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Gastroenterology. 2014 Nov;147(5):1119-33.e4. doi: 10.1053/j.gastro.2014.08.002. Epub 2014 Aug 12.

Nicotine promotes initiation and progression of KRAS-induced pancreatic cancer via Gata6-dependent dedifferentiation of acinar cells in mice.

Author information

  • 1Stem Cells and Cancer Group, Spanish National Cancer Research Centre (CNIO), Madrid, Spain.
  • 2Comparative Pathology Core Unit, Spanish National Cancer Research Centre (CNIO), Madrid, Spain.
  • 3Epithelial Carcinogenesis Group, Spanish National Cancer Research Centre (CNIO), Madrid, Spain.
  • 4Department of Gastroenterology, Endocrinology, Metabolism and Infectiology, University of Marburg, Marburg, Germany.
  • 5Instituto Teófilo Hernando, Facultad de Medicina, Universidad Autónoma de Madrid, Madrid, Spain.
  • 6Experimental Oncology Group, Spanish National Cancer Research Centre (CNIO), Madrid, Spain.
  • 7Department of Internal Medicine I, Ulm University, Ulm, Germany.
  • 8Stem Cells and Cancer Group, Spanish National Cancer Research Centre (CNIO), Madrid, Spain. Electronic address: bruno.sainz@uam.es.
  • 9Stem Cells and Cancer Group, Spanish National Cancer Research Centre (CNIO), Madrid, Spain; Centre for Stem Cells in Cancer & Ageing, Barts Cancer Institute, Queen Mary University of London, UK. Electronic address: c.heeschen@qmul.ac.uk.

Abstract

BACKGROUND & AIMS:

Although smoking is a leading risk factor for pancreatic ductal adenocarcinoma (PDAC), little is known about the mechanisms by which smoking promotes initiation or progression of PDAC.

METHODS:

We studied the effects of nicotine administration on pancreatic cancer development in Kras(+/LSLG12Vgeo);Elas-tTA/tetO-Cre (Ela-KRAS) mice, Kras(+/LSLG12D);Trp53+/LSLR172H;Pdx-1-Cre (KPC) mice (which express constitutively active forms of KRAS), and C57/B6 mice. Mice were given nicotine for up to 86 weeks to produce blood levels comparable with those of intermediate smokers. Pancreatic tissues were collected and analyzed by immunohistochemistry and reverse transcriptase polymerase chain reaction; cells were isolated and assayed for colony and sphere formation and gene expression. The effects of nicotine were also evaluated in primary pancreatic acinar cells isolated from wild-type, nAChR7a(-/-), Trp53(-/-), and Gata6(-/-);Trp53(-/-) mice. We also analyzed primary PDAC cells that overexpressed GATA6 from lentiviral expression vectors.

RESULTS:

Administration of nicotine accelerated transformation of pancreatic cells and tumor formation in Ela-KRAS and KPC mice. Nicotine induced dedifferentiation of acinar cells by activating AKT-ERK-MYC signaling; this led to inhibition of Gata6 promoter activity, loss of GATA6 protein, and subsequent loss of acinar differentiation and hyperactivation of oncogenic KRAS. Nicotine also promoted aggressiveness of established tumors as well as the epithelial-mesenchymal transition, increasing numbers of circulating cancer cells and their dissemination to the liver, compared with mice not exposed to nicotine. Nicotine induced pancreatic cells to acquire gene expression patterns and functional characteristics of cancer stem cells. These effects were markedly attenuated in K-Ras(+/LSL-G12D);Trp53(+/LSLR172H);Pdx-1-Cre mice given metformin. Metformin prevented nicotine-induced pancreatic carcinogenesis and tumor growth by up-regulating GATA6 and promoting differentiation toward an acinar cell program.

CONCLUSIONS:

In mice, nicotine promotes pancreatic carcinogenesis and tumor development via down-regulation of Gata6 to induce acinar cell dedifferentiation.

Copyright © 2014 AGA Institute. Published by Elsevier Inc. All rights reserved.

KEYWORDS:

Metastasis; Mouse Model; Pancreas; Progenitor Cells

PMID:
25127677
[PubMed - indexed for MEDLINE]

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