Heparin-binding epidermal growth factor-like growth factor eliminates constraints on activated Kras to promote rapid onset of pancreatic neoplasia

K. C. Ray, M. E. Moss, J. L. Franklin, C. J. Weaver, J. Higginbotham, Y. Song, F. L. Revetta, S. A. Blaine, L. R. Bridges, K. E. Guess, R. J. Coffey, H. C. Crawford, M. K. Washington, A. L. Means

Research output: Contribution to journalArticlepeer-review

24 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)823-831
Number of pages9
JournalOncogene
Volume33
Issue number7
DOIs
StatePublished - Feb 13 2014

Keywords

  • EGFR
  • inflammation
  • pancreatic ductal adenocarcinoma
  • transdifferentiation

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cancer Research

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