肝硬変合併肝癌治療における肝星細胞機能阻害療法の開発

• 研究課題/領域番号: 19591599
• 研究種目: 基盤研究(C)
• 配分区分: 補助金
• 応募区分: 一般
• 研究分野: 消化器外科学
• 研究機関: 岩手医科大学
• 研究代表者: 若林 剛 岩手医科大学, 医学部, 教授 (50175064)
• 研究分担者: 増田 友之 岩手医科大学, 医学部, 教授 (10199698) ; 前沢 千早 岩手医科大学, 医学部, 教授 (10326647)
• 研究期間 (年度): 2007 – 2009
• 研究課題ステータス: 完了 (2009年度)
• 配分額: 4,550千円 (直接経費: 3,500千円、間接経費: 1,050千円); 2009年度: 650千円 (直接経費: 500千円、間接経費: 150千円); 2008年度: 2,210千円 (直接経費: 1,700千円、間接経費: 510千円); 2007年度: 1,690千円 (直接経費: 1,300千円、間接経費: 390千円)
• キーワード: 肝癌 / 肝星細胞 / AgngII / EGFR / ADAM / Ang11 / クロストーク / 肝星細胞胞 / AngII / 浸潤 / 転移

研究概要

がん間質相互作用は,腫瘍細胞の生物学的特性の形成に関与するばかりでなく,発生臓器の機能にも悪影響を与え,がん治療戦略の重要なテーマの1つである.肝炎・肝硬変等の肝線維症を背景として発症する肝癌は,肝線維症において重要な役割を担う,肝星細胞(hepatic stellate cell : HSC)との相互作用は肝癌の生物学的特性に多大な影響を与えている可能性がある.本研究課題では,肝癌細胞株および肝HSC初代培養細胞株を用いて,肝癌-HSC間の相互作用について解析を行った.肝癌細胞株およびHSCいずれにおいても,肝内に豊潤に存在するangiotensin II(AngII)の影響を受け,細胞増殖能および細胞浸潤能を上昇させることが明らかとなった.さらに,この背景にはAngII-a disintegrin and metalloprotease domain(ADAM)-epidermal growth factor receptor(EGFR)のクロストークによるsHB-EGF(soluble heparin binding EGF)の分泌が関与していることが明らかとなった.さらに,現在降圧薬として頻用されているangiotensin receptor blocker(ARB)は,肝癌-HSC間の相互作用を抑制し,肝癌細胞の増殖能および浸潤能を抑制する効果をしめした.AngII-ADAM-EGFRのクロストークによる肝癌細胞-HSC間の相互作用はARBによる抑制が可能であり,新たな肝癌・肝線維症治療の標的分子となる可能性が示唆された.

研究成果

• [雑誌論文] Molecular analysis of single isolated glands in gastric cancers and their surrounding gastric intestinal metaplastic mucosa (2010)
  • 著者名/発表者名: Sugai T, Habano W, Jiao YF, Toyota M, Suzuki H, Tsukahara M, Koizuka H, Akasaka R, Koeda K, Wakabayashi G, Suzuki K.
  • 雑誌名: Oncol Rep 23 ページ: 25-33
• [雑誌論文] Molecular analysis of gastric differentiated-type intramucosal and submucosal cancers (2010)
  • 著者名/発表者名: Sugai T, Habano W, Endoh M, Konishi Y, Akasaka R, Toyota M, Yamano H, Koeda K, Wakabayashi G, Suzuki K.
  • 雑誌名: Int J Cancer
• [雑誌論文] Primary retroperitoneal spindle cell liposarcoma: pathological and immunohistochemical findings (2010)
  • 著者名/発表者名: Shioi Y, Hasegawa T, Otsuka K, Fujisawa K, Itabashi T, Kimura T, Wakabayashi G, Mue Y, Uesugi N, Sugai T.
  • 雑誌名: Pathol Int 60 ページ: 472-6
  • NAID: 10029332263
• [雑誌論文] Human intestinal spirochetosis in northern Japan (2010)
  • 著者名/発表者名: Sato H, Nakamura SI, Habano W, Wakabayashi G, Adachi Y.
