2003 年度実績報告書

上皮・間葉相互作用によるがん悪性化の分子機構とその制御

研究課題

研究課題/領域番号	12215082
研究機関	大阪大学
研究代表者	中村敏一大阪大学, 医学系研究科, 教授 (00049397)
研究分担者	水野信哉大阪大学, 医学系研究科, 助手 (10219644) 船越洋大阪大学, 医学系研究科, 助教授 (40273685) 松本邦夫大阪大学, 医学系研究科, 助教授 (90201780) 町出充大阪大学, 医学系研究科, 助手 (90346198)
キーワード	上皮・間葉相互作用 / HGF / がん悪性化 / NK4 / 制癌 / 浸潤 / 転移 / 腫瘍血管新生
研究概要	1)HGF/c-Met系を介した大腸癌肝浸潤機構の解析:スキルス癌に代表されるように間葉成分の多さと腫瘍悪性度の間には正の相関が認められる。実際、腫瘍が転移する際に線維芽細胞などの間質ストローマの影響を大きく受ける。このことから、癌-間質相互作用を介した癌悪性化機構の存在が指摘されてきたが、その詳細は不明であった。今回私達は大腸癌のモデルを用い、肝転移とともに間質ストローマにおけるHGF発現が亢進すること、一方肝実質組織に浸潤した癌細胞にはHGF受容体であるc-Metがリン酸化されていることを見出した。この意義を問うべく、HGFアンタゴニストであるNK4の遺伝子を肝特異的に発現させると、大腸癌細胞でのc-Metリン酸化の抑制に一致して癌浸潤が抑制された。以上の結果から、間質由来HGFによるパラクリン経路を介した癌浸潤機構の重要性が明らかとなった。 2)NK4による血管内皮細胞の増殖停止シグナル機構の解析:ヒト培養血管内皮細胞を用いて細胞内シグナル伝達系に対するNK4の作用を調べた。bFGF刺激によってcyclin D1の発現上昇ならびにそれに引き続くRBタンパク質のリン酸化が認められたが、NK4はbFGFによって誘導されるcyclin D1の発現上昇ならびにRBのリン酸化を阻害した。続いて、cyclin D1の発現上昇ならびにRBのリン酸化阻害に至る上流のシグナルを解析した結果、NK4はbFGFやVEGFによって誘導されるERK1/2のリン酸化(活性化)には無効であったが、bFGFやVEGFによって誘導されるAktならびにGSK3-βのリン酸化を容量依存的に阻害した。

研究成果

(40件)

すべてその他

すべて文献書誌 (40件)

