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Animal Modeling of Pancreatitis-to-Cancer Progression

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Pancreatic Cancer

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Abstract

Inflammatory diseases are the most common conditions of the exocrine pancreas. Chronic pancreatitis is often the result of recurrent bouts of acute pancreatitis and is a risk factor for pancreatic cancer. There has been a long interest in modeling the pathophysiological relationship between chronic pancreatitis and cancer and the recent development of genetic mouse models of pancreatic diseases has accelerated the discovery of mechanistic insights. The current paradigm proposes that the inability of normal pancreatic cells to recover from injury establishes a biological landscape that promotes cancer development. Multiple types of mechanisms concur in this process, in which both epithelial and nonepithelial cells participate, leading to persistent inability of epithelial cells to restore their differentiation programs. Developmental pathways involved in pancreatic differentiation are subverted to maintain cellular phenotypes that promote signaling from mutant KRAS, preneoplasia, and neoplasia. Downstream from KRAS, and in parallel with it, tyrosine kinase receptors, the MAPK, PI3K, NF-KB, and STAT pathways, and the mechanisms that control senescence and autophagy, contribute to the emergence of transformed clones. These signaling pathways, whose activity is modulated through complex cross-talks between epithelial, mesenchymal, and inflammatory cells, play crucial roles in the pancreatitis-to-cancer progression and provide opportunities for intervention in high-risk patients.

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Abbreviations

ADM:

Acinar-to-ductal metaplasia

AP:

Acute pancreatitis

CCK:

Cholecystokinin

CCKR:

CCK receptor

CDE:

Choline-deficient, ethionine-supplemented diet

CFTR:

Cystic fibrosis transmembrane conductance regulator

CP:

Chronic pancreatitis

ECM:

Extracellular matrix

EGF:

Epidermal growth factor

ER:

Endoplasmic reticulum

EUS-FNA:

Endoscopic ultrasound-guided fine needle aspiration

GEMM:

Genetically engineered mouse models

IPMN:

Intraductal papillary mucinous neoplasm

JAK:

Janus-activated kinase

LPS:

Lipopolysaccharide

PanIN:

Pancreatic intraepithelial neoplasia

PDAC:

Pancreatic ductal adenocarcinoma

PDL:

Pancreatic duct ligation

PSC:

Pancreatic stellate cells

TGF-β:

Transforming growth factor beta

TNF-α:

Tumor necrosis factor alpha

WT:

Wild type

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Authors and Affiliations

  1. Cancer Progression and Metastasis Group, Institute for Cancer Research, Medical University Wien, Vienna, Austria

    Paola Martinelli

  2. Epithelial Carcinogenesis Group, Spanish National Cancer Research Centre, CNIO, Madrid, Spain

    Francisco X. Real

  3. Departament de Ciències Experimentals i de la Salut, Universitat Pompeu Fabra, Barcelona, Spain

    Francisco X. Real

  4. CIBERONC, Madrid, Spain

    Francisco X. Real

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  1. Paola Martinelli
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  2. Francisco X. Real
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Correspondence to Paola Martinelli .

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Editors and Affiliations

  1. Department of General Surgery, University Hospital Heidelberg Department of General Surgery, Heidelberg, Germany

    John Neoptolemos

  2. Rochester, Minnesota, USA

    Raul Urrutia

  3. Dept. Gastrointestinal Medical Onco, Duke University Medical Center Dept. Gastrointestinal Medical Onco, Durham, North Carolina, USA

    James Abbruzzese

  4. Heidelberg, Germany

    Markus W. Büchler

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Martinelli, P., Real, F.X. (2018). Animal Modeling of Pancreatitis-to-Cancer Progression. In: Neoptolemos, J., Urrutia, R., Abbruzzese, J., Büchler, M. (eds) Pancreatic Cancer. Springer, New York, NY. https://doi.org/10.1007/978-1-4939-6631-8_66-1

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