  • 雑誌名: J Med Microbiol
• [雑誌論文] Evaluation of UICC-TNM and JSBS staging systems for surgical patients with extrahepatic cholangiocarcinoma (2010)
  • 著者名/発表者名: Sasaki R, Murata S, Oda T, Ohkohchi N, Takeda Y, Wakabayashi G
  • 雑誌名: Langenbecks Arch Surg
• [雑誌論文] Laparoscopic excision of retroperitoneal tumors: report of three cases (2010)
  • 著者名/発表者名: Sasaki A, Suto T, Nitta H, Shimooki O, Obuchi T, Wakabayashi G
  • 雑誌名: Surg Today 40 ページ: 176-80
  • NAID: 10027394328
• [雑誌論文] Laparoscopic liver resection (2010)
  • 著者名/発表者名: Sasaki A, Nitta H, Takahara T, Fujita M, Nakajima J, Obuchi T, Baba S, Umemura A, Otsuka K, Wakabayashi G.
  • 雑誌名: Gan To Kagaku Ryoho 37 ページ: 396-8
• [雑誌論文] Concomitant laparoscopic splenectomy and cholecystectomy (2010)
  • 著者名/発表者名: Sasaki A, Nitta H, Otuska K, Kimura Y, Obuchi T, Wakabayashi G
  • 雑誌名: Surg Laparosc Endosc Percutan Tech 20 ページ: 66-8
• [雑誌論文] Tailored laparoscopic resection for suspected gastric gastrointestinal stromal tumors (2010)
  • 著者名/発表者名: Sasaki A, Koeda K, Obuchi T, Nakajima J, Nishizuka S, Terashima M, Wakabayashi G
  • 雑誌名: Surgery 147 ページ: 516-20
• [雑誌論文] Minimally invasive surgical enucleation for esophageal leiomyoma: report of seven cases (2010)
  • 著者名/発表者名: Obuchi T, Sasaki A, Nitta H, Koeda K, Ikeda K, Wakabayashi G
  • 雑誌名: Dis Esophagus 23
• [雑誌論文] Laparoscopy-assisted major liver resections employing a hanging technique: the original procedure (2010)
  • 著者名/発表者名: Nitta H, Sasaki A, Fujita T, Itabashi H, Hoshikawa K, Takahara T, Takahashi M, Nishizuka S, Wakabayashi G
  • 雑誌名: Ann Surg 251 ページ: 450-3
• [雑誌論文] Risk factors for early postoperative small bowel obstruction after colectomy for colorectal cancer (2010)
  • 著者名/発表者名: Nakajima J, Sasaki A, Otsuka K, Obuchi T, Nishizuka S, Wakabayashi G
  • 雑誌名: World J Surg 34 ページ: 1086-90
• [雑誌論文] Laparoscopy-assisted major liver resections employing a hanging technique : the original procedure. (2010)
  • 著者名/発表者名: Nitta H, Sasaki A, Fujita T, Itabashi H, Hoshikawa K, Takahara T, Takahashi M, Nishizuka S, Wakabayashi G.
  • 雑誌名: Ann Surg 251(3) : ページ: 450-453
  • 査読あり
• [雑誌論文] Molecular analysis of single isolated glands in gastric cancers and their surrounding gastric intestinal metaplastic mucosa. (2010)
  • 著者名/発表者名: Sugai T, Habano W, Endoh M, Konishi Y, Akasaka R, Toyota M, Yamano H, Koeda K, Wakabayashi G, Suzuki K.