[文献書誌] J.Wen, et al.: "Hepatic gene expression of NK4, an HGF-antagonist/angio-genesis inhibitor suppresses liver metastasis and invasive growth of colon cancer in mice."Cancer Gene Therapy. In press. (2004)
[文献書誌] S.Mizuno, T.Nakamura: "Suppression of mesangial TGF-β1 expression by HGF contributes to attenuate glomerulosclenosis and renal dysfunction in murine diabetic nephropathy."Am.J.Physiol.. 286. F134-F143 (2004)
[文献書誌] J.Wen, et al.: "Hydrocortisone potentiates hepatocyte growth factor expression in vascular endothelial cells."Biomed.Res.. In press. (2004)
[文献書誌] K.Oshima, et al.: "Intrathecal injection of HVJ-E containing HGF gene to cerebrospinal fluid can prevent and ameliorate hearing impairment in rats."FASEB J. 18. 212-214 (2004)
[文献書誌] N.Hattori, et al.: "The plasminogen activation system reduces fibrosis in the lung by a hepatocyte growth factor-dependent mechanism."Am.J Pathol.. In press. (2004)
[文献書誌] H.Takahashi, et al.: "LIM-kinase as a regulator of actin dynamics in spermatogenesis."Cytogenie and Genome Research. In press. (2004)
[文献書誌] K.Bessho, et al.: "Counteractive effects of HGF on PDGF-induced mesangial cell proliferation in a rat model of glomerulonephritis."Am.J Physiol.. 284. F1171-F1180 (2003)
[文献書誌] S.Yoshida, et al.: "Neutralization of hepatocyte growth factor leads to retarded cutaneous wound healing associated with decreased neovascularization and granulation tissue formation."J.Invest.Dermatol.. 120. 335-343 (2003)
[文献書誌] H.Funakoshi, T.Nakamura: "Hepatocyte growth factor : from diagnosis to clinical applications."Clin.Chem Acta. 327. 1-23 (2003)
[文献書誌] K.Matsumoto, et al.: "Renotropic role and therapeutic potential of HGF in the kidney."Nephrol.Dial.Transplant.. 17. 59-61 (2003)
[文献書誌] K.Kitajima, et al.: "Anewly identified AMSH-family protein is specifically expressed in haploid stages of testicular germ cells."Biochem.Biophys.Res.Commun.. 309. 135-142 (2003)
[文献書誌] T.Inoue, et al.: "Hepatocyte growth factor counteracts transforming growth factor-β1, through attenuation of connective tissue growth factor induction, and prevents renal fibrogenesis in 5/6-nephrectomized mice."FASEB J.. 17. 268-270 (2003)
[文献書誌] H.Koike, et al.: "Enhanced angiogenesis and improvement of neuropathy by cotransfection of human hepatocyle growth factor and prostacyclin synthase gene."FASEB J.. 103. 36-48 (2003)
[文献書誌] Tomita, N, et al.: "Angiogenic property of hepatocyte growth factor is dependent on upregulation of essential transcription factor for angiogenesis, ets-1."Circulation. 107. 1411-1417 (2003)
[文献書誌] Y.Matsuno, et al.: "Hepatocyte growth factor gene transfer into liver via the portal vein using electroporation attenuates the rat liver cirrhosis."Gene Therapy. 10. 1559-1566 (2003)
[文献書誌] M.Nakabayashi, et al.: "HGF/NK4 inhibited VEGF-induced angiogenesis in in vitro cultured endothelial cells and in vivo rabbit model."Diabetologia. 46. 115-123 (2003)
[文献書誌] T.Manabe, et al.: "Cell-based protein delivery system for pancreatic cancer therapy : NK4 gene-transduced oral mucosal epithelial cell sheet."Clin Cancer Res.. 9. 3158-3166 (2003)
[文献書誌] K.Nishimura, et al.: "Effects of hepatocyte growth factor on urokinase-type plasminogen activator (uPA) and uPA receptor in Du145 prostate cancer cells."Intern.J.Androl.. 26. 175-179 (2003)
[文献書誌] S.Kato, et al.: "Expression of hepatocyte growth factor and c-Met in the anterior horn cells of the spinal cord in the patients with amyotrophic lateral sclerosis (ALS) : immunohisto chemical studies on sporadic ALS and familial ALS with superoxide dismutase 1 gene mutation."Acta Neuropathol.. 106. 112-120 (2003)
[文献書誌] L.W.Qian, et al.: "Co-cultivation of pancreatic cancer cells with orthotopic tumor-derived fibroblasts : fibroblasts stimulate tumor cell invasion via HGF secretion whereas cancer cells exert a minor regulative effect on fibroblasts HGF production."Cancer Lett.. 190. 105-112 (2003)
[文献書誌] L.W.Quin, et al.: "Radiation stimulates HGF receptor/c-met expression that leads to amplifying cellular response to HGF stimulation via upregulated receptor tyrosine phosphorylation and map kinase activity in pancreatic cancer cells."Intern.J.Cancer. 104. 542-549 (2003)
[文献書誌] R.Pai, et al.: "Prostaglandins promote colon cancer cell invasion ; signaling by cross-talk between two distinct growth factor receptors."FASEB-J.. 17. 1640-1647 (2003)
[文献書誌] T.A.Martin, et al.: "Growth and angiogenesis of human breast cancer in a nude mouse tumor model is reduced by NK4, the HGF/SF antagonist."Carcirogenesis. 24. 1317-1323 (2003)
[文献書誌] G.Davies, et al.: "The HGF/SF antagonist NK4 reverses fibroblast-and HGF-induced prostate tumot growth and angiogenesis in vivo."Intern.J.Cancer. 106. 348-354 (2003)
[文献書誌] P.Netzer, et al.: "Interaction between hepatocyte growth factor and non-steroidal anti-inflammatory drugs during gastric epithelial wound healing."Digestion. 67. 118-128 (2003)
[文献書誌] 水野信哉, 他: "医学のあゆみ"医歯薬出版. 3 (2003)
[文献書誌] 水野信哉, 他: "臨床免疫2003"科学論評社. 9 (2003)
[文献書誌] 水野信哉, 中村敏一: "The Lung Perspective"メディカルレビュー社. 11 (2003)
[文献書誌] 水野信哉, 中村敏一: "Annual Review 腎臓"中外医学社. 11 (2002)
[文献書誌] 橋ガ迫敦子, 他: "血液・免疫・腫瘍"メディカルレビュー社. 8 (2003)
[文献書誌] 中村敏一: "日本医師会雑誌"日本医師会. 5 (2003)
[文献書誌] 田村隆彦, 他: "Biotherapy"癌と化学療法社. 8 (2003)
[文献書誌] 松本邦夫, 中村敏一: "BIO Clinica"北隆館. 7 (2003)
[文献書誌] 町出充, 中村敏一: "現代医療"現代医療社. 9 (2003)
[文献書誌] 福田一弘, 他: "遺伝子医学別"メディカルドゥ. 9 (2003)
[文献書誌] 松本邦夫, 中村敏一: "日本内科学雑誌"日本内科学学会. 5 (2003)
[文献書誌] 船越洋, 中村敏一: "神経治療学"日本神経治療学会. 8 (2003)
[文献書誌] 町出充, 中村敏一: "G.I.Research"先端医学社. 6 (2003)
[文献書誌] 船越洋, 中村敏一: "脳と神経"医学書院. 5 (2003)
[文献書誌] 中村健二ら: "脳の科学増刊号「神経の再生」"星和書店. 8 (2003)

