Concomitant pancreatic activation of Kras(G12D) and Tgfa results in cystic papillary neoplasms reminiscent of human IPMN.
Growth factors have been implicated in pancreatic carcinogenesis. In this study we analyzed the effect of Tgfa overexpression in addition to mutant Kras(G12D) by crossing Elastase-Tgfa mice with p48(+/Cre);Kras(+/LSL-G12D) mice. We show that concomitant expression of TGFalpha and Kras(G12D) accelerates the progression of mPanIN lesions to metastatic pancreatic cancer and leads to the development of cystic papillary lesions resembling human intraductal papillary mucinous neoplasms (IPMN). Microarray data in mice revealed an IPMN signature and IPMNs expressed MUC1 and MUC5AC but not MUC2, similar to human pancreatobiliary IPMNs. Invasive ductal adenocarcinoma developed from PanINs and IPMNs, suggesting precursor lines for both lesion types in this model. In conclusion, Egfr signaling in synergy with oncogenic Kras may be a prerequisite for IPMN development and progression to pancreatic cancer.
Siveke
Jens T
JT
Department of Internal Medicine, Technical University of Munich, D-81675 Munich, Germany.
Einwächter
Henrik
H
Sipos
Bence
B
Lubeseder-Martellato
Clara
C
Klöppel
Günter
G
Schmid
Roland M
RM
D000818:Animals; D021441:Carcinoma, Pancreatic Ductal / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D002454:Cell Differentiation; D011905:Genes, ras; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation; D015689:Oncogene Protein p21(ras) / Q000235:genetics / Q000378:metabolism*; D010196:Pancreatic Elastase / Q000235:genetics; D010190:Pancreatic Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D011230:Precancerous Conditions / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D011401:Promoter Regions, Genetic; D015398:Signal Transduction; D016211:Transforming Growth Factor alpha / Q000235:genetics / Q000378:metabolism*