  • 雑誌名: Int J Cancer (Epub ahead of print)(印刷中)
  • 査読あり
• [雑誌論文] Standardization of basic skills for laparoscopic liver surgery towards laparoscopic donor hepatectomy (2009)
  • 著者名/発表者名: Wakabayashi G, Nitta H, Takahara T, Shimazu M, Kitajima M, Sasaki A
  • 雑誌名: J Hepatobiliary Pancreat Surg 16 ページ: 439-44
  • NAID: 10025139665
• [雑誌論文] Laparoscopic liver resection: how far can we go? (2009)
  • 著者名/発表者名: Wakabayashi G
  • 雑誌名: J Hepatobiliary Pancreat Surg 16 ページ: 403-4
  • NAID: 10025139482
• [雑誌論文] Status of endoscopic liver surgery in Japan: a questionnaire survey conducted by the Japanese Endoscopic Liver Surgery Study Group (2009)
  • 著者名/発表者名: Tsuchiya M, Otsuka Y, Tamura A, Nitta H, Sasaki A, Wakabayashi G, Kaneko H
  • 雑誌名: J Hepatobiliary Pancreat Surg 16 ページ: 405-9
  • NAID: 10025139490
• [雑誌論文] Mohs chemosurgery for local control of giant recurrent papillary thyroid cancer (2009)
  • 著者名/発表者名: Tomisawa Y, Ogasawara S, Kashiwaba M, Inaba T, Takeda Y, Sugimura Y, Hatakeyama G, Asahi H, Wakabayashi G
  • 雑誌名: Thyroid 19 ページ: 657-9
• [雑誌論文] Ghrelin and leptin levels in cachectic patients with cancer of the digestive organs (2009)
  • 著者名/発表者名: Takahashi M, Terashima M, Takagane A, Oyama K, Fujiwara H, Wakabayashi G
  • 雑誌名: Int J Clin Oncol 14 ページ: 315-20
  • NAID: 10025864071
• [雑誌論文] A novel formulation of cisplatin (CDDP) (2009)
  • 著者名/発表者名: Sugitachi A, Kimura Y, Itabashi T, Noda H, Ishida K, Nishizuka S, Otsuka K, Kashiwaba M, Nitta H, Koeda K, Mizuno M, Sasaki A, Ikeda K, Takamori Y, Wakabayashi G
  • 雑誌名: Gan To Kagaku Ryoho 36 ページ: 2294-6
• [雑誌論文] Laparoscopic Heller myotomy with Dor fundoplication for achalasia: long-term outcomes and effect on chest pain (2009)
  • 著者名/発表者名: Sasaki A, Obuchi T, Nakajima J, Kimura Y, Koeda K, Wakabayashi G
  • 雑誌名: Dis Esophagus
• [雑誌論文] Ten-year experience of totally laparoscopic liver resection in a single institution (2009)
  • 著者名/発表者名: Sasaki A, Nitta H, Otsuka K, Takahara T, Nishizuka S, Wakabayashi G
  • 雑誌名: Br J Surg 96 ページ: 274-9
• [雑誌論文] Endoscopic subtotal thyroidectomy: the procedure of choice for Graves' disease? (2009)
  • 著者名/発表者名: Sasaki A, Nitta H, Otsuka K, Obuchi T, Kurihara H, Wakabayashi G
  • 雑誌名: World J Surg 33 ページ: 67-71
• [雑誌論文] Local recurrence after surgical resection of pancreatic cancer effectively treated with combined chemoradiotherapy (2009)
  • 著者名/発表者名: Obuchi T, Sasaki A, Shimooki O, Minakawa Y, Abe T, Nitta H, Otsuka K, Koeda K, Ikeda K, Wakabayashi G
  • 雑誌名: Gan To Kagaku Ryoho 36 ページ: 991-4
• [雑誌論文] Laparoscopic surgery for splenic artery aneurysm (2009)
  • 著者名/発表者名: Obuchi T, Sasaki A, Nakajima J, Nitta H, Otsuka K, Wakabayashi G.
