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Hepatocyte growth factor and Met in tumor biology and therapeutic approach with NK4
Author(s) -
Matsumoto Kunio,
Nakamura Takahiro,
Sakai Katsuya,
Nakamura Toshikazu
Publication year - 2008
Publication title -
proteomics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.26
H-Index - 167
eISSN - 1615-9861
pISSN - 1615-9853
DOI - 10.1002/pmic.200800156
Subject(s) - hepatocyte growth factor , cancer research , angiogenesis , stromal cell , biology , receptor tyrosine kinase , tyrosine kinase , tumor progression , metastasis , cancer cell , cancer , signal transduction , microbiology and biotechnology , receptor , biochemistry , genetics
Hepatocyte growth factor (HGF) and Met/HGF receptor tyrosine kinase play a role in the progression to invasive and metastatic cancers. A variety of cancer cells secrete molecules that enhance HGF expression in stromal fibroblasts, while fibroblast‐derived HGF, in turn, is a potent stimulator of the invasion of cancer cells. In addition to the ligand‐dependent activation, Met receptor activation is negatively regulated by cell–cell contact and Ser985 phosphorylation in the juxtamembrane of Met. The loss of intercellular junctions may facilitate an escape from the cell–cell contact‐dependent suppression of Met‐signaling. Significance of juxtamembrane mutations found in human cancers is assumed to be a loss‐of‐function in the negative regulation of Met. In attempts to block the malignant behavior of cancers, NK4 was isolated as a competitive antagonist against HGF–Met signaling. Independently on its HGF‐antagonist action, NK4 inhibited angiogenesis induced by vascular endothelial cell growth factor and basic fibroblast growth factor, as well as HGF. In experimental models of distinct types of cancers, NK4 inhibited Met activation and this was associated with inhibition of tumor invasion and metastasis. NK4 inhibited tumor angiogenesis, thereby suppressing angiogenesis‐dependent tumor growth. Cancer treatment with NK4 suppresses malignant tumors to be “static” in both tumor growth and spreading.