Gastroenterology
Volume 135, Issue 2 , Pages 621-631.e8 , August 2008

Hedgehog Signaling Is Required for Effective Regeneration of Exocrine Pancreas

  • Volker Fendrich

      Affiliations

    • Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland
    • Department of Surgery, Philipps-University Marburg, Marburg, Germany
  • ,
  • Farzad Esni

      Affiliations

    • Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania
  • ,
  • Maria Veronica R. Garay

      Affiliations

    • Barbara Davis Center for Childhood Diabetes, University of Colorado Health Sciences Center, Denver, Colorado
  • ,
  • Georg Feldmann

      Affiliations

    • Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland
  • ,
  • Nils Habbe

      Affiliations

    • Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland
  • ,
  • Jan Nygaard Jensen

      Affiliations

    • Barbara Davis Center for Childhood Diabetes, University of Colorado Health Sciences Center, Denver, Colorado
  • ,
  • Yuval Dor

      Affiliations

    • Department of Cellular Biochemistry and Human Genetics, The Hebrew University-Hadassah Medical School, Jerusalem, Israel
  • ,
  • Doris Stoffers

      Affiliations

    • Department of Medicine, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania
  • ,
  • Jan Jensen

      Affiliations

    • Barbara Davis Center for Childhood Diabetes, University of Colorado Health Sciences Center, Denver, Colorado
  • ,
  • Steven D. Leach

      Affiliations

    • Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland
    • The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine, Baltimore, Maryland
    • Corresponding Author InformationAddress requests for reprints to: Anirban Maitra, MBBS, Associate Professor of Pathology and Oncology, The Sol Goldman Pancreatic Cancer Research Center, CRB-2, Suite 345, Johns Hopkins University School of Medicine, 1550 Orleans Street, Baltimore, Maryland 21231. fax: (410) 614 0671 or Steven D. Leach, MD, Professor of Surgery, Oncology, and Cell Biology; The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine, 600 N. Wolfe St/Osler 603, Baltimore, Maryland 21287. fax: (410) 614 2913.
  • ,
  • Anirban Maitra

      Affiliations

    • Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland
    • The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine, Baltimore, Maryland
    • Corresponding Author InformationAddress requests for reprints to: Anirban Maitra, MBBS, Associate Professor of Pathology and Oncology, The Sol Goldman Pancreatic Cancer Research Center, CRB-2, Suite 345, Johns Hopkins University School of Medicine, 1550 Orleans Street, Baltimore, Maryland 21231. fax: (410) 614 0671 or Steven D. Leach, MD, Professor of Surgery, Oncology, and Cell Biology; The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine, 600 N. Wolfe St/Osler 603, Baltimore, Maryland 21287. fax: (410) 614 2913.

Received 4 July 2007 ,Accepted 10 April 2008.