  • 雑誌名: Surg Laparosc Endosc Percutan Tech 19 ページ: 338-40
• [雑誌論文] Laparoscopic subtotal cholecystectomy for severe cholecystitis (2009)
  • 著者名/発表者名: Nakajima J, Sasaki A, Obuchi T, Baba S, Nitta H, Wakabayashi G
  • 雑誌名: Surg Today 39 ページ: 870-5
  • NAID: 10025555209
• [雑誌論文] DNA hypomethylation at the CpG island is involved in aberrant expression of the L1 cell adhesion molecule gene in colorectal cancer (2009)
  • 著者名/発表者名: Kato K, Maesawa C, Itabashi T, Fujisawa K, Otsuka K, Kanno S, Tada H, Tatemichi Y, Kotani K, Oikawa H, Sugai T, Wakabayashi G, Masuda T
  • 雑誌名: Int J Oncol 35 ページ: 467-76
• [雑誌論文] The ideal follow-up after breast cancer operation (2009)
  • 著者名/発表者名: Kashiwaba M, Inaba T, Takeda Y, Komatsu H, Kawagishi R, Wakabayashi G
  • 雑誌名: Gan To Kagaku Ryoho 36 ページ: 1423-7
• [雑誌論文] Palliative chemotherapy for metastatic breast cancer with capecitabine (2009)
  • 著者名/発表者名: Inaba T, Kashiwaba M, Takeda Y, Komatsu H, Tomisawa Y, Takiyama I, Wakabayashi G
  • 雑誌名: Gan To Kagaku Ryoho 36 ページ: 769-72
• [雑誌論文] CYP1B1, but not CYP1A1, is downregulated by promoter methylation in colorectal cancers (2009)
  • 著者名/発表者名: Habano W, Gamo T, Sugai T, Otsuka K, Wakabayashi G, Ozawa S
  • 雑誌名: Int J Oncol 34 ページ: 1085-91
• [雑誌論文] Assessment of gastric motor function by cine magnetic resonance imaging (2009)
  • 著者名/発表者名: Baba S, Sasaki A, Nakajima J, Obuchi T, Koeda K, Wakabayashi G
  • 雑誌名: J Gastroenterol Hepatol 24 ページ: 1401-6
• [雑誌論文] DNA hypomethylation at the CpG island is involved in aberrant expression of the L1 cell adhesion molecule gene in colorectal cancer. (2009)
  • 著者名/発表者名: Kato K, Maesawa C, Itabashi T, Fujisawa K, Otsuka K, Kanno S, Tada H, Tatemichi Y, Kotani K, Oikawa H, Sugai T, Wakabayashi G.Masuda T.
  • 雑誌名: Int J Oncol 35 ページ: 467-476
  • 査読あり
• [雑誌論文] Epigenetic modification is involved in aberrant expression of class III beta-tubulin, TUBB3, in ovarian cancer cells. (2009)
  • 著者名/発表者名: Kato K, Maesawa C, Wakabayashi G, Masuda T., et al
  • 雑誌名: Int J Oncol 33(In press)
  • 査読あり
• [雑誌論文] Kitajima M. Correlation of motility and neuronal integrity with a focus on the grade of intestinal allograft rejection (2008)
  • 著者名/発表者名: Watanabe T, Hoshino K, Tanabe M, Morikawa Y, Kawachi S, Wakabayashi G, Shimazu M
  • 雑誌名: Am J Transplant 8 ページ: 529-36
• [雑誌論文] A case of complete response in supraclavicular lymph node involvement from cancer of the sigmoid colon to FOLFOX4 therapy after laparoscopy-assisted colectomy (2008)
  • 著者名/発表者名: Suto T, Ito N, Obuchi T, Uesugi N, Sugai T, Nakamura SI, Wakabayashi G
  • 雑誌名: Gan To Kagaku Ryoho 35 ページ: 669-72
• [雑誌論文] Chitin/cisplatin-an adhesive anticancer drug (2008)
  • 著者名/発表者名: Sugitachi A, Otsuka K, Itabashi T, Chiba T, Kimura Y, Sasaki A, Ikeda K, Uesugi N, Takamori Y, Kurozumi S, Mori T, Wakabayashi G
  • 雑誌名: Gan To Kagaku Ryoho 35 ページ: 2021-3
