The Nestin progenitor lineage is the compartment of origin for pancreatic intraepithelial neoplasia

Carrière, Catherine; Seeley, E. Scott; Goetze, Tobias; Longnecker, Daniel S.; Korc, Murray

doi:10.1073/pnas.0701117104

Cited by 120 publications

(115 citation statements)

References 27 publications

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“…Recent studies have suggested that centroacinar cells or nestin-positive cells may act as progenitor cells in the pancreas and may be target cells for transformation in pancreatic tumorigenesis. 28,29 Whether either, or both, of these cell types are the cell of origin in our model is a provocative idea that remains to be elucidated.…”

Section: Discussionmentioning

confidence: 99%

Trp53 Deletion Stimulates the Formation of Metastatic Pancreatic Tumors

Morton

Klimstra

Mongeau

et al. 2008

The American Journal of Pathology

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The presence of distant metastases is a common finding on diagnosis of pancreatic cancer; however, the mechanisms underlying the dissemination of this tumor type remain poorly understood. Loss of the p53 tumor suppressor protein has been associated with tumor progression and metastasis in several tumor types including pancreatic ductal adenocarcinoma. Here, we describe the generation of a progressive and metastatic pancreatic cancer mouse model after the somatic and sporadic delivery of avian retroviruses encoding the mouse polyoma virus middle T antigen to elastase-tv-a transgenic mice with a pancreas-specific deletion of the Trp53 tumor suppressor locus. In this model, the tumors metastasize most frequently to the liver, consistent with human pancreatic carcinomas. Analysis of metastatic lesions demonstrated that concomitant loss of the Ink4a/Arf locus was not required for metastasis; however, pancreas-specific deletion of a single Ink4a/Arf allele cooperated with Trp53 deletion in a haploinsufficient manner to accelerate tumor development. Thus, our findings illustrate the potential role of p53 loss of function in pancreatic tumor progression, demonstrate the feasibility of modeling pancreatic cancer metastasis after somatic and sporadic oncogene activation, and indicate that our model may provide a useful experimental system for investigation of the molecular mechanisms underlying pancreatic cancer progression and metastasis. Pancreatic cancer is the fourth-leading cause of cancerrelated mortalities in the United States, with ϳ32,000 deaths annually.1 The median survival after diagnosis is 6 months, and the 5-year survival rate is only 5%. These statistics reflect the advanced stage at which most pancreatic tumors are identified, exemplified by extra-pancreatic invasion and metastasis to the liver and peritoneum, and the resistance of pancreatic cancers to conventional chemotherapeutic intervention. 2,3 Thus, understanding the factors that contribute to pancreatic tumor progression and metastasis is important in combating this disease.Mouse models are attractive experimental systems for exploring the genesis and behavior of human malignancies, and as a result, several mouse models for pancreatic cancer have been generated using transgenic approaches.2,4,5 These models, although valuable, were restricted in several respects including the expression of the oncogene throughout pancreatic development. Indeed, in some of the published models mice die shortly after birth, or perinatally, with architecturally abnormal pancreata. 6 Further, because all cells of a particular lineage within the pancreas express the transgene, tumors arise in an environment of aberrant intercellular signaling, unlike the scenario of sporadic tumor development in humans, in which tumor cells are surrounded by genetically normal cells.To address these issues, we recently generated a mouse model for pancreatic cancer using the RCAS-TVA gene delivery system. 7 This system allows the sporadic postnatal delivery of oncogene-bearing avian ret...

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Section: Discussionmentioning

confidence: 99%

Trp53 Deletion Stimulates the Formation of Metastatic Pancreatic Tumors

Morton

Klimstra

Mongeau

et al. 2008

The American Journal of Pathology

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“…42 Overall, the location of nestin-GFP cells, their behavior in vitro and in vivo, and the Expression of nestin in these bulge cells with stem-like properties parallels findings from our group and others that this intermediate filament marks stem/progenitor cells in other tissues as well; examples now include neural stem cells, liver oval cells, satellite cells in the muscle, stem cells in the pancreas, and progenitors of Leydig cells. 10,26,39,[43][44][45][46] This raises an intriguing question of whether expression of nestin simply marks the stem/progenitor state of the cells or contributes actively to this state.…”

