title: Heparin-binding epidermal growth factor-like growth factor eliminates constraints on activated Kras to promote rapid onset of pancreatic neoplasia.
abstract: Pancreatic cancer remains as one of the most deadly cancers with few treatment options at late stages and little information about how it develops through earlier stages. Activating mutation of the Kras gene has been implicated in, but is not sufficient for, tumorigenesis. In mouse models of pancreatic cancer, loss of tumor suppressor genes in conjunction with Kras mutation leads to gradual stochastic acquisition of neoplastic precursors and carcinomas, whereas many cells remain phenotypically unaltered in younger mice. Here, we demonstrate that two oncogenic events, mutation of Kras and production of the growth factor heparin-binding epidermal growth factor-like growth factor (HB-EGF), are sufficient for rapid and complete neoplastic transformation of the exocrine pancreas. We found that macrophages are the major source of HB-EGF production in pancreatic cancer tissue samples, and that macrophages are present in high density and in close association with human pancreatic cancer lesions. In a mouse model, high macrophage density was observed at the earliest stages of neoplastic transformation. The consequence of elevated HB-EGF signaling was investigated without the confounding effects of other macrophage-produced factors via transgenic overexpression of the active form of HB-EGF. In this model, HB-EGF was sufficient to promote Kras-initiated tumorigenesis, inducing rapid and complete neoplastic transformation of the entire exocrine pancreas shortly after birth. HB-EGF overexpression and Kras(G12D) together, but neither alone, increased proliferation with increased cyclinD1 and decreased Cdkn2a/2d (p16/p19(Ink4A/Arf)). These findings establish the importance of oncogenic synergy in cancer initiation and promotion, and establish a molecular link between inflammation and the earliest stages of tumor induction.
authors: Division of Surgical Oncology, Vanderbilt University Medical Center, Nashville, TN, USA.
authors: K C
authors: KC
authors: Ray
authors: Division of Surgical Oncology, Vanderbilt University Medical Center, Nashville, TN, USA.
authors: M E
authors: ME
authors: Moss
authors: 1] Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA [2] Department of Cell and Developmental Biology, Vanderbilt University Medical Center, Nashville, TN, USA.
authors: J L
authors: JL
authors: Franklin
authors: Division of Surgical Oncology, Vanderbilt University Medical Center, Nashville, TN, USA.
authors: C J
authors: CJ
authors: Weaver
authors: Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA.
authors: J
authors: J
authors: Higginbotham
authors: Department of Pharmacological Sciences, Stony Brook University, Stony Brook, NY, USA.
authors: Y
authors: Y
authors: Song
authors: Department of Pathology, Vanderbilt University Medical Center, Nashville, TN, USA.
authors: F L
authors: FL
authors: Revetta
authors: Division of Surgical Oncology, Vanderbilt University Medical Center, Nashville, TN, USA.
authors: S A
authors: SA
authors: Blaine
authors: Division of Surgical Oncology, Vanderbilt University Medical Center, Nashville, TN, USA.
authors: L R
authors: LR
authors: Bridges
authors: Division of Surgical Oncology, Vanderbilt University Medical Center, Nashville, TN, USA.
authors: K E
authors: KE
authors: Guess
authors: 1] Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA [2] Department of Cell and Developmental Biology, Vanderbilt University Medical Center, Nashville, TN, USA.
authors: R J
authors: RJ
authors: Coffey
authors: 1] Department of Pharmacological Sciences, Stony Brook University, Stony Brook, NY, USA [2] Department of Research, Veterans Affairs Medical Center, Northport, NY, USA.
authors: H C
authors: HC
authors: Crawford
authors: Department of Pathology, Vanderbilt University Medical Center, Nashville, TN, USA.
authors: M K
authors: MK
authors: Washington
authors: 1] Division of Surgical Oncology, Vanderbilt University Medical Center, Nashville, TN, USA [2] Department of Cell and Developmental Biology, Vanderbilt University Medical Center, Nashville, TN, USA.
authors: A L
authors: AL
authors: Means
mesh_terms: D000818:Animals; D063646:Carcinogenesis / Q000235:genetics / Q000378:metabolism; D021441:Carcinoma, Pancreatic Ductal / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D049109:Cell Proliferation; D002478:Cells, Cultured; D066257:Heparin-binding EGF-like Growth Factor; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000502:physiology*; D008264:Macrophages / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D020125:Mutation, Missense; D010179:Pancreas / Q000473:pathology; D010190:Pancreatic Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational; D011518:Proto-Oncogene Proteins / Q000235:genetics* / Q000378:metabolism; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins / Q000235:genetics* / Q000378:metabolism
chemical_list: C587883:HBEGF protein, human; C587884:Hbegf protein, mouse; D066257:Heparin-binding EGF-like Growth Factor; D036341:Intercellular Signaling Peptides and Proteins; C117307:KRAS protein, human; D011518:Proto-Oncogene Proteins; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins
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