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| 1.
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Eri, Adachi ; Katsuya, Sakai ; Takumi, Nishiuchi ; Ryu, Imamura ; Hiroki, Sato ; Kunio, Matsumoto
概要:
A dynamic phenotypic change contributes to the metastatic progression and drug resistance in malignant melanoma. Nevertheless, mechanisms for a phenotypic change have remained to be addressed. Here, we show that Met receptor expression
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changes in a cell-autonomous manner and can distinguish phenotypical differences in growth, as well as in metastatic and drug-resistant characteristics. In metastatic melanoma, the cells are composed of Met-low and Met-high populations. Met-low populations have stem-like gene expression profiles, are resistant to chemotherapeutic agents, and have shown abundant angiogenesis and rapid tumor growth in subcutaneous inoculation. Met-high populations have a differentiated phenotype, are relatively resistant to B-RAF inhibitor, and are highly metastatic to the lungs. Met plays a definitive role in lung metastasis because the lung metastasis of Met-high cells requires Met, and treatment of mice with the Met-containing exosomes from Met-high cells facilitates lung metastasis by Met-low cells. Clonal cell fate analysis showed the hierarchical phenotypical changes from Met-low to Met-high populations. Met-low cells either showed self-renewal or changed into Met-high cells, whereas Met-high cells remained Met-high. Clonal transition from Met-low to Met-high cells accompanied changes in the gene expression profile, in tumor growth, and in metastasis that were similar to those in Met-high cells. These findings indicate that malignant melanoma has the ability to undergo phenotypic change by a cell-intrinsic/autonomous mechanism that can be characterized by Met expression.
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| 2.
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矢野, 聖二
概要:
Lung cancer with epidermal growth factor receptor (EGFR)-activating mutations (EGFRmu) responds favorably to the EGFR ty
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rosine kinase inhibitors (EGFR-TKIs), gefitinib or erlotinib. However, 25-30% of patients with EGFRmu show intrinsic resistance, and even responders invariably acquire resistance to EGFR-TKIs. Two mechanisms, second-site T790M point mutation in EGFR and MET amplification, which contribute to acquired resistance to EGFR-TKIs have been reported. T790M secondary mutation and MET amplification are found in approximately 50% and 20%, respectively, of patients acquiring resistance to EGFR-TKIs. However, the mechanisms of intrinsic resistance and the other 30% of cases of acquired resistance are still unknown. We recently reported hepatocyte growth factor (HGF) induced resistance as the third mechanism of EGFR-TKI resistance. HGF, produced by either cancer cells or host fibroblasts, induced resistance by restoring PI3K/Akt pathway via MET, independently of ErbB3. In addition, inhibitors of HGF-MET successfully overcame HGF-induced resistance to EGFR-TKIs, indicating the importance of HGF-MET signaling as a considerable target for more successful treatment with EGFR-TKIs. EGFR活性型変異を有する肺腺癌はEGFRチロシンキナーゼ阻害薬であるゲフィチニブやエルロチニブが著効する．しかし，EGFR活性型変異を有する肺腺癌の25∼30%はゲフィチニブに自然耐性を示す．また，奏効症例においてもその大半が1年程度で獲得耐性を生じ再燃するため，EGFR活性型変異を有する肺腺癌におけるゲフィチニブ耐性の克服は臨床的にも重要な検討課題である．EGFRのT790M second mutationやMET増幅が,獲得耐性のそれぞれ50%および20%に関与することが知られているが，残りの30%の症例の耐性機序および自然耐性の機序は不明である．著者らは，肝細胞増殖因子（HGF）による第三の耐性機序を明らかにした．癌細胞自身あるいは間質の線維芽細胞が産生するHGFは，その受容体であるMETをリン酸化し，EGFRやErbB3とは無関係にPI3K/Akt経路を活性化することにより，ゲフィチニブ耐性を誘導した．HGF-MET阻害薬はHGFによるEGFR-TKI耐性を克服することも見出した．以上より，HGF-MET経路はEGFR-TKIの治療効果をより高める上で，非常に重要な標的と考えられる．
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| 3.
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Nakamura, Takahiro ; Sakai, Katsuya ; Nakamura, Toshikazu ; Matsumoto, Kunio
概要:
金沢大学がん研究所<br />Liver regeneration depends on the proliferation of mature hepatocytes. In the 1980s, the method for the c
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ultivation of mature hepatocytes provided an opportunity for the discovery of hepatocyte growth factor (HGF) as a protein that is structurally and functionally different from other growth factors. In 1991, the scatter factor, tumor cytotoxic factor, and 3-D epithelial morphogen were identified as HGF, and Met tyrosine kinase was identified as the receptor for HGF. Thus, the connection of apparently unrelated research projects rapidly enriched the research on HGF in different fields. The HGF-Met pathway plays important roles in the embryonic development of the liver and the placenta, in the migration of myogenic precursor cells, and in epithelial morphogenesis. The use of tissue-specific knockout mice demonstrated that in mature tissues the HGF-Met pathway plays a critical role in tissue protection and regeneration, and in providing less susceptibility to chronic inflammation and fibrosis. In various injury and disease models, HGF promotes cell survival, regeneration of tissues, and suppresses and improves chronic inflammation and fibrosis. Drug development using HGF has been challenging, but extensive preclinical studies to address its therapeutic effects have provided significant results sufficient for the development of HGF as a biological drug in the regeneration-based therapy of diseases. Clinical trials using recombinant human HGF protein, or HGF genes, are in progress for the treatment of diseases. © 2011 Journal of Gastroenterology and Hepatology Foundation and Blackwell Publishing Asia Pty Ltd.