2003 年度 実績報告書

上皮・間葉相互作用によるがん悪性化の分子機構とその制御

研究代表者

中村 敏一 大阪大学, 医学系研究科, 教授 (00049397)

研究成果

[文献書誌] J.Wen, et al.: "Hepatic gene expression of NK4, an HGF-antagonist/angio-genesis inhibitor suppresses liver metastasis and invasive growth of colon cancer in mice."Cancer Gene Therapy. In press. (2004)

[文献書誌] S.Mizuno, T.Nakamura: "Suppression of mesangial TGF-β1 expression by HGF contributes to attenuate glomerulosclenosis and renal dysfunction in murine diabetic nephropathy."Am.J.Physiol.. 286. F134-F143 (2004)

[文献書誌] J.Wen, et al.: "Hydrocortisone potentiates hepatocyte growth factor expression in vascular endothelial cells."Biomed.Res.. In press. (2004)

[文献書誌] K.Oshima, et al.: "Intrathecal injection of HVJ-E containing HGF gene to cerebrospinal fluid can prevent and ameliorate hearing impairment in rats."FASEB J. 18. 212-214 (2004)

[文献書誌] N.Hattori, et al.: "The plasminogen activation system reduces fibrosis in the lung by a hepatocyte growth factor-dependent mechanism."Am.J Pathol.. In press. (2004)

[文献書誌] H.Takahashi, et al.: "LIM-kinase as a regulator of actin dynamics in spermatogenesis."Cytogenie and Genome Research. In press. (2004)

[文献書誌] K.Bessho, et al.: "Counteractive effects of HGF on PDGF-induced mesangial cell proliferation in a rat model of glomerulonephritis."Am.J Physiol.. 284. F1171-F1180 (2003)

[文献書誌] S.Yoshida, et al.: "Neutralization of hepatocyte growth factor leads to retarded cutaneous wound healing associated with decreased neovascularization and granulation tissue formation."J.Invest.Dermatol.. 120. 335-343 (2003)

[文献書誌] H.Funakoshi, T.Nakamura: "Hepatocyte growth factor : from diagnosis to clinical applications."Clin.Chem Acta. 327. 1-23 (2003)

[文献書誌] K.Matsumoto, et al.: "Renotropic role and therapeutic potential of HGF in the kidney."Nephrol.Dial.Transplant.. 17. 59-61 (2003)

[文献書誌] K.Kitajima, et al.: "Anewly identified AMSH-family protein is specifically expressed in haploid stages of testicular germ cells."Biochem.Biophys.Res.Commun.. 309. 135-142 (2003)

[文献書誌] T.Inoue, et al.: "Hepatocyte growth factor counteracts transforming growth factor-β1, through attenuation of connective tissue growth factor induction, and prevents renal fibrogenesis in 5/6-nephrectomized mice."FASEB J.. 17. 268-270 (2003)

[文献書誌] H.Koike, et al.: "Enhanced angiogenesis and improvement of neuropathy by cotransfection of human hepatocyle growth factor and prostacyclin synthase gene."FASEB J.. 103. 36-48 (2003)

[文献書誌] Tomita, N, et al.: "Angiogenic property of hepatocyte growth factor is dependent on upregulation of essential transcription factor for angiogenesis, ets-1."Circulation. 107. 1411-1417 (2003)

