigaya and T Kitamura for providing KM-104 fibroblasts and the retroviral plasmid pMX-GFP, respectively. This work was supported by the Grant-in-Aid for Cancer Research from the Ministry of Health, Labour and Welfare; the Grant for Scientific Research Expenses for Health Labour and Welfare Programs; the Foundation for the Promotion of Cancer Research, 2nd-Term Comprehensive 10-Year Strategy for Cancer Control; and Special Coordination Funds for Promoting Science and Technology from the Ministry of Education, Culture, Sports, Science and Technology, the Japanese Government.

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Authors and Affiliations

  1. Department of Integrated Biosciences, Laboratory of Cancer Biology, Graduate School of Frontier Sciences, The University of Tokyo, Kashiwa-City, Chiba, Japan

    T-K Ito, H Chiba & A Ochiai

  2. Pathology Division, Research Center for Innovative Oncology, National Cancer Center Hospital East, Kashiwa-City, Chiba, Japan

    T-K Ito, G Ishii, H Chiba & A Ochiai

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  1. T-K Ito
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Correspondence to A Ochiai.

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Supplementary Information accompanies the paper on the Oncogene website (http://www.nature.com/onc).

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Ito, TK., Ishii, G., Chiba, H. et al. The VEGF angiogenic switch of fibroblasts is regulated by MMP-7 from cancer cells. Oncogene 26, 7194–7203 (2007). https://doi.org/10.1038/sj.onc.1210535

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