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Fundamental research on the treatment for pancreatic cancer based on developmental biology of the pancreas

Research Project

Project/Area Number 15390395
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeSingle-year Grants
Section一般
Research Field Digestive surgery
Research InstitutionKYOTO UNIVERSITY

Principal Investigator

DOI Ryuichiro  Kyoto University, Graduate School of Medicine, Lecturer, 医学研究科, 講師 (20301236)

Co-Investigator(Kenkyū-buntansha) FUJIMOTO Koji  Kyoto University, Graduate School of Medicine, Assistant Professor, 医学研究科, 助手 (70335280)
KAWAGUCHI Yoshiya  Kyoto University, Graduate School of Medicine, Assistant Professor, 医学研究科, 助手 (60359792)
今村 正之  京都大学, 医学研究科, 教授 (00108995)
Project Period (FY) 2003 – 2004
Project Status Completed (Fiscal Year 2004)
Budget Amount *help
¥14,700,000 (Direct Cost: ¥14,700,000)
Fiscal Year 2004: ¥4,700,000 (Direct Cost: ¥4,700,000)
Fiscal Year 2003: ¥10,000,000 (Direct Cost: ¥10,000,000)
KeywordsPancreatic duodenal homeobox gene-1 / Pancreatic ductal carcinoma / Invasion / Insulin / Streptozocin
Research Abstract

Pancreatic duodenal homeobox gene-1 (pdx-1) has a dual task as a key regulator in pancreatic organogenesis and in functional maintenance of beta cells in adults. Pdx-1 is thought to be a marker of de-differentiated cells with the capacity to re-differentiate into several pancreatic cell types. In this project, we analyzed pdx-1 expression in human pancreatic cancer specimens, as well as pancreatic cancer cell lines, and also analyzed the effects of forced expression of pdx-1 in pancreatic cancer cells. In addition, we analyzed the plasticity of the liver by enforced expression of pdx-1 in streptozotocin(STZ)-treated mice under the condition of hepatic regeneration.
Forty-three percent of pancreatic cancers were positive for pdx-1 expression and 57% were negative. Lymph node metastasis (p=0.02) and histological grade (p=0.04) were significantly correlated with pdx-1 expression. Patients with positive pdx-1 had a significantly worse prognosis than those with negative pdx-1 (p=0.02). Impor … More tantly, pdx-1 was an independent variable that affected overall survival (p=0.03). Pancreatic cancer cell lines showed no pdx-1 expression. There were no significant differences in cell proliferation or morphology between Ad-pdx-1 and Ad-lacZ infected Panc-1 cells. However, Ad-pdx-1 infected Panc-1 cells did show a significantly higher migration rate than Ad-lacZ infected Panc-1 cells. In experiments in mice, most hepatocytes of Ad-pdx-1 infected mice were positive for pdx-1 expression by immunohistochemistry. In non-treated mice, very few cells expressed insulin and other hormones. In contrast, insulin and somatostatin were expressed in STZ treated-mice, and the more cells expressed in STZ plus Hx-treated mice. Hyperglycemia was improved in STZ-treated mice and STZ plus Hx-treated mice. IRI of serum and liver extract was increased in STZ-treated mice and STZ plus Hx-treated mice. The insulin positive area of the liver in STZ plus Hx-treated mice was larger than that in non-treated and STZ-treated mice.
From the current project, re-expression of pdx-1 may represent a return to a more de-differentiated state by more aggressive pancreatic cancers, and may also represent an important new tumor marker for these aggressive cancers. The pdx-1 expression pattern that we observed also strongly suggests that specific embryonic differentiation pathways may be active in tumor progression of pancreatic cancers. From the latter part of the project, ectopic pdx-1 expression alone may be insufficient to induce insulin-producing cells in the liver. STZ-induced hyperglycemia plus partial hepatectomy that leads to diabetic state and hepatic regeneration may stimulate the transdifferentiation of liver cells into insulin-producing cells. Less

Report

(3 results)
  • 2004 Annual Research Report   Final Research Report Summary
  • 2003 Annual Research Report
  • Research Products

    (41 results)

All 2005 2004 2003 Other

All Journal Article (34 results) Publications (7 results)

  • [Journal Article] Analysis of E-, N-cadherin, α-, β- and γ-catenin expression in human pancreatic cancer2005

    • Author(s)
      Toyoda, E., Doi, R.
    • Journal Title

      Pancreas 30/2

      Pages: 168-173

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Impact of reconstruction methods on outcome of pancreatoduodenectomy in pancreatic cancer patients2005

    • Author(s)
      Doi, R.
    • Journal Title

      World Journal of Surgery (発表予定)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Regulation of the resistance to TRAIL-induced apoptosis as a new strategy to pancreatic cancer2005