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| 4.
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Matsumoto, Kunio ; Nakamura, Takahiro ; Sakai, Katsuya ; Nakamura, Toshikazu
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金沢大学がん研究所分子標的がん医療研究開発センター<br />Hepatocyte growth factor (HGF) and Met/HGF receptor tyrosine kinase play a role in the pr
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ogression 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. © 2008 Wiley-VCH Verlag GmbH & Co. KGaA.
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| 5.
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Adachi, Eri ; Sakai, Katsuya ; Nishiuchi, Takumi ; Imamura, Ryu ; Sato, Hiroki ; Matsumoto, Kunio
概要:
A dynamic phenotypic change contributes to the metastatic progression and drug resistance in malignant melanoma. Nevertheless, mechanisms for a phenotypic change have remained to be addressed. Here, we show that Met receptor expression
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changes in a cell-autonomous manner and can distinguish phenotypical differences in growth, as well as in metastatic and drug-resistant characteristics. In metastatic melanoma, the cells are composed of Met-low and Met-high populations. Met-low populations have stem-like gene expression profiles, are resistant to chemotherapeutic agents, and have shown abundant angiogenesis and rapid tumor growth in subcutaneous inoculation. Met-high populations have a differentiated phenotype, are relatively resistant to B-RAF inhibitor, and are highly metastatic to the lungs. Met plays a definitive role in lung metastasis because the lung metastasis of Met-high cells requires Met, and treatment of mice with the Met-containing exosomes from Methigh cells facilitates lung metastasis by Met-low cells. Clonal cell fate analysis showed the hierarchical phenotypical changes from Met-low to Met-high populations. Met-low cells either showed self-renewal or changed into Met-high cells, whereas Met-high cells remained Met-high. Clonal transition from Met-low to Met-high cells accompanied changes in the gene expression profile, in tumor growth, and in metastasis that were similar to those in Met-high cells. These findings indicate that malignant melanoma has the ability to undergo phenotypic change by a cell-intrinsic/autonomous mechanism that can be characterized by Met expression.
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| 6.
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Michikoshi, Hiromitsu ; Nakamura, Takahiro ; Sakai, Katsuya ; Suzuki, Yoshinori ; Adachi, Eri ; Matsugo, Seiichi ; Matsumoto, Kunio
概要:
α-Lipoic acid (α-LA), a naturally occurring anti-oxidant and co-factor for metabolic enzymes, suppresses the growth of d
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ifferent types of tumor cells. The mechanisms that are responsible for these results, however, remain to be elucidated. In the present study, we investigated the effects of α-LA on the proliferation and activation status of definitive receptor tyrosine kinases, epidermal growth factor receptor (EGFR) and Met/hepatocyte growth factor (HGF) receptor, in gefitinib-sensitive human non-small cell lung cancer cells harboring EGFRs with an activating mutation. The enantiomers R-α-LA and S-α-LA suppressed cell proliferation and increased the level of reactive oxygen species in HCC-827 and PC-9 human non-small cell lung cancer cells in an indistinguishable dose-dependent fashion. A phospho-receptor tyrosine kinase array and cell cycle analysis indicated that α-LA decreased tyrosine phosphorylation levels of EGFR, ErbB2, and Met, and this was associated with an inhibition in the cell-cycle transition from the G1 phase to the S phase without inducing apoptosis. Gefitinib, an inhibitor for EGFR tyrosine kinase, inhibited EGFR tyrosine phosphorylation/activation and proliferation of the cells. Instead, the addition of HGF induced Met tyrosine phosphorylation, and this was associated with a resistance to gefitinib-induced growth inhibition, which meant a gain in proliferative ability. In the presence of gefitinib and HGF, the addition of α-LA suppressed Met tyrosine phosphorylation, and this was associated with an inhibition in cell growth. These results suggest that the suppression of tyrosine phosphorylation/activation of growth factor receptors that is critical for the proliferation of human non-small cell lung cancer cells is a mechanism by which α-LA exerts growth inhibition for cancer cells. © 2013 Elsevier Ireland Ltd. All rights reserved.
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| 7.
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Matsumoto, Kunio ; Umitsu, Masataka ; Silva, Dinuka M. De ; Roy, Arpita ; Bottaro, Donald P.