[文献書誌] Y.Matsuno, et al.: "Hepatocyte growth factor gene transfer into liver via the portal vein using electroporation attenuates the rat liver cirrhosis."Gene Therapy. 10. 1559-1566 (2003)

[文献書誌] M.Nakabayashi, et al.: "HGF/NK4 inhibited VEGF-induced angiogenesis in in vitro cultured endothelial cells and in vivo rabbit model."Diabetologia. 46. 115-123 (2003)

[文献書誌] T.Manabe, et al.: "Cell-based protein delivery system for pancreatic cancer therapy : NK4 gene-transduced oral mucosal epithelial cell sheet."Clin Cancer Res.. 9. 3158-3166 (2003)

[文献書誌] K.Nishimura, et al.: "Effects of hepatocyte growth factor on urokinase-type plasminogen activator (uPA) and uPA receptor in Du145 prostate cancer cells."Intern.J.Androl.. 26. 175-179 (2003)

[文献書誌] L.W.Qian, et al.: "Co-cultivation of pancreatic cancer cells with orthotopic tumor-derived fibroblasts : fibroblasts stimulate tumor cell invasion via HGF secretion whereas cancer cells exert a minor regulative effect on fibroblasts HGF production."Cancer Lett.. 190. 105-112 (2003)

[文献書誌] L.W.Quin, et al.: "Radiation stimulates HGF receptor/c-met expression that leads to amplifying cellular response to HGF stimulation via upregulated receptor tyrosine phosphorylation and map kinase activity in pancreatic cancer cells."Intern.J.Cancer. 104. 542-549 (2003)

[文献書誌] R.Pai, et al.: "Prostaglandins promote colon cancer cell invasion ; signaling by cross-talk between two distinct growth factor receptors."FASEB-J.. 17. 1640-1647 (2003)

[文献書誌] T.A.Martin, et al.: "Growth and angiogenesis of human breast cancer in a nude mouse tumor model is reduced by NK4, the HGF/SF antagonist."Carcirogenesis. 24. 1317-1323 (2003)

[文献書誌] G.Davies, et al.: "The HGF/SF antagonist NK4 reverses fibroblast-and HGF-induced prostate tumot growth and angiogenesis in vivo."Intern.J.Cancer. 106. 348-354 (2003)

[文献書誌] P.Netzer, et al.: "Interaction between hepatocyte growth factor and non-steroidal anti-inflammatory drugs during gastric epithelial wound healing."Digestion. 67. 118-128 (2003)

[文献書誌] 水野信哉, 他: "医学のあゆみ"医歯薬出版. 3 (2003)

[文献書誌] 水野信哉, 他: "臨床免疫2003"科学論評社. 9 (2003)

[文献書誌] 水野信哉, 中村敏一: "The Lung Perspective"メディカルレビュー社. 11 (2003)

[文献書誌] 水野信哉, 中村敏一: "Annual Review 腎臓"中外医学社. 11 (2002)

[文献書誌] 橋ガ迫敦子, 他: "血液・免疫・腫瘍"メディカルレビュー社. 8 (2003)

[文献書誌] 中村敏一: "日本医師会雑誌"日本医師会. 5 (2003)

[文献書誌] 田村隆彦, 他: "Biotherapy"癌と化学療法社. 8 (2003)

[文献書誌] 松本邦夫, 中村敏一: "BIO Clinica"北隆館. 7 (2003)

[文献書誌] 町出充, 中村敏一: "現代医療"現代医療社. 9 (2003)

[文献書誌] 福田一弘, 他: "遺伝子医学別"メディカルドゥ. 9 (2003)

[文献書誌] 松本邦夫, 中村敏一: "日本内科学雑誌"日本内科学学会. 5 (2003)

[文献書誌] 船越洋, 中村敏一: "神経治療学"日本神経治療学会. 8 (2003)

[文献書誌] 町出充, 中村敏一: "G.I.Research"先端医学社. 6 (2003)

[文献書誌] 船越洋, 中村敏一: "脳と神経"医学書院. 5 (2003)

[文献書誌] 中村健二ら: "脳の科学 増刊号「神経の再生」"星和書店. 8 (2003)

2003 年度実績報告書

中村敏一大阪大学, 医学系研究科, 教授 (00049397)

[文献書誌] 中村健二ら: "脳の科学増刊号「神経の再生」"星和書店. 8 (2003)