References 

  1. Alison MR, Poulsom R, Forbes SJ. Update on hepatic stem cells. Liver. 2001;21:367–373
  2. Blau HM, Brazelton TR, Weimann JM. The evolving concept of a stem cell: entity or function?. Cell. 2001;105:829–841
  3. Dor Y, Brown J, Martinez OI, et al. Adult pancreatic β-cells are formed by self-duplication rather than stem-cell differentiation. Nature. 2004;429:41–46
  4. Jensen JN, Cameron E, Garay MV, et al. Recapitulation of elements of embryonic development in adult mouse pancreatic regeneration. Gastroenterology. 2005;128:728–741
  5. Desai BM, Oliver-Krasinski J, De Leon DD, et al. Preexisting pancreatic acinar cells contribute to acinar cell, but not islet β-cell, regeneration. J Clin Invest. 2007;117:971–977
  6. Means AL, Meszoely IM, Suzuki K, et al. Pancreatic epithelial plasticity mediated by acinar cell transdifferentiation and generation of nestin-positive intermediates. Development. 2005;132:3767–3776
  7. Adler G, Hupp T, Kern HF. Course and spontaneous regression of acute pancreatitis in the rat. Virchows Arch A Pathol Anat Histol. 1979;382:31–47
  8. Strobel O, Dor Y, Stirman A, et al. Beta cell transdifferentiation does not contribute to preneoplastic/metaplastic ductal lesions of the pancreas by genetic lineage tracing in vivo. Proc Natl Acad Sci U S A. 2007;104:4419–4424
  9. Apelqvist A, Ahlgren U, Edlund H. Sonic Hedgehog directs specialised mesoderm differentiation in the intestine and pancreas. Curr Biol. 1997;7:801–804
  10. Zhang Y, Kalderon D. Hedgehog acts as a somatic stem cell factor in the Drosophila ovary. Nature. 2001;410:599–604
  11. Machold R, Hayashi S, Rutlin M, et al. Sonic hedgehog is required for progenitor cell maintenance in telencephalic stem cell niches. Neuron. 2003;39:937–950
  12. Beachy PA, Karhadkar SS, Berman DM. Tissue repair and stem cell renewal in carcinogenesis. Nature. 2004;432:324–331
  13. Berman DM, Karhadkar SS, Maitra A, et al. Widespread requirement for Hedgehog ligand stimulation in growth of digestive tract tumours. Nature. 2003;425:846–851
  14. Karhadkar SS, Bova GS, Abdallah N, et al. Hedgehog signalling in prostate regeneration, neoplasia and metastasis. Nature. 2004;431:707–712
  15. Watkins DN, Berman DM, Burkholder SG, et al. Hedgehog signalling within airway epithelial progenitors and in small-cell lung cancer. Nature. 2003;422:313–317
  16. Kayed H, Kleeff J, Keleg S, et al. Distribution of Indian Hedgehog and its receptors patched and smoothened in human chronic pancreatitis. J Endocrinol. 2003;178:467–478
  17. Nakashima H, Nakamura M, Yamaguchi H, et al. Nuclear factor-κB contributes to Hedgehog signaling pathway activation through sonic Hedgehog induction in pancreatic cancer. Cancer Res. 2006;66:7041–7049
  18. Goodrich LV, Milenkovic L, Higgins KM, et al. Altered neural cell fates and medulloblastoma in mouse patched mutants. Science. 1997;277:1109–1113
  19. Hingorani SR, Petricoin EF, Maitra A, et al. Preinvasive and invasive ductal pancreatic cancer and its early detection in the mouse. Cancer Cell. 2003;4:437–450
  20. Stanger BZ, Stiles B, Lauwers GY, et al. Pten constrains centroacinar cell expansion and malignant transformation in the pancreas. Cancer Cell. 2005;8:185–195
  21. Esni F, Stoffers DA, Takeuchi T, et al. Origin of exocrine pancreatic cells from nestin-positive precursors in developing mouse pancreas. Mech Dev. 2004;121:15–25
  22. Prasad NB, Biankin AV, Fukushima N, et al. Gene expression profiles in pancreatic intraepithelial neoplasia reflect the effects of Hedgehog signaling on pancreatic ductal epithelial cells. Cancer Res. 2005;65:1619–1626
  23. Chen JK, Taipale J, Cooper MK, et al. Inhibition of Hedgehog signaling by direct binding of cyclopamine to Smoothened. Genes Dev. 2002;16:2743–2748
  24. Song SY, Gannon M, Washington MK, et al. Expansion of Pdx1-expressing pancreatic epithelium and islet neogenesis in transgenic mice overexpressing transforming growth factor α. Gastroenterology. 1999;117:1416–1426
