A transgenic mouse model of metastatic carcinoma involving transdifferentiation of a gastric epithelial lineage progenitor to a neuroendocrine phenotype

Syder, Andrew J.; Karam, Sherif M.; Mills, Jason C.; Ippolito, Joseph E.; Ansari, Hena A; Farook, Vidya S.; Gordon, Jeffrey I.

doi:10.1073/pnas.0307983101

Cited by 94 publications

(105 citation statements)

References 58 publications

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“…3 A and Fig. S3 A), confirming the reported lineage-restricted pattern (Syder et al, 2004). A few basally located YFP + cells failed to stain with Atp4b Ab, but expressed the chief cellspecific product, gastric intrinsic factor (Gif, Fig.…”

Section: Activation Of Notch Signaling In Parietal Cells Confers Stemsupporting

confidence: 79%

“…3, A and B, arrows). As expected, the proliferation marker EdU and the Atp4b marker of terminal parietal cytodifferentiation did not overlap the parietal cell-specific H + /K + -ATPase -subunit (Atp4b) promoter (Syder et al, 2004). To delineate the domain of Cre expression, we crossed Atp4b-Cre and Rosa26 YFP mice.…”

Section: Activation Of Notch Signaling In Parietal Cells Confers Stemmentioning

confidence: 70%

“…Osr1-cre mice (Grieshammer et al, 2008) were provided by G. Martin (University of California, San Francisco, CA). Atp4b-Cre mice (Syder et al, 2004) were provided by J. Gordon (Washington University, St. Louis, MO). Rosa26 YFP (Srinivas et al, 2001), Rosa26 LacZ (Soriano, 1999), Rosa26 NICD1-Ires-GFP (Murtaugh et al, 2003), and Lgr5 EGFP-IRES-Cre (Barker et al, 2007) mice were purchased from The Jackson Laboratory.…”

Section: Discussionmentioning

confidence: 99%

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Notch signaling in stomach epithelial stem cell homeostasis

Kim¹,

Shivdasani²

2011

J Cell Biol

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Section: Activation Of Notch Signaling In Parietal Cells Confers Stemsupporting

confidence: 79%

Section: Activation Of Notch Signaling In Parietal Cells Confers Stemmentioning

confidence: 70%

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Notch signaling in stomach epithelial stem cell homeostasis

Kim¹,

Shivdasani²

2011

J Cell Biol

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“…In this case, the epithelial cells might lose their original epithelial markers. A mouse model with Tag expression in the acid-producing parietal cell progenitors of the stomach showed similar transdifferentiation, leading to invasive tumors with neuroendocrine phenotype (Syder et al, 2004). The described solid, undifferentiated, 'neuroendocrine' carcinomatous component was observed in human colorectal cancer, and these tumors metastasized frequently to the regional lymph node and liver, similar as in our model (Sarsfield and Anthony, 1990;Burke et al, 1991).…”

Section: Sporadic Colorectal Cancer Modelsupporting

confidence: 77%

The immune response to sporadic colorectal cancer in a novel mouse model

et al. 2010

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Current mouse models do not reflect the sporadic nature of colon cancer and do not allow the analysis of antitumor immune response because of the lack of known tumorspecific antigens. Two transgenic mouse models with spontaneous tumor development were generated, directing the expression of SV40T antigen (Tag) either constitutively (Vil-Cre Â LoxP-Tag-transgenic mice) or stochastically (Vil-Cre-ER T2 Â LoxP-Tag-transgenic mice) into the putative stem cell region of the crypt of Lieberku¨hn. Tumor development and antitumor immune response were monitored. Vil-Cre Â LoxP-Tag mice developed multiple adenocarcinomas of the small intestine and colon at an average age of 6 months. During the tumor development, Tag-specific immunoglobulin G (IgG) antibodies were induced in half of the mice, although they had developed neonatal cytotoxic T lymphocyte (CTL) tolerance. This model shows similarity to hereditary colon cancer but not to the sporadic tumor development. Therefore, the conditional Vil-Cre-ER T2 Â LoxP-Tag mice were established, in which expression of the dormant Tag was induced by stochastic, tissue-specific activation of Cre recombinase. These mice spontaneously developed highly invasive, metastasizing colon carcinomas at an average age of 20 months. Colon carcinomas expressed epithelial and/or neuroendocrine markers depending on the grade of differentiation. Young Vil-Cre-ER T2 Â LoxP-Tag mice had retained CTL responses against epitope IV of Tag. The tumors induced strong anti-Tag IgG responses. We report, for the first time, a mouse model based on stochastic, tissue-specific activation of a dormant oncogene in the colon allowing the analysis of antitumor immune response against primary colorectal cancer.

