Expression of CCK2 receptors in the murine pancreas: Proliferation, transdifferentiation of acinar cells, and neoplasia

Clerc, Pascal; Leung–Theung–Long, Stéphane; Wang, Yichen; Dockray, Graham J.; Bouisson, M; Delisle, Marie–Bernadette; Vaysse, Nicole; Pradayrol, Lucien; Fourmy, Daniel; Dufresne, Marlène

doi:10.1053/gast.2002.30984

Cited by 73 publications

(70 citation statements)

References 41 publications

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“…41,42 In the TGF alpha and ElasCCK2 transgenic mice models, substitution of acinar tissue by duct-like cells is associated with an increased susceptibility to develop pancreatic tumors. 19,36 This process has also been reported to occur in experimental pancreatic cancer in rats. 31 The fact that altering epithelial differentiation can promote formation of precursor lesions was further demonstrated in the TGF alpha transgenic model with accelerated tumor formation upon losing p53.…”

Section: Discussionmentioning

confidence: 67%

“…Indeed, based on previous demonstration that acinar expression of the CCK2 receptor is involved in the development of tumors, we hypothesized a role in initiation phases of carcinogenesis and submitted transgenic ElasCCK2 and control mice to treatment with a procarcinogen, azaserine. 19 Azaserine was chosen because it specifically targets acini owing to the presence of carcinogen-metabolizing enzymes in these cells thus allowing the study of its cumulative effects with acinar CCK2 receptor expression. 25,26 Moreover, to realize a kinetic analysis and identify initial mechanisms, surveys were sequentially performed in transgenic and control mice at different time points following carcinogen treatment.…”

Section: Discussionmentioning

confidence: 99%

“…32 Moreover, we demonstrate the presence of gastrin in tubular complexes raising the possibility of an autocrine loop that contributes to tubular complexes proliferation since CCK2 receptor is expressed in these structures. 19,33 A paracrine loop taking place in ElasCCK2 pancreas with continuous local stimulation of transgenic acinar CCK2 receptor is also highly likely to play a role in alteration of normal acinar growth, increased proliferation and development of tubular complexes as well as adenomas of larger size and increased mitogenic properties compared to control pancreas. In addition, we demonstrate overexpression of the mitogenic factor p8 in ElasCCK2 pancreas and not in control pancreas that further supports initiation of a carcinogenic process resulting from CCK2 receptor expression.…”

Section: Discussionmentioning

confidence: 99%

“…Immunohistochemistry was done on 5 mm tissue sections using an indirect immunoperoxidase protocol with diaminobenzidine (DAB) or 3-amino-9-ethylcarbazole (AEC) chromogens. 19 Indirect immunofluorescence used anti-rabbit Cy3-coupled secondary antibodies (Jackson Immunoresearch Laboratories, Inc., West Grove, PA) in place of peroxydase-labeled IgG. Primary antibodies used were: monoclonal mouse anti-nestin antibody (clone Rat 401, 1:100, Chemicon International, Inc., Temecula, CA), rabbit anti-cytokeratin 19 (CK19) antibody (1:20, generous gift from Dr. R. Kemler), rabbit anti-amylase antibody (1:6,000, generous gift from Dr. C. Figarella), rabbit anti-Pdx1 antibody (1:2,000, generous gift from Dr. H. Edlund), anti-clived caspase 3 antibody (1:500, Cell Signaling, Beverly, MA), mouse monoclonal anti-Bcl2 antibody (1:40, Dako Co., Carpinteria, CA), rabbit anti-phosphorylated Akt (1:50, Dako), mouse anti-phosphorylated ERK antibodies (1:400, Dako), goat anti-epidermal growth factor (EGF) receptor antibody (1:250, Santa-Cruz Biotechnology, Inc., Santa Cruz, CA), mouse antitransforming growth factor (TGF) alpha antibody (1:25, Oncogene Science, Manhasset, NY), rabbit anti-p8 antibody (1:1500, generous gift from Dr. J.L.…”

Section: Immunohistochemistrymentioning

confidence: 99%

“…18 Our previous study reported that 15% of homozygous mice develop pancreatic tumors with ageing clearly supporting a role for the CCK2 receptor in the development of pancreatic neoplasia. 19 The aim of our present study was to examine the initial steps of pancreatic carcinogenesis in ElasCCK2 mice, taking advantage of the slow kinetic of tumor formation in this model. However, given the low tumor incidence, we add a supplementary defect for carcinogenesis using a chemical carcinogen, azaserine, and investigated acinar responses to the chemical stress sequentially after the induction.…”

