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

Oncogene volume 33, pages 823–831 (2014)Cite this article

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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 KrasG12D together, but neither alone, increased proliferation with increased cyclinD1 and decreased Cdkn2a/2d (p16/p19Ink4A/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.

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Acknowledgements

We thank R Daniel Beauchamp for support and helpful discussions, Steven D Leach, Barbara Fingleton and Harold L Moses for critically reading the manuscript, and Heidi Moreno and Christian Kis for technical assistance. This work was supported by NIH grants CA123061 (ALM), P30DK058404 and P50CA095103 (MKW), CA136754, VA Merit, and the Knapp Chair in Pancreatic Cancer Research (HCC).

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Authors and Affiliations

  1. Division of Surgical Oncology, Vanderbilt University Medical Center, Nashville, TN, USA

    K C Ray, M E Moss, C J Weaver, S A Blaine, L R Bridges, K E Guess & A L Means

  2. Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA

    J L Franklin, J Higginbotham & R J Coffey

  3. Department of Cell and Developmental Biology, Vanderbilt University Medical Center, Nashville, TN, USA

    J L Franklin, R J Coffey & A L Means

  4. Department of Pharmacological Sciences, Stony Brook University, Stony Brook, NY, USA

    Y Song & H C Crawford

  5. Department of Pathology, Vanderbilt University Medical Center, Nashville, TN, USA

    F L Revetta & M K Washington

  6. Department of Research, Veterans Affairs Medical Center, Northport, NY, USA

    H C Crawford

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Correspondence to A L Means.

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Ray, K., Moss, M., Franklin, J. et al. Heparin-binding epidermal growth factor-like growth factor eliminates constraints on activated Kras to promote rapid onset of pancreatic neoplasia. Oncogene 33, 823–831 (2014). https://doi.org/10.1038/onc.2013.3

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