Submandibular Gland Adenocarcinoma of Intercalated Duct Origin in Smgb-Tag Mice

Dardick, Irving; Ho, J. C.; Paulus, Michelle; Mellon, Pamela L.; Mirels, Lily

doi:10.1038/labinvest.3780176

Cited by 12 publications

(21 citation statements)

References 51 publications

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“…The above transgenic mice develop tumors more frequently in mammary gland than in salivary glands and none of them pathologically displays the typical characteristics of human pleomorphic adenomas. The pathologic analysis of mammary gland tumors in MMTV driving Ras, Myc and Neu transgenic mice reveals that the different oncogenes activated in the same cell type result in different tumor types, 21 and SV40 T-antigen overexpression in different cells in salivary glands results in tumors with similar morphol- ogy, 20,22 suggesting that the tumor types in transgenic mice are closely associated with the activated oncogenes in certain cell types. The fact that PLAG1 overexpression specifically induces pleomorphic adenomas of salivary glands in mice indicates that MMTV-PLAG1 transgenic mice would be an ideal animal model for the study of human pleomorphic adenomas in terms of tumor pathology and molecular mechanism of tumorigenesis.…”

Section: Discussionmentioning

confidence: 99%

Wnt pathway is involved in pleomorphic adenomas induced by overexpression of PLAG1 in transgenic mice

Zhao¹,

Ren²,

Yang³

et al. 2005

Intl Journal of Cancer

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Pleomorphic adenoma gene 1 (PLAG1) was found frequently rearranged and activated in human salivary gland pleomorphic adenomas. It encodes a developmentally regulated transcription factor. Ectopic overexpression of PLAG1 has been proposed to play a crucial role in tumorigenesis of salivary gland pleomorphic adenomas. It was reported that PLAG1 can activate the transcription of insulin-like growth factor 2 (IGF2), functioning as a protooncogene. In this report, we show that the salivary gland tumors developed in PLAG1 transgenic mice share major histopathologic features with human pleomorphic adenomas. It was found that b-catenin, the key component of Wnt signaling pathway, was upregulated at transcriptional level in tumors developed in 3 independent transgenic mouse lines. Immunohistochemical staining revealed that expression of b-catenin as well as c-myc, downstream of b-catenin in Wnt signaling pathway, was highly upregulated with overexpression of PLAG1 transgene in tumor and normal transgenic salivary gland tissues. Moreover, we found that PLAG1 can activate the transcription of mouse but not human b-catenin in the 3T3 cells cotransfected with reporter constructs. Sequence analysis shows there are 4 PLAG1 consensus binding sites in mouse b-catenin promoter region but not in human. Our findings provide the first in vivo evidence for the oncogenic activity of PLAG1 in pleomorphic adenoma tumorigenesis, reveal a valued animal model for human salivary gland tumors and suggest that Wnt signaling pathway may also contribute to the development of pleomorphic adenomas in transgenic mice. ' 2005 Wiley-Liss, Inc.Key words: pleomorphic adenoma gene 1; transgenic mice; b-catenin; pleomorphic adenomas The pleomorphic adenoma is the most common type of salivary gland tumor, which accounts for more than 50% of all salivary gland neoplasms. It usually behaves as the benign slow-growing tumor morphologically characterized by a biphasic pattern containing both epithelial and mesenchymal areas. 1 In recent years, a series of studies on tumorigenesis of salivary gland tumors has revealed that oncogenic activation of pleomorphic adenoma gene 1 (PLAG1) on 8q12 plays a crucial role in the development of pleomorphic adenomas originating from salivary glands. The major form of PLAG1 activation is reciprocal chromosomal translocations that lead to promoter swapping between PLAG1 gene, which is not expressed or weakly expressed in adult salivary glands, and the genes ubiquitously expressed in adult tissues, such as the b-catenin gene on 3p21, 2 the leukemia-inhibitory factor receptor (LIFR) gene on 5p13 and the transcription elongation factor SII gene on 3p21. 3-22. 3,4 The breakpoints of both fusion partner genes invariably occur in the 5 0 noncoding regions and consequently lead to ectopic expression of PLAG1 gene in salivary glands. In fact, the chromosomal translocations involving 8q12 only account for 39% of tumors. Other chromosomal abnormalities were also found to be associated with the formation of pleomorphic adenomas, such ...

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Section: Discussionmentioning

confidence: 99%

Wnt pathway is involved in pleomorphic adenomas induced by overexpression of PLAG1 in transgenic mice

Zhao¹,

Ren²,

Yang³

et al. 2005

Intl Journal of Cancer

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“…Early dysplastic changes were seen in the salivary gland by 2.5 months of age, and adenocarcinoma by 10-12 months. 26 Salivary gland adenocarcinomas developed in B50% of male mice and o1% of female mice. Transgenic mice exhibited abnormalities only in submandibular glands.…”

Section: Histological Findingsmentioning

confidence: 99%

“…26 Mice were maintained at the Animal Resource Center of the Ontario Cancer Institute/Princess Margaret Hospital, Toronto, Ontario, Canada. All animal experiments were performed in accordance with the Public Health Service Policy on Humane Care and Use of Laboratory Animals.…”

Section: Transgenic Mice and Animal Carementioning

confidence: 99%

“…For histopathological analysis, we used two fixation procedures. 26 Samples were fixed in 10% neutral-buffered formalin or in methacarn (10% acetic acid, 90% methanol) overnight at 41C and paraffin-embedded. Five micrometer sections were cut from the paraffin blocks and placed on slides using standard techniques.…”