    • Author(s)
      Mori, T., Doi, R.
    • Journal Title

      Surgery (発表予定)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Dual-phase (18)F-fluoro-2-deoxy-d-glucose positron emission tomography as a prognostic parameter in patients with pancreatic cancer.2005

    • Author(s)
      Lyshchik, A., Doi, R.
    • Journal Title

      Eur J Nucl Med Mol Imaging. 32(4)

      Pages: 389-397

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] New pancreas-preserving total duodenectomy technique.2005

    • Author(s)
      Imamura, M., Doi, R.
    • Journal Title

      World J Surg 29(2)

      Pages: 203-207

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Analysis of E-,N-cadherin,a-,b- and g-catenin expression in human pancreatic cancer.2005

    • Author(s)
      Toyoda, E., Doi, R.
    • Journal Title

      Pancreas 30(2)

      Pages: 168-173

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Impact of reconstruction methods on outcome of pancreatoduodenectomy in pancreatic cancer patients.2005

    • Author(s)
      Doi, R.
    • Journal Title

      World J Surg(Published online)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Analysis of E-, N-cadherin, α-,β- and γ-catenin expression in human pancreatic cancer2005

    • Author(s)
      Toyoda, E., Doi, R.
    • Journal Title

      Pancreas 30・2

      Pages: 168-173

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Impact of reconstruction methods on outcome of pancreatoduodenectomy in pancreatic cancer patients2005

    • Author(s)
      Doi, R.
    • Journal Title

      World Journal of Surgery (印刷中)

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Regulation of the resistance to TRAIL-induced apoptosis as a new strategy to pancreatic cancer2005

    • Author(s)
      Mori, T., Doi, R.
    • Journal Title

      Surgery (印刷中)

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Hepatic regeneration and enforced PDX-1 expression accelerate transdifferentiation in liver2004

    • Author(s)
      Koizumi, M., Doi, R.
    • Journal Title

      Surgery 136/2

      Pages: 353-361

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Chronic exposure of Transforming growth factor-beta 1 confers a more aggressive tumor phenotype through downregulation of p21WAF1/CIP1 in conditionally immortalized pancreatic epithelial cells2004

    • Author(s)
      Ito, D., Doi, R.
    • Journal Title

      Surgery 136/2

      Pages: 265-275

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] A randomized multicenter trial comparing resection and radiochemotherapy for resectable locally invasive pancreatic cancer2004

    • Author(s)
      Imamura, M., Doi, R.
    • Journal Title

      Surgery 136/5

      Pages: 1004-1012

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] CXCR4 antagonist inhibits stromal cell-derived factor 1-induced migration and invasion of human pancreatic cancer.2004

    • Author(s)
      Mori, T., Doi, R.
    • Journal Title

      Mol Cancer Ther 3(1)

      Pages: 29-37

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Metastin and its variant forms suppress migration of pancreatic cancer cells.2004

    • Author(s)
      Masui, T., Doi, R.
    • Journal Title

      Biochem Biophys Res Commun 315(1)

      Pages: 85-92

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Pancreatic endocrine tumor in Japan.2004

    • Author(s)
      Doi, R.
    • Journal Title

      Pancreas 28(3)

      Pages: 247-252

    • NAID

      10016168034

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Effects of preceding gastrectomy on the outcome of pancreatoduodenectomy.2004

    • Author(s)
      Doi, R.
    • Journal Title

      J.Gastrointest.Surg. 8(5)

      Pages: 575-579

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Conditional transformation of mouse pancreatic epithelial cells : An in vitro model for analysis of genetic events in pancreatocarcinogenesis.2004

    • Author(s)
      Koizumi, M., Doi, R.
    • Journal Title

      Biochem Biophys Res Commun 319(12)

      Pages: 612-621

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] N-cadherin expression and epithelial-mesenchymal transition in pancreatic carcinoma.2004

    • Author(s)
      Nakajima, S., Doi, R.
    • Journal Title

      Clin Cancer Res. 10(12)

      Pages: 4125-4133

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Surgical resection deteriorates gemcitabine-induced leukopenia in pancreatic cancer.2004

    • Author(s)
      Onoue, M, Doi, R.
    • Journal Title

      Int.J.Clin.Oncol. 9(3)

      Pages: 174-178

    • NAID

      50000009364

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Survivin expression is a prognostic marker in pancreatic cancer patients.2004

    • Author(s)
      Kami, K., Doi, R.
    • Journal Title

      Surgery 136(2)

      Pages: 347-352

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Hepatic regeneration and enforced PDX-1 expression accelerate transdifferentiation in liver.2004

    • Author(s)
      Koizumi, M., Doi, R.
    • Journal Title

      Surgery 136(2)

      Pages: 353-361

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Chronic exposure of Transforming growth factor-beta 1 confers a more aggressive tumor phenotype through downregulation of p21WAF1/CIP1 in conditionally immortalized pancreatic epithelial cells.2004

