Notch mediates TGFα-induced changes in epithelial differentiation during pancreatic tumorigenesis

Miyamoto, Yoshiharu; Maitra, Anirban; Ghosh, Bidyut; Zechner, Ulrich; Argani, Pedram; Iacobuzio‐Donahue, Christine A.; Sriuranpong, Virote; Iso, Tatsuya; Meszoely, Ingrid M.; Wolfe, Michael S.; Hruban, Ralph H.; Ball, Douglas W.; Schmid, Roland M.; Leach, Steven D.

doi:10.1016/s1535-6108(03)00140-5

Cited by 607 publications

(666 citation statements)

References 59 publications

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“…However, this metaplastic epithelium also exhibits expression of other genes not normally expressed in pancreatic ductal epithelium, including Pdx1 and Hes1, reflecting the dedifferentiated nature of these cells. 24,32 In the current study, we have therefore avoided the term "acinar-to-ductal metaplasia" and favor the simple term "transient metaplastic intermediates" to refer to the transient lesions generated following cerulein injury.…”

Section: Discussionmentioning

confidence: 99%

Hedgehog Signaling Is Required for Effective Regeneration of Exocrine Pancreas

et al. 2008

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Although both endocrine and the exocrine pancreas display a significant capacity for tissue regeneration and renewal, the existence of progenitor cells in the adult pancreas remains uncertain. Using a model of cerulein-mediated injury and repair, we demonstrate that mature exocrine cells, defined by expression of an Elastase1 promoter, actively contribute to regenerating pancreatic epithelium through formation of metaplastic ductal intermediates. Acinar cell regeneration is associated with activation of Hedgehog (Hh) signaling, as assessed by up-regulated expression of multiple pathway components, as well as activation of a Ptch-lacZ reporter allele. Using both pharmacologic and genetic techniques, we also show that the ability of mature exocrine cells to accomplish pancreatic regeneration is impaired by blockade of Hh signaling. Specifically, attenuated regeneration in the absence of an intact Hh pathway is characterized by persistence of metaplastic epithelium expressing markers of pancreatic progenitor cells, suggesting an inhibition of redifferentiation into mature exocrine cells. Given the known role of Hh signaling in exocrine pancreatic cancer, these findings may provide a mechanistic link between injury-induced activation of pancreatic progenitors and subsequent pancreatic neoplasia. In addition to its well-established role in directing the patterning of embryonic tissues, 9 the Hedgehog (Hh) pathway has been implicated in the maintenance of stem or progenitor cell number in a growing list of adult tissues. 10-15 Mature tissue homeostasis at these sites appears to be a consequence of Hh-mediated stem or progenitor cell self-renewal within the organspecific stem cell niche. In addition to this observed role in "baseline" states, more recent work suggests that the Hh pathway also plays a critical role in regenerative responses to tissue injury. For example, Hh pathway activity is required for androgen-triggered regeneration of prostate epithelium in male mouse castrates, 14 as well as in the course of pulmonary epithelial regeneration in a napthalene-induced model of acute pulmonary injury. 15 Based on observations that inhibition of Hh signaling is associated with diminished tissue repair, these studies have suggested that up-regulated Hh signaling is a prerequisite for the stem/progenitor cell expansion that occurs in response to injury.The aim of the current study was to determine the role of Hh signaling in the process of exocrine regeneration following cerulein-induced pancreatitis. Recent empiric studies in archived human specimens of chronic pancreatitis have demonstrated aberrant expression of Hh components, 16,17 but these studies have not explored the functional implications of Hh blockade in the setting of exocrine injury. Confirming previous observations, we demonstrate by using lineage tracing experiments that pancreatic regeneration is mediated by mature acinar cells through the formation of transient metaplastic epithelium, expressing markers of pancreatic progenitor cells (nestin, P...

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Section: Discussionmentioning

confidence: 99%

Hedgehog Signaling Is Required for Effective Regeneration of Exocrine Pancreas

et al. 2008

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“…It consists of two cleavages, occurring at the extracellular side, followed by a third cleavage that liberates the intracellular Notch receptor domain, which is translocated to the cell nucleus (40,41), where it regulates the balance between cell differentiation and stem cell proliferation, during the development of numerous tissues, including the pancreas (34,42). It is likely that this latter form participates in neoplastic cell transformation in several organs, such as the cervix, uteri, lung, breast, nerve tissue and also in the pancreas (43)(44)(45)(46)(47).…”

Section: Discussionmentioning

confidence: 99%

Comparative evaluation of cancer stem cell markers in normal pancreas and pancreatic ductal adenocarcinoma

Vizio

Mauri²,

Prati³

et al. 2011

Oncol Rep

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“…Indeed activation of Notch signaling is crucial in mediating the TGF alpha-induced acinar dedifferentiation and transition towards duct-like epithelium exhibiting properties of embryonic pancreas. 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.…”

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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Notch mediates TGFα-induced changes in epithelial differentiation during pancreatic tumorigenesis

Cited by 607 publications

References 59 publications

Hedgehog Signaling Is Required for Effective Regeneration of Exocrine Pancreas

Hedgehog Signaling Is Required for Effective Regeneration of Exocrine Pancreas

Comparative evaluation of cancer stem cell markers in normal pancreas and pancreatic ductal adenocarcinoma

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

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