title: Concurrent PEDF deficiency and Kras mutation induce invasive pancreatic cancer and adipose-rich stroma in mice.
abstract: OBJECTIVE
  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-Kras(G12D) mouse model of non-invasive cystic papillary neoplasms.
  
  
  RESULTS
  EL-Kras(G12D)/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-Kras(G12D)/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.
authors.affiliation: Department of Surgery, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA. p-grippo@northwestern.edu
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Grippo
authors.forename: Philip S
authors.initials: PS
authors.lastname: Fitchev
authors.forename: David J
authors.initials: DJ
authors.lastname: Bentrem
authors.forename: Laleh G
authors.initials: LG
authors.lastname: Melstrom
authors.forename: Surabhi
authors.initials: S
authors.lastname: Dangi-Garimella
authors.forename: Seth B
authors.initials: SB
authors.lastname: Krantz
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Heiferman
authors.forename: Chuhan
authors.initials: C
authors.lastname: Chung
authors.forename: Kevin
authors.initials: K
authors.lastname: Adrian
authors.forename: Mona L
authors.initials: ML
authors.lastname: Cornwell
authors.forename: Jan B
authors.initials: JB
authors.lastname: Flesche
authors.forename: Sambasiva M
authors.initials: SM
authors.lastname: Rao
authors.forename: Mark S
authors.initials: MS
authors.lastname: Talamonti
authors.forename: Hidayatullah G
authors.initials: HG
authors.lastname: Munshi
authors.forename: Susan E
authors.initials: SE
authors.lastname: Crawford
mesh_terms: D052438:Adipocytes, White / Q000378:metabolism / Q000473:pathology*; D050154:Adiposity; D000818:Animals; D014408:Biomarkers, Tumor / Q000172:deficiency* / Q000378:metabolism; D015153:Blotting, Western; D021441:Carcinoma, Pancreatic Ductal / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D005136:Eye Proteins; D005819:Genetic Markers; D006801:Humans; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D009154:Mutation; D009361:Neoplasm Invasiveness; D009414:Nerve Growth Factors / Q000172:deficiency*; D010179:Pancreas / Q000378:metabolism / Q000473:pathology; D010190:Pancreatic Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics*; D060888:Real-Time Polymerase Chain Reaction; D015843:Serpins / Q000172:deficiency*; D017154:Stromal Cells / Q000378:metabolism / Q000473:pathology; D000099174:Pigment Epithelium-Derived Factor
chemical_list: D014408:Biomarkers, Tumor; D005136:Eye Proteins; D005819:Genetic Markers; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9; D009414:Nerve Growth Factors; D016283:Proto-Oncogene Proteins p21(ras); D015843:Serpins; D000099174:Pigment Epithelium-Derived Factor; C495971:Hras protein, mouse