• [雑誌論文] Protein and lysate array technologies in cancer research (2008)
  • 著者名/発表者名: Spurrier B, Honkanen P, Holway A, Kumamoto K, Terashima M, Takenoshita S, Wakabayashi G, Austin J, Nishizuka S
  • 雑誌名: Biotechnol Adv 26 ページ: 361-9
• [雑誌論文] Laparoscopic spleen-preserving distal pancreatectomy with conservation of the splenic artery and vein: report of three cases (2008)
  • 著者名/発表者名: Sasaki A, Nitta H, Nakajima J, Obuchi T, Baba S, Wakabayashi G
  • 雑誌名: Surg Today 38 ページ: 955-8
  • NAID: 10022612689
• [雑誌論文] Laparoscopic cholecystectomy in patients with a history of gastrectomy. (2008)
  • 著者名/発表者名: Sasaki A, Nakajima J, Nitta H, Obuchi T, Baba S, Wakabayashi G
  • 雑誌名: Surg Today 38 ページ: 790-4
  • NAID: 10022611958
• [雑誌論文] Endoscopic thyroidectomy by the breast approach: a single institution's 9-year experience (2008)
  • 著者名/発表者名: Sasaki A, Nakajima J, Ikeda K, Otsuka K, Koeda K, Wakabayashi G
  • 雑誌名: World J Surg 32 ページ: 381-5
• [雑誌論文] Application of quantitative proteomic analysis for cancer therapy using "reverse-phase" protein lysate microarrays (2008)
  • 著者名/発表者名: Nishizuka S, Spurrier B, Honkanen P, Austin J, Wakabayashi G
  • 雑誌名: Gan To Kagaku Ryoho 35 ページ: 200-5
• [雑誌論文] High density 'reverse-phase' protein lysate microarray (2008)
  • 著者名/発表者名: Nishizuka S, Ishida K, Noda H, Takahashi M, Wakabayashi G
  • 雑誌名: Seikagaku 80 ページ: 1047-54
  • NAID: 10024455069
• [雑誌論文] Downregulation of miR-138 is associated with overexpression of human telomerase reverse transcriptase protein in human anaplastic thyroid carcinoma cell lines (2008)
  • 著者名/発表者名: Mitomo S, Maesawa C, Ogasawara S, Iwaya T, Shibazaki M, Yashima-Abo A, Kotani K, Oikawa H, Sakurai E, Izutsu N, Kato K, Komatsu H, Ikeda K, Wakabayashi G, Masuda T
  • 雑誌名: Cancer Sci 99 ページ: 280-6
  • NAID: 10024002213
• [雑誌論文] Angiotensin II and epidermal growth factor receptor cross-talk mediated by a disintegrin and metalloprotease accelerates tumor cell proliferation of hepatocellular carcinoma cell lines (2008)
  • 著者名/発表者名: Itabashi H, Maesawa C, Oikawa H, Kotani K, Sakurai E, Kato K, Komatsu H, Nitta H, Kawamura H, Wakabayashi G, Masuda T
  • 雑誌名: Hepatol Res 38 ページ: 601-13
  • NAID: 10024148920
• [雑誌論文] Angiotensin II and epidermal growth factor receptor cross-talk mediated by a disintegrin and metalloprotease accelerates tumor cell proliferation of hepatocellular carcinoma cell lines. (2008)
  • 著者名/発表者名: Itabashi H, Maesawa C, Wakawayashi G, Masuda T.
  • 雑誌名: Hepatol Res 38 ページ: 601-613
  • NAID: 10024148920
  • 査読あり
• [雑誌論文] Angiotensin II and epidermal growth factor receptor cross-talk mediated by a disintegrin and metalloprotease accelerates tumor cell proliferation of hepatocellular carcinoma cell lines
  • 著者名/発表者名: Itabashi H, Maesawa C, Oikawa H, Kotani K, Sakurai E, Kato K, Komatsu H, Nitta H, Kawamura H, Wakabayashi G, Masuda T
  • 雑誌名: Hep Res (In press)
  • NAID: 10024148920
  • 査読あり