Increased circulating cell signaling phosphoproteins in sera are useful for early detection and the tailor-made therapy for pancreatic and biliary duct cancer patients.

• Project/Area Number: 21390372
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Digestive surgery
• Research Institution: Chiba University
• Principal Investigator: MIYAZAKI Masaru 千葉大学, 大学院・医学研究院, 教授 (70166156)
• Co-Investigator(Kenkyū-buntansha): KIMURA Fumio 千葉大学, 大学院・医学研究院, 准教授 (70334208) ; SHIMIZU Hiroaki 千葉大学, 大学院・医学研究院, 講師 (80272318) ; YOSHIDOME Hiroyuki 千葉大学, 大学院・医学研究院, 講師 (10312935) ; KATO Atushi 千葉大学, 大学院・医学研究院, 助教 (70344984) ; 高野 重紹 千葉大学, 大学院・医学研究院, 助教 (20436380)
• Project Period (FY): 2009 – 2011
• Project Status: Completed (Fiscal Year 2011)
• Budget Amount: ¥18,070,000 (Direct Cost: ¥13,900,000、Indirect Cost: ¥4,170,000); Fiscal Year 2011: ¥3,250,000 (Direct Cost: ¥2,500,000、Indirect Cost: ¥750,000); Fiscal Year 2010: ¥2,990,000 (Direct Cost: ¥2,300,000、Indirect Cost: ¥690,000); Fiscal Year 2009: ¥11,830,000 (Direct Cost: ¥9,100,000、Indirect Cost: ¥2,730,000)
• Keywords: proteomics / 膵癌 / 胆道癌 / 腫瘍マーカー / リン酸化蛋白 / ERK / Proteomics / シグナル伝達物質 / 自己抗体複合体

Research Abstract

Intracellular phosphoprotein activation significantly regulatescancer progression. We investigated the serum phosphoprotein profile involved in pancreatic cancer by a novel approach that comprehensively measured serum phosphoproteins levels, and clinically applied this method to the detection of pancreatic cancer. We analyzed the serum phosphoproteins that comprised cancer cellular signal pathways by comparing sera from pancreatic cancer patients and benign controls including healthy volunteers and pancreatitis patients. Hierarchical clustering analysis between pancreatic cancer patients and healthy volunteers revealed differential pathway-specific profiles. In particular, the components of the extracellular signal-regulated kinase (ERK) signaling pathway were significantly increased in the sera from pancreatic cancer patients compared with healthy volunteers. The positive rate of p-ERKI/2 (82%) was found to be superior to that of CA19-9 (53%) for early stage pancreatic cancer. For the combination of these serum levels, the area under the receiver-operator-characteristics curves were showing significant ability to distinguish between the two populations in independent validation set, and between cancer and non-cancer populations in another validation set. The comprehensive measurement of serum cell signal phosphoproteins is useful for, the detection of pancreatic cancer. Further investigations will lead to the implementation of tailor-made molecular-targeted therapeutics.