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confidence: 99%

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Transgenic expression of CCK2 receptors sensitizes murine pancreatic acinar cells to carcinogen‐induced preneoplastic lesions formation

Mathieu

Clerc

Portolan

et al. 2005

Intl Journal of Cancer

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In humans, initial events of pancreatic carcinogenesis remain unknown, and the question of whether this cancer, which has a ductal phenotype, exclusively arises from duct cells has been raised. Previous studies have demonstrated that transgenic expression of the CCK2 receptor in acinar cells of ElasCCK2 mice plays a role in the development of pancreatic neoplasia. The aim of our study was to examine initial steps of carcinogenesis in ElasCCK2 mice, adding a supplementary defect by using a chemical carcinogen, azaserine. Results of posttreatment sequential immunohistochemical examinations and quantifications demonstrate that mice responded to azaserine. Transition of acinar cells into duct-like cells expressing Pdx1 and gastrin, as well as proliferation of acinar cells, were transiently observed in both transgenic and control mice. The carcinogen also induced formation of preneoplastic lesions, adenomas, exhibiting properties of autonomous growth. Importantly, expression of the CCK2 receptor increased the susceptibility of pancreas to azaserine. Indeed, treated ElasCCK2 mice exhibited larger areas of pancreatic acinar-ductal transition, increased cellular proliferation as well as larger adenomas areas vs. control mice. These amplified responses may be related to auto/paracrine stimulation of CCK2 receptor by gastrin expressed in newly formed duct-like cells. Our results demonstrate that activation of CCK2 receptor and azaserine result in cumulative effects to favor the emergence of a risk situation that is a potential site for initiation of carcinogenesis. ' 2005 Wiley-Liss, Inc.Key words: G protein coupled receptors; CCK2 receptor; precancerous conditions; gastrin; transdifferentiation; experimental animal model; developmental gene Peptides of the cholecystokinin (CCK)/gastrin family are present in the gastrointestinal tract where they are known to physiologically regulate gallbladder and bowel motility, pancreatic and gastric secretion as well as growth and trophicity of gastrointestinal epithelial mucosa. 1 Two receptors that mediate the actions of cholecystokinin and gastrin have been pharmacologically classified as CCK1 and CCK2 receptors on the basis of their binding affinity for their natural ligands. While the CCK1 receptor is highly selective towards cholecystokinin vs. gastrin, the CCK2 receptor binds the 2 agonists with similar high affinities. 2 Both are G-protein coupled receptors with extrinsic tyrosine kinase activity. They activate many intracellular mediators classically described in the regulation of mitogenesis by growth factors. 3 Mitogen-activated protein kinases, ERK1/2, Jun kinase and p38MAPK, as well as the phosphatidylinositol 3-kinase (PI3K) and early responsive genes (c-fos, c-myc and c-jun), are known targets of gastrin. 4-7 Several groups including ours, have documented the contribution of Src and focal adhesion kinase (Fak) families' tyrosine kinases upstream the activation of these pathways. 4,8 The role of gastrin and CCK2 receptors as positive regulators of proliferation of normal...

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Section: Discussionmentioning

confidence: 67%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Immunohistochemistrymentioning

confidence: 99%

mentioning

confidence: 99%

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Transgenic expression of CCK2 receptors sensitizes murine pancreatic acinar cells to carcinogen‐induced preneoplastic lesions formation

Mathieu

Clerc

Portolan

et al. 2005

Intl Journal of Cancer

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Id3 modulates cellular localization of bHLH Ptf1‐p48 protein