概要:
Signaling driven by hepatocyte growth factor (HGF) and MET receptor facilitates conspicuous biological responses such as
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epithelial cell migration, 3-D morphogenesis, and survival. The dynamic migration and promotion of cell survival induced by MET activation are bases for invasion–metastasis and resistance, respectively, against targeted drugs in cancers. Recent studies indicated that MET in tumor-derived exosomes facilitates metastatic niche formation and metastasis in malignant melanoma. In lung cancer, gene amplification-induced MET activation and ligand-dependent MET activation in an autocrine/paracrine manner are causes for resistance to epidermal growth factor receptor tyrosine kinase inhibitors and anaplastic lymphoma kinase inhibitors. Hepatocyte growth factor secreted in the tumor microenvironment contributes to the innate and acquired resistance to RAF inhibitors. Changes in serum/plasma HGF, soluble MET (sMET), and phospho-MET have been confirmed to be associated with disease progression, metastasis, therapy response, and survival. Higher serum/plasma HGF levels are associated with therapy resistance and/or metastasis, while lower HGF levels are associated with progression-free survival and overall survival after treatment with targeted drugs in lung cancer, gastric cancer, colon cancer, and malignant melanoma. Urinary sMET levels in patients with bladder cancer are higher than those in patients without bladder cancer and associated with disease progression. Some of the multi-kinase inhibitors that target MET have received regulatory approval, whereas none of the selective HGF-MET inhibitors have shown efficacy in phase III clinical trials. Validation of the HGF-MET pathway as a critical driver in cancer development/progression and utilization of appropriate biomarkers are key to development and approval of HGF-MET inhibitors for clinical use. © 2017 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.
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| 8.
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Imamura, Ryu ; Matsumoto, Kunio
概要:
Hepatocyte growth factor (HGF) is a pleiotropic cytokine composed of an α-chain and a β-chain, and these chains contain
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four kringle domains and a serine protease-like structure, respectively. The receptor for HGF was identified as the c-met proto-oncogene product of transmembrane receptor tyrosine kinase. HGF-induced signaling through the receptor Met provokes dynamic biological responses that support morphogenesis, regeneration, and the survival of various cells and tissues, which includes hepatocytes, renal tubular cells, and neurons. Characterization of tissue-specific Met knockout mice has further indicated that the HGF-Met system modulates immune cell functions and also plays an inhibitory role in the progression of chronic inflammation and fibrosis. However, the biological actions that are driven by the HGF-Met pathway all play a role in the acquisition of the malignant characteristics in tumor cells, such as invasion, metastasis, and drug resistance in the tumor microenvironment. Even though oncogenic Met signaling remains the major research focus, the HGF-Met axis has also been implicated in infectious diseases. Many pathogens try to utilize host HGF-Met system to establish comfortable environment for infection. Their strategies are not only simply change the expression level of HGF or Met, but also actively hijack HGF-Met system and deregulating Met signaling using their pathogenic factors. Consequently, the monitoring of HGF and Met expression, along with real-time detection of Met activation, can be a beneficial biomarker of these infectious diseases. Preclinical studies designed to address the therapeutic significance of HGF have been performed on injury/disease models, including acute tissue injury, chronic fibrosis, and cardiovascular and neurodegenerative diseases. Likewise, manipulating the HGF-Met system with complete control will lead to a tailor made treatment for those infectious diseases. © 2016 Elsevier Ltd.<br />Embargo Period 12 months
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| 9.
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木下, 誉富
概要:
HGFβ・ベンゼン誘導体複合体のX線構造に基づき、辺縁に正電荷及び負電荷を有するサブポケット（S2）を狙ったStructure-Based Drug Design (SBDD)を行ったが、活性向上には至らなかった。このことはS2サブポケット
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を埋めるだけでは活性向上が難しいことを示唆している。そこで、HGFβ-Metの相互作用に関わる他のサブポケット（S1, S1’）を同時に阻害するペプチド性化合物を分子モデリングにより設計した。これらの化合物は弱いながら阻害活性を示した。今後、エントロピーロスを最小限にするためにコンホメーションを分子内で固定化した化合物を設計して高活性HGFアンタゴニストの創出を目指す。
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| 10.
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中村, 隆弘 ; Nakamura, Takahiro
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金沢大学がん進展制御研究所<br />再生・病態・発癌制御におけるJMドメインを欠失するMet(ΔJM-Met)の役割を明らかにするため、ΔJM-Met安定強制発現MDCK 細胞を用いたin vitroの解析およびΔJM-Metノックインマ
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ウスを用いたin vivoの解析を行った.その結果、ΔJM-MetおよびWTを安定発現するMDCK細胞はともにHGF-Metシグナル特有の生物活性であるスキャッター活性および管腔形成が認められ、またΔJM-Metノックインホモマウスは胎生致死となることが明らかとなった.<br />To address the function of the natural isoform of the Met/HGF receptor during tissue regeneration, disease and oncogenesis, I prepared the MDCK cells that stably express the ΔJM-Met or WT-Met gene and ΔJM-Met knockin mice. As a result, I could not find the any difference between ΔJM-Met and WT-Met expressed MDCK cells in the ability of motility and morphogenesis. Δ JM-Met knockin mice were resulted in embryonic lethal.<br />研究課題/領域番号:21790312, 研究期間(年度):2009-2010
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