Smad4 Loss Synergizes with TGFα Overexpression in Promoting Pancreatic Metaplasia, PanIN Development, and Fibrosis

Abstract

AimsWhile overexpression of TGFα has been reported in human pancreatic ductal adenocarcinoma (PDAC), mice with overexpressed TGFα develop premalignant pancreatic acinar-to-ductal metaplasia (ADM) but not PDAC. TGF-β signaling pathway is pivotal to the development of PDAC and tissue fibrosis. Here we sought to investigate the interplay between TGFα and TGF-β signaling in pancreatic tumorigenesis and fibrosis, namely via Smad4 inactivation.MethodsThe MT-TGFα mouse was crossed with a new Smad4 conditional knock-out mouse (Smad4flox/flox;p48-Cre or S4) to generate Smad4flox/flox;MT-TGFα;p48-Cre (STP). After TGFα overexpression was induced with zinc sulfate water for eight months, the pancreata of the STP, MT-TGFα, 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 (α-SMA, Shh, COX-2, Muc6, Col1a1, and Ctgf) were performed by IHC and/or qRT-PCR.ResultsOur 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-TGFα 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.ConclusionWe 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.

Baicalein inhibits acinar‐to‐ductal metaplasia of pancreatic acinal cell AR42J via improving the inflammatory microenvironment

“…ADM was reproduced experimentally, in a caerulein‐induced pancreatitis mouse model, and in multiple transgenic mouse models (Grabliauskaite et al, ; Guerra et al, ; Lowenfels & Maisonneuve, ). Metaplastic duct cells are more likely accumulate gene mutations leading to cell cycle disruption, loss of tumor suppressor and DNA repair genes and to progress to pancreatic intraepithelial neoplasia (PanIN) first and invasive PDAC later (Garcia‐Carracedo et al, ; Shi et al, ). Many cytokines and activated signaling pathways may drive ADM in the inflammatory microenvironment.…”

“…ADM was reproduced experimentally, in a caerulein-induced pancreatitis mouse model, and in multiple transgenic mouse models (Grabliauskaite et al, 2015;Guerra et al, 2007;Lowenfels & Maisonneuve, 2006). Metaplastic duct cells are more likely accumulate gene mutations leading to cell cycle disruption, loss of tumor suppressor and DNA repair genes and to progress to pancreatic intraepithelial neoplasia (PanIN) first and invasive PDAC later (Garcia-Carracedo et al, 2015;Shi et al, 2009) showed that TNFα is overexpressed in pancreatitis and could induce ADM in acinar cells through NF-κB activation (Liou et al, 2013). Further, tumor cell-and macrophage-derived TNFα plays a profound role in pancreatitis and pancreas malignancy, and inhibition of TNFα had a protective effect (Egberts et al, 2008;Hughes et al, 1996).…”

Chemoprevention and Treatment of Pancreatic Cancer: Update and Review of the Literature

“…It occurs in 6-12 patients in 100,000 per year in the United States [1][2][3]. With advancing age, the risk of PDAC increases and the median age of diagnosis is 71 years [1].…”

New aspects of formation and progression of pancreatic fibrosis in pancreatitis

“…Согласно недавно проведенному исследованию, снижение активности SMAD-4 с чрезмерным повышением показателей TGF-α приводило к развитию фиброзных изменений в ткани поджелудочной железы [8]. Повышение активности TGF-β1 при воспалительных изменениях поджелудочной железы сопровождается нарушением регуляции микро РНК-217-SIRT1 с усилением развития фиброза в под желу доч ной железе [7].…”