Section: Harvesting and Fixation Of Mouse Submandibular Glandsmentioning

confidence: 99%

“…24,25 Previously, one of us worked with a transgenic mouse line (Smgb-Tag) that develops submandibular gland adenocarcinoma of intercalated duct origin. 26 In these mice, the oncogene SV40T antigen (Tag) is expressed from the neonatal submandibular gland secretory protein-b (Smgb) gene promoter. Expression of Tag within the salivary gland results in the development of gland dysplasia in all animals by 3-4 months of age.…”

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Molecular characterization of salivary gland malignancy using the Smgb-Tag transgenic mouse model

Mäkitie

Reis

Arora

et al. 2005

Laboratory Investigation

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The molecular mechanisms underlying salivary gland tumorigenesis remain unclear. In order to identify genetic changes that occur during the development of invasive adenocarcinoma from normal salivary gland, we used the Smgb-Tag transgenic mouse model. This transgene induces the progressive development of dysplasia to invasive adenocarcinoma in the submandibular salivary gland. Gene expression patterns from 20 submandibular glands (two normal, nine dysplasia and nine adenocarcinoma samples) were assessed using a mouse 15 K cDNA array. Unsupervised hierarchical clustering was used to group gene expression based on 157 differentially expressed genes distinguishing between dysplasias and adenocarcinomas. Further analysis identified 25 significantly overexpressed and 28 underexpressed cDNA sequences in adenocarcinoma as compared to dysplasia. Differential expression of five genes (Lcn2, Ptn, Cd24a, Mapk6 and Rnps1) was validated by quantitative real-time RT-PCR in a total of 48 mouse salivary gland tissues (seven histologically normal, 13 dysplasias and 28 adenocarcinomas), including the 20 samples analyzed by cDNA arrays. Immunohistochemical analysis was used to validate the expression of Ptn and Cd24a at the protein level in a subset of 16 mouse salivary glands (four normal, five dysplasia and seven adenocarcinoma samples), as well as in 23 human submandibular gland tumors (16 pleomorphic adenomas, three adenoid cystic carcinomas, one acinic cell carcinoma, one adenocarcinoma NOS, one myoepithelial and one mucoepidermoid carcinoma). We thus demonstrated that the Smgb-Tag transgenic mouse model is a useful tool for the identification of genes that are deregulated in salivary gland adenocarcinomas. Our data suggest that Ptn and Cd24a may be genetic markers associated with salivary gland tumorigenesis and/or progression. Keywords: salivary gland; adenocarcinoma; transgenic mouse; carcinogenesis; gene expression; microarrays Salivary gland tumors are a heterogeneous and relatively rare class of head and neck cancer, with several histologically diverse subtypes, such as carcinoma ex-pleomorphic adenomas, adenoid cystic carcinomas (ACC), mucoepidermoid carcinomas (MECA) and acinic cell carcinomas (AcCA). 1 Risk factors may include external radiation to the head and neck, viral infection, and exposure to carcinogens. 2 The morphological origin and clinical behavior of these tumors differ from the majority of other head and neck tumors, which are squamous cell carcinomas; their genetic origins remain to be elucidated.

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Potential role for inhibition of protein phosphatase 2A tumor suppressor in salivary gland malignancies

Routila

Mäkelä

Luukkaa

et al. 2015

Genes Chromosomes & Cancer

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The aetiology and pathogenesis of salivary gland malignancies remain unknown. To reveal novel molecular factors behind the development of salivary gland cancer, we performed gene expression analyses from Smgb-Tag mouse salivary gland samples. The overall purpose was to apply these results for clinical use to find new approaches for both possible therapeutic targets and more accurate diagnostic tools. Smgb-Tag mouse strain, in which salivary neoplasms arise through a dysplastic phase in submandibular glands, was investigated using genome-wide microarray expression analysis, ingenuity pathway analysis, RT-PCR, and immunohistochemistry. Thirty-eight human salivary gland adenoid cystic carcinoma samples were investigated using immunohistochemistry for validation purposes. Our genome-wide study showed that Ppp2r1b, a PP2A subunit encoding tumor suppressor gene, is underexpressed in submandibular gland tumors of Smgb-Tag mice. mTOR signaling pathway was significantly enriched and mTOR linked PP2A subunit gene B55 gamma was significantly underexpressed in the analyses. Furthermore, parallel immunohistochemical analysis of three PP2A inhibitors demonstrated that two PP2A inhibitors, CIP2A and SET, are highly expressed in both dysplastic and adenocarcinomatous tumors of the Smgb-Tag mice. In addition, all 38 investigated human salivary adenoid cystic carcinoma samples stained positively for CIP2A and most for SET. Finally, p-S6 staining showed activation of mTOR pathway in human adenoid cystic carcinoma samples. Our results suggest that PP2A inhibition either via PP2A subunit underexpression or PP2A inhibitor overexpression play an important role in the formation of salivary gland malignancy, potentially due to mTOR signaling activation.

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Submandibular Gland Adenocarcinoma of Intercalated Duct Origin in Smgb-Tag Mice

Cited by 12 publications

References 51 publications

Wnt pathway is involved in pleomorphic adenomas induced by overexpression of PLAG1 in transgenic mice

Wnt pathway is involved in pleomorphic adenomas induced by overexpression of PLAG1 in transgenic mice

Molecular characterization of salivary gland malignancy using the Smgb-Tag transgenic mouse model

Potential role for inhibition of protein phosphatase 2A tumor suppressor in salivary gland malignancies

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