Origin of pancreatic ductal adenocarcinoma from atypical flat lesions: a comparative study in transgenic mice and human tissues

• Published in: The Journal of pathology Vol. 226; no. 5; pp. 723 - 734
• Main Authors: Aichler, Michaela, Seiler, Christopher, Tost, Monica, Siveke, Jens, Mazur, Pawel K, Da Silva-Buttkus, Patricia, Bartsch, Detlef K, Langer, Peter, Chiblak, Sara, Dürr, Anna, Höfler, Heinz, Klöppel, Günter, Müller-Decker, Karin, Brielmeier, Markus, Esposito, Irene
• Format: Journal Article
• Language: English
• Published: Chichester, UK John Wiley & Sons, Ltd 01.04.2012; Wiley
• Subjects: Animals; Biological and medical sciences; Biomarkers, Tumor - genetics; Biomarkers, Tumor - metabolism; Carcinoma in Situ - genetics; Carcinoma in Situ - metabolism; Carcinoma in Situ - pathology; Carcinoma, Pancreatic Ductal - genetics; Carcinoma, Pancreatic Ductal - metabolism; Carcinoma, Pancreatic Ductal - pathology; Cell Differentiation; Cell Proliferation; Cell Transformation, Neoplastic - genetics; Cell Transformation, Neoplastic - metabolism; Cell Transformation, Neoplastic - pathology; familial pancreatic cancer; Gastroenterology. Liver. Pancreas. Abdomen; Gene Expression Regulation, Neoplastic; Genes, ras; Genetic Predisposition to Disease; Heredity; Humans; Immunohistochemistry; Investigative techniques, diagnostic techniques (general aspects); Kras; Liver. Biliary tract. Portal circulation. Exocrine pancreas; Medical sciences; Metaplasia; Mice; Mice, Inbred C57BL; Mice, Transgenic; mouse model; Neoplasms, Experimental - genetics; Neoplasms, Experimental - metabolism; Neoplasms, Experimental - pathology; Pancreatic Neoplasms - genetics; Pancreatic Neoplasms - metabolism; Pancreatic Neoplasms - pathology; PanIN; Pathology. Cytology. Biochemistry. Spectrometry. Miscellaneous investigative techniques; Pedigree; Phenotype; Precancerous Conditions - genetics; Precancerous Conditions - metabolism; Precancerous Conditions - pathology; precursor lesions; Transcription Factors - genetics; tubular complexes; Tumors; Animal model; Transgenic animal; Precursor; K ras Gene; Tissue; precursor lesions; Pancreas cancer; Familial cancer; Kras; Protooncogene; Pancreatic disease; Human; mouse model; Rodentia; Pancreas ductal adenocarcinoma; Malignant tumor; Complexes; Vertebrata; Anatomic pathology; Mammalia; Mouse; C-Onc gene; PanIN; Digestive diseases; Atypical; Lesion; familial pancreatic cancer; tubular complexes; Comparative study; Cancer
• ISSN: 0022-3417; 1096-9896; 1096-9896
• DOI: 10.1002/path.3017

Pancreatic ductal adenocarcinoma (PDAC) and its precursor lesions, pancreatic intraepithelial neoplasia (PanIN), display a ductal phenotype. However, there is evidence in genetically defined mouse models for PDAC harbouring a mutated kras under the control of a pancreas‐specific promoter that ductal cancer might arise in the centroacinar‐acinar region, possibly through a process of acinar‐ductal metaplasia (ADM). In order to further elucidate this model of PDAC development, an extensive expression analysis and molecular characterization of the putative and already established (PanIN) precursor lesions were performed in the Kras$^{G{\it{\bf{12}}}D/+}$ ; Ptf1a‐Cre$^{ex{\it{\bf{1}}}/+}$ mouse model and in human tissues, focusing on lineage markers, developmental pathways, cell cycle regulators, apomucins, and stromal activation markers. The results of this study show that areas of ADM are very frequent in the murine and human pancreas and represent regions of increased proliferation of cells with precursor potential. Moreover, atypical flat lesions originating in areas of ADM are the most probable precursors of PDAC in the Kras$^{G{\it{\bf{12}}}D/+}$; Ptf1a‐Cre$^{ex{\it{\bf{1}}}/+}$ mice and similar lesions were also found in the pancreas of three patients with a strong family history of PDAC. In conclusion, PDAC development in Kras$^{G{\it{\bf{12}}}D/+}$; Ptf1a‐Cre$^{ex{\it{\bf{1}}}/+}$ mice starts from ADM and a similar process might also take place in patients with a strong family history of PDAC. Copyright © 2012 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.