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Garcia-Carracedo, Dario; Yu, Chih-Chieh; Akhavan, Nathan; Fine, Stuart A.; Schönleben, Frank; Maehara, Naoki; Karg, Dillon C.; Xie, Chuangao; Qiu, Wanglong; Fine, Robert L.; Remotti, Helen E.; Su, Gloria H. (2015): Smad4 Loss Synergizes with TGF alpha Overexpression in Promoting Pancreatic Metaplasia, PanIN Development, and Fibrosis.
In: PLOS ONE 10(3), e0120851
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Abstract

Aims While overexpression of TGF alpha has been reported in human pancreatic ductal adenocarcinoma (PDAC), mice with overexpressed TGF alpha develop premalignant pancreatic acinar-to-ductal metaplasia (ADM) but not PDAC. TGF-beta signaling pathway is pivotal to the development of PDAC and tissue fibrosis. Here we sought to investigate the interplay between TGFa and TGF-beta signaling in pancreatic tumorigenesis and fibrosis, namely via Smad4 inactivation. Methods The MT-TGF alpha mouse was crossed with a new Smad4 conditional knock-out mouse (Smad4(flox/flox); p48-Cre or S4) to generate Smad4(flox/flox); MT-TGF alpha; p48-Cre (STP). After TGFa overexpression was induced with zinc sulfate water for eight months, the pancreata of the STP, MT-TGF alpha, and S4 mice were examined for tumor development and fibrotic responses. PanIN lesions and number of ducts were counted, and proliferation was measured by Ki67 immunohistochemistry (IHC). Qualitative analysis of fibrosis was analyzed by Trichrome Masson and Sirius Red staining, while vimentin was used for quantification. Expression analyses of fibrosis, pancreatitis, or desmoplasia associated markers (alpha-SMA, Shh, COX-2, Muc6, Col1a1, and Ctgf) were performed by IHC and/or qRT-PCR. Results Our STP mice exhibited advanced ADM, increased fibrosis, increased numbers of PanIN lesions, overexpression of chronic pancreatitis-related marker Muc6, and elevated expression of desmoplasia-associated marker Col1A1, compared to the MT-TGFa mice. The inactivation of Smad4 in the exocrine compartment was responsible for both the enhanced PanIN formation and fibrosis in the pancreas. The phenotype of the STP mice represents a transient state from ADMs to PanINs, closely mimicking the interface area seen in human chronic pancreatitis associated with PDAC. Conclusion We have documented a novel mouse model, the STP mice, which displayed histologic presentations reminiscent to those of human chronic pancreatitis with signs of early tumorigenesis. The STP mice could be a suitable animal model for interrogating the transition of chronic pancreatitis to pancreatic cancer.