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Concurrent PEDF deficiency and Kras mutation induce invasive pancreatic cancer and adipose-rich stroma in mice
  1. Paul J Grippo1,
  2. Philip S Fitchev2,
  3. David J Bentrem1,
  4. Laleh G Melstrom1,
  5. Surabhi Dangi-Garimella3,
  6. Seth B Krantz1,
  7. Michael J Heiferman1,
  8. Chuhan Chung4,
  9. Kevin Adrian1,
  10. Mona L Cornwell2,
  11. Jan B Flesche5,
  12. Sambasiva M Rao6,
  13. Mark S Talamonti2,
  14. Hidayatullah G Munshi3,
  15. Susan E Crawford2
  1. 1Department of Surgery, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA
  2. 2Department of Surgery, NorthShore University Research Institute, Evanston, Illinois, USA
  3. 3Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA
  4. 4Section of Digestive Diseases, Department of Medicine, Yale University School of Medicine, West Haven, Connecticut, USA
  5. 5The Medical School at Ruprecht-Karls-Universität Heidelberg, Heidelberg, Germany
  6. 6Department of Pathology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA
  1. Correspondence to Dr Paul Grippo, Robert H Lurie Comprehensive Cancer Center, Northwestern University, 303 E. Superior St., Lurie 3-105, Chicago, IL 60611; p-grippo{at}northwestern.edu

Abstract

Background and aims Pigment epithelium-derived factor (PEDF), a non-inhibitory SERPIN with potent antiangiogenic activity, has been recently implicated in metabolism and adipogenesis, both of which are known to influence pancreatic cancer progression. Increased pancreatic fat in human pancreatic tumour correlates with greater tumour dissemination while PEDF deficiency in mice promotes pancreatic hyperplasia and visceral obesity. Oncogenic Ras, the most common mutation in pancreatic ductal adenocarcinoma (PDAC), has similarly been shown to promote adipogenesis and premalignant lesions.

Methods In order to determine whether concurrent loss of PEDF is sufficient to promote adipogenesis and tumorigenesis in the pancreas, the authors ablated PEDF in an EL-KrasG12D mouse model of non-invasive cystic papillary neoplasms.

Results EL-KrasG12D/PEDF deficient mice developed invasive PDAC associated with enhanced matrix metalloproteinase (MMP)-2 and MMP-9 expression and increased peripancreatic fat with adipocyte hypertrophy and intrapancreatic adipocyte infiltration (pancreatic steatosis). In support of increased adipogenesis, the stroma of the pancreas of EL-KrasG12D/PEDF deficient mice demonstrated higher tissue levels of two lipid droplet associated proteins, tail-interacting protein 47 (TIP47, perilipin 3) and adipose differentiation-related protein (ADRP, Pperilipin 2), while adipose triglyceride lipase, a key factor in lipolysis, was decreased. In patients with PDAC, both tissue and serum levels of PEDF were decreased, stromal TIP47 expression was higher and the tissue VEGF to PEDF ratio was increased (p<0.05).

Conclusions These data highlight the importance of lipid metabolism in the tumour microenvironment and identify PEDF as a critical negative regulator of both adiposity and tumour invasion in the pancreas.

  • Pancreatic cancer
  • PEDF
  • adipogenesis
  • TIP47
  • angiogenesis
  • pancreas
  • pancreatic disease
  • pancreatic fibrosis
  • pancreatic tumours
  • abdominal surgery
  • surgical oncology
  • cancer
  • endothelial cells
  • fatty liver
  • hepatocellular carcinoma
  • matrix metalloproteinase

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Footnotes

  • An additional figure is published online only. To view this file please visit the journal online (http://dx.doi.org/10.1136/gutjnl-2011-300821).

  • Funding The research described herein was generously supported by funds provided by the Barnum Foundation and Zell Family Foundation at the Northwestern University, the Nathan and Isabel Miller Family Foundation, the IDP Foundation, NIH R01-CA126888 (HGM) and NIH R01-CA64239 (SEC).

  • Competing interests None.

  • Patient consent The Northwestern University IRB has consent forms signed by patients/guardians for the use of blood and tissue samples.

  • Ethics approval Northwestern University IRB.

  • Provenance and peer review Not commissioned; externally peer reviewed.

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