Research Products

• [Journal Article] Usefulness of Preoperative Partial Splenic Embolization in Hepatocellular carcinoma and Hypersplenic (2011)
  • Author(s): Yoshidome H, Kimura F, Shimizu H, Ohtsuka M, Kato A, Yoshitomi H, Furukawa K, Takeuchi D, Takayashiki T, Suda K, Takano S, Miyazaki M.
  • Journal Title: Thrombocyto penia Hapato-Gastroenterology Volume: 58 Pages: 2062-2066
  • Peer Reviewed
• [Journal Article] Similarties and Differences Between Intra ducal Papillary Tumors of the Bile Duct Wi th and Without Macroscopically Visible Mu cin Secretion (2011)
  • Author(s): Ohtsuka M, Kimura M, Shimizu H, Yoshidame H, Kato A, Yoshitomi. H, Furukawa K, Takeuchi D, Takayashiki T, Suda K, Takino S, Kondo Y, Miyazaki M
  • Journal Title: Am J Surg Pathol Volume: 35(4) Pages: 512-521
  • Peer Reviewed
• [Journal Article] Treatment Strategy for Hepatocellular Car rcinoma with Major Portal Vein or Inferior Vona Cava Invasion : A Single Institution. Experience (2011)
  • Author(s): Yoshidome H, Takeuchi D, Kimura F, Shimizu H, Ohtsuka M, Kate A, Furukawa K, Yoshitomi H, Miyazaki M
  • Journal Title: J Am Coll Surg Volume: 212(5) Pages: 796-803
  • Peer Reviewed
• [Journal Article] Hepatocyte apoptosis is enhanced after isc hernia/ reperfusion in the steatotic liver (2011)
  • Author(s): Suzuki T, Yoshidome H, Kimura F, Shimizu H, Ohtsua M Takeuchi D, Kate A, Furukawa K, Yoshitomi H, Iida A, Dochi T, Miyazaki M
  • Journal Title: J. Clin Volume: 48(2) Pages: 142-148
  • Peer Reviewed
• [Journal Article] CXCR4/CXCL12 expression profile is associated with tumor microenvironment and clinical outcome of liver metastases of colorectal cancer (2011)
  • Author(s): Sakai N, et al.
  • Journal Title: Clin Exp metastasis Volume: 29(Epub ahead of print) Issue: 2 Pages: 101-110
  • DOI: 10.1007/s10585-011-9433-5
  • Peer Reviewed
• [Journal Article] 膵発生における血管内皮細胞の役割 (2011)
  • Author(s): 吉富秀幸, ら
  • Journal Title: 胆と膵 Volume: 32 Pages: 1213-1218
• [Journal Article] One hundred seven consective surgical resections for hilar cholangiocarcinoma of Bismuth types II, III, IV between 2001 and 2008 J Hepatobiliary Pancreat (2010)
  • Author(s): Miyazaki M, Kimura F, Shimizu H, Yoshidome H, Ohtuka M, Kate A, Yoshitomi H, Furukawa K, Takeuchi D, Takayashiki T, Suda K, Takano S
  • Journal Title: Sci Volume: 17 Pages: 470-475
  • Peer Reviewed
• [Journal Article] Hepatocyte nuclear factor-kappa (NF-kB) activation is protective but is decreased in the cholestatic liver with endotoxemia (2010)
  • Author(s): Iida A, Yoshidome H, Shida T, Takano S, Takeuchi D, Kimura F, Shimizu H, Ohtsuka, Miyazaki M
  • Journal Title: Surgery Volume: 148(3) Pages: 477-489
  • Peer Reviewed
• [Journal Article] Effects of Partial Hepatic Venous Congesti on on Hepatic (2010)
  • Author(s): Okuno A, Kimura F, Nakagawa K, Shimizu H, Yoshidome H, Ohtsuka M, Kate A, Fukuda T, Miyazaki M
  • Journal Title: Hepato-Gastroenterology Volume: 57 Pages: 127-133
  • Peer Reviewed
• [Journal Article] Increased circulating cell signalling phosphoproteins in sera are useful for the detection of pancreatic cancer (2010)
  • Author(s): Takano S, Sogawa K, Yoshitomi H, Shida T, Mogushi K, Shimizu H, Yoshidome H, Ohtsuka M, Kate A, Ishihara T, Tanaka H, Yokosuka O, Nomura F, Miyazaki M
  • Journal Title: British Journal of Cancer Volume: 103 Pages: 223-231
  • Peer Reviewed
• [Journal Article] Effects of perioperative immunonutrition on cell-mediated immunity, T helper type 1(Th1)/Th2 differentiation, and Th17 rasp onse after pancreaticoduodenectomy (2010)
  • Author(s): Suzuki D, Furukawa K, Kimura F, Shimizu H, Yoshidome H, Ohtsuka M, Kate A, Yoshitomi H, Miyazaki M
  • Journal Title: Surgery Volume: 148(3) Pages: 573-581
  • Peer Reviewed
• [Journal Article] Effects of Partial Hepatic Venous Congesti on on Hepatic Hemodynamics and Historo ogy (2010)
  • Author(s): Okuno A, Kimura F, Nakamura K, Shimizu H, Yoshidome H, Ohtsuka M, Kate A, Fukada T, Miyazaki M
  • Journal Title: hepato-Gastroenterology Volume: 57 Pages: 127-133
  • Peer Reviewed
• [Journal Article] Multicentric evaluation of a clnical and prognostic scoring system predictive of survival after resection of intrahepatic cholangiocarcinomas (2010)
  • Author(s): Georgios C. Sotiropoulous, Miyazaki M, Mancusos M. Konstadoulakis, Andreas Paul, Ernest P. Molmenti, Ilias P. Gomatos, Arnold Raadtke, Hideo A. Baba, Susanne Beckebaum, Erini I. Brokalaki, Ohtsuka M, Myron E. Schwartz, Christoph E. Broelsh George Sgourakis
  • Journal Title: Liver International Volume: 30 Pages: 966-1002
