Telomerase deficiency and telomere dysfunction inhibit mammary tumors induced by polyomavirus middle T oncogene

Jaskelioff, Mariela; Song, Wenbo; Xia, Jianchuan; Liu, C; Kramer, John C.; Koido, Shigeo; Gendler, Sandra J.; Calderwood, Stuart K.; Gong, Jianlin

doi:10.1038/onc.2009.268

Cited by 23 publications

(23 citation statements)

References 51 publications

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“…However, these paradoxical observations are consistent with recent studies demonstrating that constitutive telomerase dysfunction inhibits metastatic progression in murine breast and prostate cancer models [67], [68].…”

Section: Discussionsupporting

confidence: 90%

Telomerase Variant A279T Induces Telomere Dysfunction and Inhibits Non-Canonical Telomerase Activity in Esophageal Carcinomas

et al. 2014

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BackgroundAlthough implicated in the pathogenesis of several chronic inflammatory disorders and hematologic malignancies, telomerase mutations have not been thoroughly characterized in human cancers. The present study was performed to examine the frequency and potential clinical relevance of telomerase mutations in esophageal carcinomas.MethodsSequencing techniques were used to evaluate mutational status of telomerase reverse transcriptase (TERT) and telomerase RNA component (TERC) in neoplastic and adjacent normal mucosa from 143 esophageal cancer (EsC) patients. MTS, flow cytometry, time lapse microscopy, and murine xenograft techniques were used to assess proliferation, apoptosis, chemotaxis, and tumorigenicity of EsC cells expressing either wtTERT or TERT variants. Immunoprecipitation, immunoblot, immunofluorescence, promoter-reporter and qRT-PCR techniques were used to evaluate interactions of TERT and several TERT variants with BRG-1 and β-catenin, and to assess expression of cytoskeletal proteins, and cell signaling. Fluorescence in-situ hybridization and spectral karyotyping techniques were used to examine telomere length and chromosomal stability.ResultsSequencing analysis revealed one deletion involving TERC (TERC del 341-360), and two non-synonymous TERT variants [A279T (2 homozygous, 9 heterozygous); A1062T (4 heterozygous)]. The minor allele frequency of the A279T variant was five-fold higher in EsC patients compared to healthy blood donors (p<0.01). Relative to wtTERT, A279T decreased telomere length, destabilized TERT-BRG-1-β-catenin complex, markedly depleted β-catenin, and down-regulated canonical Wnt signaling in cancer cells; these phenomena coincided with decreased proliferation, depletion of additional cytoskeletal proteins, impaired chemotaxis, increased chemosensitivity, and significantly decreased tumorigenicity of EsC cells. A279T expression significantly increased chromosomal aberrations in mouse embryonic fibroblasts (MEFs) following Zeocin™ exposure, as well as Li Fraumeni fibroblasts in the absence of pharmacologically-induced DNA damage.ConclusionsA279T induces telomere dysfunction and inhibits non-canonical telomerase activity in esophageal cancer cells. These findings warrant further analysis of A279T expression in esophageal cancers and premalignant esophageal lesions.

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Section: Discussionsupporting

confidence: 90%

Telomerase Variant A279T Induces Telomere Dysfunction and Inhibits Non-Canonical Telomerase Activity in Esophageal Carcinomas

et al. 2014

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“…Telomerase activity is downregulated during cell differentiation, likely as a protection against cellular transformation and tumor development (20,22,33,35,51,64,70). However, since TERT also possesses extratelomeric cellular functions which might play an important role in normal cells, the complete reduction of TERT transcription would eliminate these functions.…”

Section: Discussionmentioning

confidence: 99%

Alternatively Spliced Telomerase Reverse Transcriptase Variants Lacking Telomerase Activity Stimulate Cell Proliferation

Hrdličková

Nehyba

Bose

2012

Molecular and Cellular Biology

113

138

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Eight human and six chicken novel alternatively spliced (AS) variants of telomerase reverse transcriptase (TERT) were identified, including a human variant (⌬4-13) containing an in-frame deletion which removed exons 4 through 13, encoding the catalytic domain of telomerase. This variant was expressed in telomerase-negative normal cells and tissues as well as in transformed telomerase-positive cell lines and cells which employ an alternative method to maintain telomere length. The overexpression of the ⌬4-13 variant significantly elevated the proliferation rates of several cell types without enhancing telomerase activity, while decreasing the endogenous expression of this variant by use of small interfering RNA (siRNA) technology reduced cell proliferation. The expression of the ⌬4-13 variant stimulated Wnt signaling. In chicken cells, AS TERT variants containing internal deletions or insertions that eliminated or reduced telomerase activity also enhanced cell proliferation. This is the first report that naturally occurring AS TERT variants which lack telomerase activity stimulate cell proliferation.

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“…The lungs were collected, minced and digested in collagenase enzyme cocktail solution as previously described (38, 39). Single cells were cultured in 10% FCS DMEM medium for two weeks and stained with anti-CD44 and anti-Sca1 antibodies using standard immunocytochemical staining (ICC).…”

Section: Methodsmentioning

confidence: 99%

Immunotherapy of Radioresistant Mammary Tumors with Early Metastasis Using Molecular Chaperone Vaccines Combined with Ionizing Radiation

Weng

Song

Koido

et al. 2013

The Journal of Immunology

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In the present study, exposure of mammary tumor cells derived from mice transgenic for the polyomavirus middle T (PyMT) oncogene to ionizing radiation resulted in the generation of a tumor cell population that preferentially expressed cancer stem cell markers. In addition, these cells were more resistant to further radiation treatments and appeared to acquire enhanced capacity for dissemination to the lungs of mice. We therefore tested an immunotherapy approach to treatment of local and disseminated mammary tumor cells in a murine model, employing a recently developed molecular chaperone-based vaccine that specifically targets the radioresistant subpopulation of tumor cells. Heat shock protein 70-peptide complexes (Hsp70.PC-F) were extracted from fusions of dendritic cells (DC) and radiation enriched tumor cells and the resulting chaperone vaccines used to treat mice with pre-existing lung metastases. Immunization of mice with the Hsp70.PC-F vaccine resulted in a T-cell-mediated immune response including a significant increase in CD4 and CD8 T cell proliferations and the induction of effector T cells capable of targeting radioresistant tumor cells. Importantly, the growth of primary tumors was inhibited and the number of tumor cells metastasizing to lung significantly reduced by combining chaperone vaccine with radiotherapy. These results indicate that Hsp70.PC-F vaccine can induce specific immunity to radioresistant populations of mammary tumor cells and can thus compliment radiotherapy, leading to synergistic killing.

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Telomerase deficiency and telomere dysfunction inhibit mammary tumors induced by polyomavirus middle T oncogene

Cited by 23 publications

References 51 publications

Telomerase Variant A279T Induces Telomere Dysfunction and Inhibits Non-Canonical Telomerase Activity in Esophageal Carcinomas

Telomerase Variant A279T Induces Telomere Dysfunction and Inhibits Non-Canonical Telomerase Activity in Esophageal Carcinomas

Alternatively Spliced Telomerase Reverse Transcriptase Variants Lacking Telomerase Activity Stimulate Cell Proliferation

Immunotherapy of Radioresistant Mammary Tumors with Early Metastasis Using Molecular Chaperone Vaccines Combined with Ionizing Radiation

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