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“…Many types of NECs are aggressive and diagnosed only after metastatic spread (1,2). In addition, the appearance of NE features in cancers arising from cells that do not normally express neural or endocrine fates is often associated with more aggressive disease (3)(4)(5). A panel of biomarkers and mediators of tumorigenesis is needed for better diagnosis and stratification of NECs and new, more efficacious therapeutic approaches.…”

mentioning

confidence: 99%

An integrated functional genomics and metabolomics approach for defining poor prognosis in human neuroendocrine cancers

Ippolito

Jain

et al. 2005

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

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103

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Human neuroendocrine (NE) cancers range from relatively indolent to highly aggressive. In this study, we combine functional genomics with metabolomics to identify features of NE cancers associated with a poor outcome. Analysis of GeneChip datasets of primary prostate tumors, as well as lymph node and liver metastases from transgenic mice with a NE cell cancer, plus derived NE cell lines yielded a signature of 446 genes whose expression is enriched in neoplastic mouse prostatic NE cells. This signature was used for in silico metabolic reconstructions of NE cell metabolism, directed liquid chromatography͞tandem MS analysis of metabolites in prostatic NE tumors and cell lines, and analysis of GeneChip datasets of human NE tumors with good or poor prognoses. The results indicate that a distinguishing feature of poor-prognosis NE tumors is a glutamic acid decarboxylase-independent pathway for production of GABA and a pathway for production of imidazole-4-acetate that involves dopa decarboxylase and a membraneassociated amine oxidase, amiloride-binding protein 1. Electrophysiological studies disclosed that imidazole-4-acetate can bind and activate GABAA receptors expressed by transformed NE cells, thus providing a previously uncharacterized paradigm for NE tumor cell signaling. Transcriptional, metabolic, and electrophysiologic features of transformed mouse NE cells are also evident in neural progenitor cells.GABA signaling ͉ MS ͉ metastatic neuroendocrine cancers ͉ polyamine metabolism ͉ transcriptome-directed metabolomics H uman neuroendocrine (NE) cancers (NECs) can arise in neuroectodermal tissues or in endoderm-derived epithelia (e.g., pheochromocytomas and small cell lung cancers, respectively). Many types of NECs are aggressive and diagnosed only after metastatic spread (1, 2). In addition, the appearance of NE features in cancers arising from cells that do not normally express neural or endocrine fates is often associated with more aggressive disease (3-5). A panel of biomarkers and mediators of tumorigenesis is needed for better diagnosis and stratification of NECs and new, more efficacious therapeutic approaches. In this report, we present one approach for addressing this issue that uses a combination of transgenic mice with a metastatic cancer arising from their prostatic NE cell lineage, NE cell lines established from this cancer, human NE tumors with varying degrees of aggressiveness, functional genomics, and MS-based metabolomics.The prostate contains three epithelial lineages: secretory, basal, and NE (6). The secretory or luminal cell is the most abundant type and requires continuous exposure to androgens for its survival (7-11). Basal cells represent the primary proliferating epithelial population and are not androgen-dependent (12, 13). NE cells are rare (Ͻ1% of the total), have distinctive projections that allow them to contact epithelial neighbors located several cell diameters away, and secrete a variety of neuropeptides and neurotransmitters (14-17). Conventional adenocarcinoma of the prostate (C...

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A transgenic mouse model of metastatic carcinoma involving transdifferentiation of a gastric epithelial lineage progenitor to a neuroendocrine phenotype

Abstract: neuroendocrine carcinogenesis ͉ metastatic gastric cancer ͉ functional genomic studies ͉ mouse͞human epithelial cancers

Cited by 94 publications

References 58 publications

Notch signaling in stomach epithelial stem cell homeostasis

Notch signaling in stomach epithelial stem cell homeostasis

The immune response to sporadic colorectal cancer in a novel mouse model

An integrated functional genomics and metabolomics approach for defining poor prognosis in human neuroendocrine cancers

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