Chronic Pancreatitis and Pancreatic Cancer

Maisonneuve, Patrick; Lowenfels, Albert B.

doi:10.1159/000063165

Cited by 101 publications

(49 citation statements)

References 64 publications

(40 reference statements)

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“…12,51 On the other hand, the CCK2 receptor is expressed in chronic pancreatitis, a pathology that is associated with a high risk of developing cancer and that exhibits similar genetical and morphological lesions than pancreatic adenocarcinoma. 13,52,53 Accordingly, the fact that pseudoductular complexes are typical lesions of chronic pancreatitis, together with experimental evidence for the presence of the CCK2 receptor and gastrin in transitional acinar cells, leads to take a role for this receptor in initiation steps of carcinogenesis into account. 33 In conclusion, data presented in our study show that expression and activation of a G protein-coupled receptor, the CCK2 receptor, increase sensitivity to an acinar carcinogen and upregulate emergence of pancreatic progenitor cells, expressing Pdx1, that are also potential sites for initiation of carcinogene-sis.…”

Section: Discussionmentioning

confidence: 99%

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: 99%

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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“…Recurrent attacks of acute pancreatitis are believed to result in chronic pancreatitis, which is associated with increased risk of developing pancreatic cancer [161,162]. Extracellular nucleotides have been implicated as inflammatory and stress mediators in many pathological states and thus it is appropriate to look at this in the human pancreas.…”

Section: Exocrine Pathophysiology and Therapeutic Potentialsmentioning

confidence: 99%

Purinergic receptors in the endocrine and exocrine pancreas

Novak

2007

Purinergic Signalling

115

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The pancreas is a complex gland performing both endocrine and exocrine functions. In recent years there has been increasing evidence that both endocrine and exocrine cells possess purinergic receptors, which influence processes such as insulin secretion and epithelial ion transport. Most commonly, these processes have been viewed separately. In β cells, stimulation of P2Y 1 receptors amplifies secretion of insulin in the presence of glucose. Nucleotides released from secretory granules could also contribute to autocrine/paracrine regulation in pancreatic islets. In addition to P2Y 1 receptors, there is also evidence for other P2 and adenosine receptors in β cells (P2Y 2 , P2Y 4 , P2Y 6 , P2X subtypes and A 1 receptors) and in glucagon-secreting α cells (P2X 7 , A 2 receptors). In the exocrine pancreas, acini release ATP and ATP-hydrolysing and ATP-generating enzymes. P2 receptors are prominent in pancreatic ducts, and several studies indicate that P2Y 2 , P2Y 4 , P2Y 11 , P2X 4 and P2X 7 receptors could regulate secretion, primarily by affecting Cl − and K + channels and intracellular Ca 2+ signalling. In order to understand the physiology of the whole organ, it is necessary to consider the full complement of purinergic receptors on different cells as well as the structural and functional relation between various cells within the whole organ. In addition to the possible physiological function of purinergic receptors, this review analyses whether the receptors could be potential therapeutic targets for drug design aimed at treatment of pancreatic diseases.

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“…The only other type of pancreatitis that is highly prone to malignancy is hereditary pancreatitis where the risk ratio is 53 compared with the general population. 112 The duration of exposure to inflammation seems to be the major factor involved in the transition to a malignant condition in chronic pancreatitis and smoking remains the strongest risk factor that is amenable to preventive intervention 113 in temperate zone pancreatitis, while the risk factors for cancer in TCP remain unknown.…”

Section: Complicationsmentioning

confidence: 99%