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HGF-c-Met Receptor Pathway in Tumor Invasion-metastasis and Potential Cancer Treatment With NK4

  • Chapter
Growth Factors and their Receptors in Cancer Metastasis

Part of the book series: Cancer Metastasis - Biology and Treatment ((CMBT,volume 2))

Abstract

Hepatocyte growth factor (HGF), a ligand for the c-Met receptor tyrosine kinase, has mitogenic, motogenic, anti-apoptotic, and angiogenic activities. In tumor tissues, HGF potently enhances dissociation and invasion of a wide variety of tumor cells, thereby facilitating tumor metastasis. Aberrant expression of the c-Met receptor in cancer tissues, up-regulation of the HGF gene expression in tumor cells and/or host stroma, and mutational activation of c-Met receptor tyrosine kinase are particularly associated with the malignant progression of tumors. Likewise, in a variety of carcinomas (tumors of epithelial origin), HGF functions as a stromal-derived mediator in tumor-stromal interaction which confers malignant behavior in carcinoma cells. Therefore, blockage of HGF-c-Met receptor coupling or c-Met receptor-mediated signals has potential value for treatment of cancer patients. NK4, originally prepared as a competitive antagonist for HGF, is an internal fragment of HGF and it contains N-terminal hairpin and four kringle domains. NK4 binds to but does not activate the c-Met receptor, thereby competitively antagonizing biological activities of HGF. Unexpectedly, NK4 was subsequently shown to be an angiogenesis inhibitor and this angioinhibitory activity is independent of its action as an HGF-antagonist. Importantly, NK4, HGF-antagonist/angiogenesis inhibitor, inhibits tumor invasion, growth, angiogenesis, and metastasis of tumors in laboratory animals. Invasion and subsequent establishment of metastasis are devastating events in patients with cancer, but many past approaches did not address what is perhaps a most important issue in cancer treatment, i.e., invasion and metastasis. The therapeutic strategy of NK4 is based on suppression of intrinsic characteristics of malignant tumors. The possibility that NK4 can be an effective therapeutic for cancer patients warrants ongoing attention.

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Authors and Affiliations

  1. Division of Biochemistry, Department of Oncology, Biomedical Research Center, Osaka University Graduate School of Medicine, Suita, Osaka, 565-0871, Japan

    Kunio Matsumoto & Toshikazu Nakamura

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  1. Kunio Matsumoto
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  1. University of Kansas, Lawrence, Kansas

    C. R. Snyder

  2. University of Wales College of Medicine, Cardiff, UK

    Wen G. Jiang

  3. University of Osaka Medical School, Osaka, Japan

    Kunio Matsumoto  & Toshikazu Nakamura  & 

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Matsumoto, K., Nakamura, T. (2001). HGF-c-Met Receptor Pathway in Tumor Invasion-metastasis and Potential Cancer Treatment With NK4. In: Snyder, C.R., Jiang, W.G., Matsumoto, K., Nakamura, T. (eds) Growth Factors and their Receptors in Cancer Metastasis. Cancer Metastasis - Biology and Treatment, vol 2. Springer, Dordrecht. https://doi.org/10.1007/0-306-48399-8_11

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  • DOI: https://doi.org/10.1007/0-306-48399-8_11

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