Dufresne¹,

Clerc²,

Dieng³

et al. 2010

Intl Journal of Cancer

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Ptf1-p48 is a pancreas-specific bHLH transcriptional protein, which, in the normal adult pancreas, shows a restricted expression in acinar cells where it is predominantly localized in the nucleus and activates the transcription of exocrinespecific genes. Ptf1-p48 partners with two proteins to form the PTF1 active complex: a bHLH E-protein and suppressor of hairless RBP-J. Cytoplasmic mislocalization of Ptf1-p48 has been reported in pancreatic pathologies, suggesting its contribution in the early steps of pancreatic carcinogenesis. The aim of the our work was to elucidate the mechanisms regulating Ptf1-p48 subcellular localization. We hypothesized a role of Id proteins acting in a dominant-negative fashion by heterodimerizing with bHLH proteins. We reproduced Ptf1-p48 cytoplasmic mislocalization in acinar AR4-2J cells and demonstrated that a proliferative signal elicited by gastrin leads to increases in Id3 protein expression and levels of Id3/E47 and Id3/Ptf1-p48 interactions, and a decrease in the level of E47/Ptf1-p48 interaction. By contrast, Id3 silencing reversed the cytoplasmic mislocalization of Ptf1-p48 induced by gastrin. As E47 is responsible for the nuclear import of the PTF1 complex, disruption of this complex via Id3 interactions with both E47 and Ptf1-p48 appears to induce cytoplasmic mislocalization of Ptf1-p48. We then found that Ptf1-p48 is either absent or mislocalized in the cytoplasm and Id3 is overexpressed in human and murine pancreatic preneoplastic lesions. Our data provide novel insight into the regulation of Ptf1-p48 function and provide evidence that Ptf1-p48 cytoplasmic mislocalization and Id3 overexpression are early events in pancreatic cancer progression.Pancreatic cancer is a devastating disease with an overall 5-year survival of less than 5%. It is often not diagnosed until after the cancer has metastasized and therefore becomes very challenging to treat. During the last 10 years, the precursor lesions to invasive pancreatic cancer have been defined. 1 Pancreatic intraepithelial neoplasia (PanIN) are by far the most common of these lesions and are thought to initiate in the small ducts of the pancreas. PanIN have been validated by murine models that recapitulate the histologic progression hypothesized to occur in humans. These genetically engineered mouse models direct the endogenous expression of mutant KrasG12D to progenitor cells or acinar and centroacinar cells of the mouse pancreas. [2][3][4] Careful examination of the pathologic changes in these models suggests that, in addition to ductal cells, centroacinar cells and/or acinar cells can give rise to PanIN. 5 Lineage tracing studies with reporter mice confirmed that ductal elements can have an acinar histogenesis. They demonstrated that PanIN lesions are derivatives of differentiated acinar cells in response to chronic injury or when a mutant endogenous KrasG12D allele is expressed from its endogenous promoter in acinar cells. 3,4,6 In addition to these results from the mouse models, it has been demonstrated that acinar cel...

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The E3 ubiquitin ligase TRIP12 is required for pancreatic acinar cell plasticity and pancreatic carcinogenesis

Brunet,

Vargas,

Fanjul

et al. 2024

The Journal of Pathology

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The E3 ubiquitin ligase thyroid hormone receptor interacting protein 12 (TRIP12) has been implicated in pancreatic adenocarcinoma (PDAC) through its role in mediating the degradation of pancreas transcription factor 1a (PTF1a). PTF1a is a transcription factor essential for the acinar differentiation state that is notably diminished during the early steps of pancreatic carcinogenesis. Despite these findings, the direct involvement of TRIP12 in the onset of pancreatic cancer has yet to be established. In this study, we demonstrated that TRIP12 protein was significantly upregulated in human pancreatic preneoplastic lesions. Furthermore, we observed that TRIP12 overexpression varied within PDAC samples and PDAC‐derived cell lines. We further demonstrated that TRIP12 was required for PDAC‐derived cell growth and for the expression of E2F‐targeted genes. Acinar‐to‐ductal cell metaplasia (ADM) is a reversible process that reflects the high plasticity of acinar cells. ADM becomes irreversible in the presence of oncogenic Kras mutations and leads to the formation of preneoplastic lesions. Using two genetically modified mouse models, we showed that a loss of TRIP12 prevented acini from developing ADM in response to pancreatic injury. With two additional mouse models, we further discovered that a depletion of TRIP12 prevented the formation of KrasG12D‐induced preneoplastic lesions and impaired metastasis formation in the presence of mutated KrasG12D and Trp53R172H genes. In summary our study identified an overexpression of TRIP12 from the early stages of pancreatic carcinogenesis and proposed this E3 ubiquitin ligase as a novel regulator of acinar plasticity with an important dual role in initiation and metastatic steps of PDAC. © 2024 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

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Expression of CCK2 receptors in the murine pancreas: Proliferation, transdifferentiation of acinar cells, and neoplasia

Cited by 73 publications

References 41 publications

Transgenic expression of CCK2 receptors sensitizes murine pancreatic acinar cells to carcinogen‐induced preneoplastic lesions formation

Transgenic expression of CCK2 receptors sensitizes murine pancreatic acinar cells to carcinogen‐induced preneoplastic lesions formation

Id3 modulates cellular localization of bHLH Ptf1‐p48 protein

The E3 ubiquitin ligase TRIP12 is required for pancreatic acinar cell plasticity and pancreatic carcinogenesis

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