Section: Discussionmentioning

confidence: 99%

Neural Potential of a Stem Cell Population in the Hair Follicle

Mignone¹,

Roig-López²,

Fedtsova³

et al. 2007

Cell Cycle

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The bulge region of the hair follicle serves as a repository for epithelial stem cells that can regenerate the follicle in each hair growth cycle and contribute to epidermis regeneration upon injury. Here we describe a population of multipotential stem cells in the hair follicle bulge region; these cells can be identified by fluorescence in transgenic nestin-GFP mice. The morphological features of these cells suggest that they maintain close associations with each other and with the surrounding niche. Upon explantation, these cells can give rise to neurosphere-like structures in vitro. When these cells are permitted to differentiate, they produce several cell types, including cells with neuronal, astrocytic, oligodendrocytic, smooth muscle, adipocytic, and other phenotypes. Furthermore, upon implantation into the developing nervous system of chick, these cells generate neuronal cells in vivo. We used transcriptional profiling to assess the relationship between these cells and embryonic and postnatal neural stem cells and to compare them with other stem cell populations of the bulge. Our results show that nestin-expressing cells in the bulge region of the hair follicle have stem cell-like properties, are multipotent, and can effectively generate cells of neural lineage in vitro and in vivo.

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“…Finally, we wish to emphasize that the observations in the current study do not negate the possibility that mPanINs might also arise after activation of oncogenic Kras in additional nonacinar cell types. For example, Korc and colleagues have demonstrated that activation of oncogenic Kras in nestin-expressing cells also results in mPanIN formation (36). Nestin is a marker of progenitor cells, and nestin-positive progenitors contribute to the formation of the differentiated acinar cells (37).…”

Section: Discussionmentioning

confidence: 99%

Spontaneous induction of murine pancreatic intraepithelial neoplasia (mPanIN) by acinar cell targeting of oncogenic Kras in adult mice

Habbe

Shi

Meguid³

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

370

327

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Pancreatic ductal adenocarcinoma (PDAC) is believed to arise through a multistep model comprised of putative precursor lesions known as pancreatic intraepithelial neoplasia (PanIN). Recent genetically engineered mouse models of PDAC demonstrate a comparable morphologic spectrum of murine PanIN (mPanIN) lesions. The histogenesis of PanIN and PDAC in both mice and men remains controversial. The most faithful genetic models activate an oncogenic Kras G12D knockin allele within the pdx1-or ptf1a/p48-expression domain of the entire pancreatic anlage during development, thus obscuring the putative cell(s)-of-origin from which subsequent mPanIN lesions arise. In our study, activation of this knockin Kras G12D allele in the Elastase-and Mist1-expressing mature acinar compartment of adult mice resulted in the spontaneous induction of mPanIN lesions of all histological grades, although invasive carcinomas per se were not seen. We observed no requirement for concomitant chronic exocrine injury in the induction of mPanIN lesions from the mature acinar cell compartment. The acinar cell derivation of the mPanINs was established through lineage tracing in reporter mice, and by microdissection of lesional tissue demonstrating Cre-mediated recombination events. In contrast to the uniformly penetrant mPanIN phenotype observed following developmental activation of Kras G12D in the Pdx1-expressing progenitor cells, the Pdx1-expressing population in the mature pancreas (predominantly islet ␤ cells) appears to be relatively resistant to the effects of oncogenic Kras. We conclude that in the appropriate genetic context, the differentiated acinar cell compartment in adult mice retains its susceptibility for spontaneous transformation into mPanIN lesions, a finding with potential relevance vis-à -vis the origins of PDAC.lineage tracing ͉ transdifferentiation ͉ precursor lesions ͉ pancreatic cancer

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The Nestin progenitor lineage is the compartment of origin for pancreatic intraepithelial neoplasia

Cited by 120 publications

References 27 publications

Trp53 Deletion Stimulates the Formation of Metastatic Pancreatic Tumors

Trp53 Deletion Stimulates the Formation of Metastatic Pancreatic Tumors

Neural Potential of a Stem Cell Population in the Hair Follicle

Spontaneous induction of murine pancreatic intraepithelial neoplasia (mPanIN) by acinar cell targeting of oncogenic Kras in adult mice

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