    • Author(s)
      Ito, D., Doi, R.
    • Journal Title

      Surgery 136(2)

      Pages: 265-275

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] A randomized multicenter trial comparing resection and radiochemotherapy for resectable locally invasive pancreatic cancer.2004

    • Author(s)
      Imamura, M., Doi, R.
    • Journal Title

      Surgery 136(5)

      Pages: 1004-1012

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Hepatic regeneration and enforced PDX-1 expression accelerate transdifferentiation in liver2004

    • Author(s)
      Koizumi, M., Doi, R.
    • Journal Title

      Surgery 136・2

      Pages: 353-361

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Chronic exposure of Transforming growth factor-beta 1 confers a more aggressive tumor phenotype through downregulation of p21WAF1/CIP1 in conditionally immortalized pancreatic epithelial cells2004

    • Author(s)
      Ito, D., Doi, R.
    • Journal Title

      Surgery 136・2

      Pages: 265-275

    • Related Report
      2004 Annual Research Report
  • [Journal Article] A randomized multicenter trial comparing resection and radiochemotherapy for resectable locally invasive pancreatic cancer2004

    • Author(s)
      Imamura, M., Doi, R.
    • Journal Title

      Surgery 136・5

      Pages: 1004-1012

    • Related Report
      2004 Annual Research Report
  • [Journal Article] All-trans retinoic acid induces differentiation of ducts and endocrine cells by mesenchymal/epithelial interactions in embryonic pancreas.2003

    • Author(s)
      Tulachan, S.S., Doi, R.
    • Journal Title

      Diabetes 52(1)

      Pages: 76-84

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Expression and Function of the Calcium-Sensing Receptor in Pancreatic Islets and Insulinoma Cells.2003

    • Author(s)
      Komoto, I., Doi, R.
    • Journal Title

      Pancreas Mar 26(2)

      Pages: 178-184

    • NAID

      10016164152

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] RECK expression in pancreatic cancer. Its correlation with lower invasiveness and better prognosis.2003

    • Author(s)
      Masui, T., Doi, R.
    • Journal Title

      Clin Cancer Res 9(5)

      Pages: 1779-1784

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Endogenous decoy receptor 3 blocks the growth inhibition signals mediated by Fas ligand in human pancreatic adenocarcinoma.2003

    • Author(s)
      Tsuji, S., Doi, R.
    • Journal Title

      Int J Cancer 106(1)

      Pages: 17-25

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Diagnosis of pancreatic cancer using fluorine-18 fluorodeoxyglucose positron emission tomography (FGD PET). Usefulness and limitation in "clinical reality".2003

    • Author(s)
      Higashi, T., Doi, R.
    • Journal Title

      Ann Nucl Med 17(4)

      Pages: 261-279

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Increased pdx-1 expression is associated with outcome in pancreatic cancer patients.2003

    • Author(s)
      Koizumi, M., Doi, R.
    • Journal Title

      Surgery 134(2)

      Pages: 260-266

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Hand-assisted laparoscopic resection of serous cystadenoma of the pancreas.2003

    • Author(s)
      Doi, R.
    • Journal Title

      Surg Endosc 17(12)

      Pages: 2028-2031

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Publications] Tulachan, S.S.: "All-trans retinoic acid induces differentiation of ducts and endocrine cells by mesenchymal/epithelial interactions in embryonic pancreas"Diabetes. 52・1. 76-84 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Hosotani, R.: "Expression of pancreatic duodenal hoemobox-1 in pancreatic islet neogenesis after surgical wrapping in rats"Surgery. 135・3. 297-306 (2004)

    • Related Report
      2003 Annual Research Report
  • [Publications] Koizumi, M.: "Increased PDX-1 expression is associated with outcome in patients with pancreatic cancer"Surgery. 134・2. 260-266 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Mori, T.: "CXCR4 antagonist inhibits stromal cell-derived factor 1 -induced migration and invasion of human pancreatic cancer"Molecular Cancer Therapeutics. 3・1. 29-37 (2004)

    • Related Report
      2003 Annual Research Report
  • [Publications] Higashi, T.: "Diagnosis of pancreatic cancer using fluorine-18 fluorodeoxyglucose positron emission tomography (FDG PET)-usefulness and limitations in "clinical reality""Annals of Nuclear Medicine. 17・4. 261-279 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Tsuji, S.: "Endogenous decoy receptor 3 blocks the growth inhibition signals mediated by Fas ligand in human pancreatic adenocarcinoma"International Journal of Cancer. 106・1. 17-25 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] 土井隆一郎: "先端医療シリーズ25[肝・胆・膵疾患の最新医療] 局所進行膵癌に対する治療法選択(分担)"先端医療技術研究所,東京. 449 (2003)

    • Related Report
      2003 Annual Research Report

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Published: 2003-04-01   Modified: 2016-04-21  

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