  25. Ramalho-Santos M, Melton DA, McMahon AP. Hedgehog signals regulate multiple aspects of gastrointestinal development. Development. 2000;127:2763–2772
  26. Forbes AJ, Lin H, Ingham PW, et al. Hedgehog is required for the proliferation and specification of ovarian somatic cells prior to egg chamber formation in Drosophila. Development. 1996;122:1125–1135
  27. Echeverri K, Tanaka EM. Ectoderm to mesoderm lineage switching during axolotl tail regeneration. Science. 2002;298:1993–1996
  28. Schnapp E, Kragl M, Rubin L, et al. Hedgehog signaling controls dorsoventral patterning, blastema cell proliferation and cartilage induction during axolotl tail regeneration. Development. 2005;132:3243–3253
  29. Tsonis PA, Vergara MN, Spence JR, et al. A novel role of the Hedgehog pathway in lens regeneration. Dev Biol. 2004;267:450–461
  30. Wang RN, Rehfeld JF, Nielsen FC, et al. Expression of gastrin and transforming growth factor-α during duct to islet cell differentiation in the pancreas of duct-ligated adult rats. Diabetologia. 1997;40:887–893
  31. Menke A, Yamaguchi H, Giehl K, et al. Hepatocyte growth factor and fibroblast growth factor 2 are overexpressed after cerulein-induced acute pancreatitis. Pancreas. 1999;18:28–33
  32. Miyamoto Y, Maitra A, Ghosh B, et al. Notch mediates TGF-α-induced changes in epithelial differentiation during pancreatic tumorigenesis. Cancer Cell. 2003;3:565–576
  33. Minami K, Okuno M, Miyawaki K, et al. Lineage tracing and characterization of insulin-secreting cells generated from adult pancreatic acinar cells. Proc Natl Acad Sci U S A. 2005;102:15116–15121
  34. Crawford HC, Scoggins CR, Washington MK, et al. Matrix metalloproteinase-7 is expressed by pancreatic cancer precursors and regulates acinar-to-ductal metaplasia in exocrine pancreas. J Clin Invest. 2002;109:1437–1444
  35. Hruban RH, Adsay NV, Albores-Saavedra J, et al. Pathology of genetically engineered mouse models of pancreatic exocrine cancer: consensus report and recommendations. Cancer Res. 2006;66:95–106
  36. Thayer SP, di Magliano MP, Heiser PW, et al. Hedgehog is an early and late mediator of pancreatic cancer tumorigenesis. Nature. 2003;425:851–856
  37. Feldmann G, Dhara S, Fendrich V, et al. Blockade of Hedgehog signaling inhibits pancreatic cancer invasion and metastases: a new paradigm for combination therapy in solid cancers. Cancer Res. 2007;67:2187–2196
  38. Morton JP, Mongeau ME, Klimstra DS, et al. Sonic Hedgehog acts at multiple stages during pancreatic tumorigenesis. Proc Natl Acad Sci U S A. 2007;104:5103–5108
  39. Lowenfels AB, Maisonneuve P. Epidemiology and risk factors for pancreatic cancer. Best Pract Res Clin Gastroenterol. 2006;20:197–209

 Supported by NIH grants CA113669 and DK072532 and the Sol Goldman Pancreatic Cancer Research Center (to A.M.); NIH grants DK61215 and DK56211 and the Paul Neumann Professorship in Pancreatic Cancer Research (to S.D.L.); a fellowship grant within the Postdoctoral Program of the German Academic Exchange Service (DAAD; to G.F.); the Barbara S. Goodman Pancreatic Cancer Career Development Award of the Israel Cancer Research Fund (to Y.D.); and, for mouse husbandry costs, by funds from a Mouse Models of Human Cancer Consortium grant to Robert J. Coffey at Vanderbilt University (U01CA084239).

 Conflicts of interest: The authors declare no competing financial conflicts of interest.

 V.F. and F.E. contributed equally to this work.

 The S.D.L. and A.M. laboratories contributed equally to this work.

 J.J.'s present address is Department of Stem Cell Biology and Regenerative Medicine, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio.

PII: S0016-5085(08)00640-9

doi: 10.1053/j.gastro.2008.04.011

Gastroenterology
Volume 135, Issue 2 , Pages 621-631.e8 , August 2008