  • Peer Reviewed
• [Journal Article] Expression of an activated mammalian targetof rapamycin (mTOR) in gastoroente ropancreatic neuroendocrine tumors (2010)
  • Author(s): Shida T, Kishimoto T, Furuya M, Nikaido T, Koda K, Takano S, Kimura F, Shimizu H, Yoshidome H, Ohtsuka M, Tanizawa T, Nakatani Y, Miyazaki M
  • Journal Title: Cancer Chemother Pharmacol Volume: 65 Pages: 889-893
  • Peer Reviewed
• [Journal Article] Aggressive Surgical Resection for Hilar Cholangiocarcinoma of the Left-side Predo minance (2010)
  • Author(s): Shimizu H, Kimura F, Yoshidome H, Ohtsuka M, Kato A, Yoshitomi H, Furukawa K, Miyazaki M
  • Journal Title: Ann Surg Volume: 251 Pages: 281-286
  • Peer Reviewed
• [Journal Article] Expression of an activated mammalian target of rapamycin (mTOR)in gastoroenteropancreatic neuroendocrine tumors. (2010)
  • Author(s): Miyazaki M
  • Journal Title: Cancer Chemother Pharmacol Volume: 65 Pages: 889-893
  • Peer Reviewed
• [Journal Article] One hundred seven consective surgical resections for hilar cholangiocarcinoma of Bismuth types II, III, IV between 2001 and 2008 (2010)
  • Author(s): Miyazaki M
  • Journal Title: Japan Hepatobihary Pancreat Science Volume: 17 Pages: 470-475
  • Peer Reviewed
• [Journal Article] Induction of Antitumor Response by In Vivo Allogeneic Major Histocompatibility Complex Gene Transfer Using Electropora Tion (2009)
  • Author(s): Shimizu H, Nukui Y, Mitsuhashi N, Kimura F, Yoshidome H, Ohtsuka M, Kato A, Miyazaki M
  • Journal Title: J Surg Res Volume: 154 Pages: 60-67
  • Peer Reviewed
• [Journal Article] Risk Factors of liver dysfunction after extended hepatic resection in biliary tract malignancies (2009)
  • Author(s): Suda K, Ohtsuka M, Ambiru S, Kimura F, Shimizu H, Yoshidome H, Miyazaki M.
  • Journal Title: J Am Coll Surg Pages: 752-758
  • Peer Reviewed
• [Journal Article] Effect of Excessive Acute-phase Response on Liver Regeneration after Partial Hepate ctomy in Rats (2009)
  • Author(s): Kusashio K, Shimizu H, Kimura F, Yoshidome H, Ohtsuka M, Kato A, Yoshitomi H, Furukawa K, Fukada T, Miyazaki M
  • Journal Title: Hepato-Gastroenterol Volume: 56 Pages: 824-828
  • Peer Reviewed
• [Journal Article] Role of Kupffer Cells in Tolerance Indac tion after Portal Venous Administration of Alloantigen (2009)
  • Author(s): Shimizu H, Kataoka M, Kimura F, Yoshi dome H, Ohtsuka M, Kato A, Miyazaki M
  • Journal Title: Hepato-Gastroenterol Volume: 56 Pages: 783-787
  • Peer Reviewed
• [Journal Article] Randomized, Controlled Study of Continu ous 5-FU Infusion Starting Immediately after Curative Surgery for Advanced Cal orectal Cancer (2009)
  • Author(s): Koda K, Saito N, Ochiai T, Miyazaki M, Sarashina H, Nakajima N
  • Journal Title: Hepato-Gastroenterol Volume: 56 Pages: 116-119
  • Peer Reviewed
• [Journal Article] Risk factor of liver dysfunction after extended hepatic resection in biliary tract malignancies (2009)
  • Author(s): Masaru Miyazaki
  • Journal Title: The American Journal of Surgery 197 Pages: 752-758
  • Peer Reviewed
• [Journal Article] Clinical Significance of Biliary Vascular Anatomy of the Right Liver For Hilar Cholangiocarcinoma Applied to Left Hemihepatectomy (2009)
  • Author(s): Masaru Miyazaki
  • Journal Title: Ann Srug 249 Pages: 435-439
  • Peer Reviewed
• [Journal Article] Interval Period Tumor Progression : Delaye d Hepatectomy Detect Occult Metastases in Synchronous Colorectal Liver Metasta ses (2008)
  • Author(s): Yoshidome H, Fumio Kimura, Shimizu H, Ohtsuka M, Kato A, Yoshitomi H, Furukaw a K, Mitsuhashi. N, Takeuchi D, Iida A, Mi yazaki M
  • Journal Title: J Gastrointest Surg Volume: 12 Pages: 1391-1398
  • Peer Reviewed
• [Presentation] 網羅的蛋白質解析による新規膵癌血中マーカー開発への試み (2011)
  • Author(s): 吉富秀幸, ら
  • Organizer: JDDW 2011
  • Place of Presentation: 福岡
  • Year and Date: 2011-10-22
• [Presentation] 膵癌術後補助療法の個別化を目指したGemcitabine耐性因子の同定とAkt/mTORシグナル制御の意義 (2011)
  • Author(s): 吉富秀幸, ら
  • Organizer: 第66回日本消化器外科学会総会
  • Place of Presentation: 名古屋
  • Year and Date: 2011-07-15
• [Presentation] 胆道・膵臓悪性腫瘍の病態と治療の進歩 (2010)
  • Author(s): 宮崎勝
  • Organizer: 日本消化器病学会東海支部第112回例会
  • Place of Presentation: 三島東レ総合研修センター
  • Year and Date: 2010-06-26
• [Presentation] 教育セッション7 講師 がん治療update (2009)
  • Author(s): 宮崎勝
  • Organizer: 第47回 日本癌治療学会
  • Place of Presentation: パシフィコ横浜
  • Year and Date: 2009-10-22
• [Presentation] 膵癌における癌幹細胞マーカー発現形式の検討と臨床病理学因子との関係
  • Author(s): 高原義博, ら
  • Organizer: 第111回日本外科学会定期学術集会
  • Place of Presentation: (紙上発表)
• [Remarks]
  • URL: http://www.ho.chiba-u.ac.jp/5/