Telomerase Reactivation following Telomere Dysfunction Yields Murine Prostate Tumors with Bone Metastases
To determine the role of telomere dysfunction and telomerase reactivation in generating pro-oncogenic genomic events and in carcinoma progression, an inducible telomerase reverse transcriptase (mTert) allele was crossed onto a prostate cancer-prone mouse model null for Pten and p53 tumor suppressors...
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| Veröffentlicht in: | Cell 2012-03, Vol.148 (5), p.896-907 |
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| creator | Ding, Zhihu Wu, Chang-Jiun Jaskelioff, Mariela Ivanova, Elena Kost-Alimova, Maria Protopopov, Alexei Chu, Gerald C. Wang, Guocan Lu, Xin Labrot, Emma S. Hu, Jian Wang, Wei Xiao, Yonghong Zhang, Hailei Zhang, Jianhua Zhang, Jingfang Gan, Boyi Perry, Samuel R. Jiang, Shan Li, Liren Horner, James W. Wang, Y. Alan Chin, Lynda DePinho, Ronald A. |
| description | To determine the role of telomere dysfunction and telomerase reactivation in generating pro-oncogenic genomic events and in carcinoma progression, an inducible telomerase reverse transcriptase (mTert) allele was crossed onto a prostate cancer-prone mouse model null for Pten and p53 tumor suppressors. Constitutive telomerase deficiency and associated telomere dysfunction constrained cancer progression. In contrast, telomerase reactivation in the setting of telomere dysfunction alleviated intratumoral DNA-damage signaling and generated aggressive cancers with rearranged genomes and new tumor biological properties (bone metastases). Comparative oncogenomic analysis revealed numerous recurrent amplifications and deletions of relevance to human prostate cancer. Murine tumors show enrichment of the TGF-β/SMAD4 network, and genetic validation studies confirmed the cooperative roles of Pten, p53, and Smad4 deficiencies in prostate cancer progression, including skeletal metastases. Thus, telomerase reactivation in tumor cells experiencing telomere dysfunction enables full malignant progression and provides a mechanism for acquisition of cancer-relevant genomic events endowing new tumor biological capabilities.
[Display omitted]
► Telomerase reactivation in murine prostate cancer model promotes malignant progression ► The malignancies acquire capabilities, such as bone metastases, typical of human disease ► The telomere-based genome instability generates human-relevant genomic aberrations ► Comparative genomic analysis identifies a prognosis signature with clinical potential
Tumors cells that initially acquire dysfunctional telomeres do not exhibit genomic instability until telomerase becomes reactivated. Genetically engineering this sequence of events in mice promotes a malignant progression in prostate cancer that reproduces features of the human disease and generates a genetic signature with potential prognostic value. |
| doi_str_mv | 10.1016/j.cell.2012.01.039 |
| format | Article |
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[Display omitted]
► Telomerase reactivation in murine prostate cancer model promotes malignant progression ► The malignancies acquire capabilities, such as bone metastases, typical of human disease ► The telomere-based genome instability generates human-relevant genomic aberrations ► Comparative genomic analysis identifies a prognosis signature with clinical potential
Tumors cells that initially acquire dysfunctional telomeres do not exhibit genomic instability until telomerase becomes reactivated. Genetically engineering this sequence of events in mice promotes a malignant progression in prostate cancer that reproduces features of the human disease and generates a genetic signature with potential prognostic value.</description><identifier>ISSN: 0092-8674</identifier><identifier>EISSN: 1097-4172</identifier><identifier>DOI: 10.1016/j.cell.2012.01.039</identifier><identifier>PMID: 22341455</identifier><language>eng</language><publisher>United States: Elsevier Inc</publisher><subject>alleles ; Animal models ; Animals ; Bone Neoplasms - secondary ; Bone tumors ; Carcinoma ; Cell Line, Tumor ; Crosses, Genetic ; Disease Models, Animal ; DNA Copy Number Variations ; DNA damage ; Female ; Genomes ; Genomic Instability ; genomics ; Humans ; Male ; Metastases ; metastasis ; Mice ; neoplasm cells ; p53 protein ; prostate ; Prostate cancer ; prostatic neoplasms ; Prostatic Neoplasms - genetics ; Prostatic Neoplasms - pathology ; PTEN protein ; Smad4 protein ; telomerase ; Telomerase - metabolism ; telomerase reverse transcriptase ; Telomere - metabolism ; Telomeres ; Transforming growth factor- beta ; Tumor cells ; Tumor suppressor genes ; Tumor Suppressor Protein p53 - metabolism ; Tumors ; yields</subject><ispartof>Cell, 2012-03, Vol.148 (5), p.896-907</ispartof><rights>2012 Elsevier Inc.</rights><rights>Copyright © 2012 Elsevier Inc. All rights reserved.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c489t-4f0b040a026aac68a951d329eaed41cf2bbc7e4d88b8e05cc5f59653321b9e1f3</citedby><cites>FETCH-LOGICAL-c489t-4f0b040a026aac68a951d329eaed41cf2bbc7e4d88b8e05cc5f59653321b9e1f3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://www.sciencedirect.com/science/article/pii/S0092867412001444$$EHTML$$P50$$Gelsevier$$Hfree_for_read</linktohtml><link.rule.ids>314,776,780,3537,27901,27902,65534</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/22341455$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Ding, Zhihu</creatorcontrib><creatorcontrib>Wu, Chang-Jiun</creatorcontrib><creatorcontrib>Jaskelioff, Mariela</creatorcontrib><creatorcontrib>Ivanova, Elena</creatorcontrib><creatorcontrib>Kost-Alimova, Maria</creatorcontrib><creatorcontrib>Protopopov, Alexei</creatorcontrib><creatorcontrib>Chu, Gerald C.</creatorcontrib><creatorcontrib>Wang, Guocan</creatorcontrib><creatorcontrib>Lu, Xin</creatorcontrib><creatorcontrib>Labrot, Emma S.</creatorcontrib><creatorcontrib>Hu, Jian</creatorcontrib><creatorcontrib>Wang, Wei</creatorcontrib><creatorcontrib>Xiao, Yonghong</creatorcontrib><creatorcontrib>Zhang, Hailei</creatorcontrib><creatorcontrib>Zhang, Jianhua</creatorcontrib><creatorcontrib>Zhang, Jingfang</creatorcontrib><creatorcontrib>Gan, Boyi</creatorcontrib><creatorcontrib>Perry, Samuel R.</creatorcontrib><creatorcontrib>Jiang, Shan</creatorcontrib><creatorcontrib>Li, Liren</creatorcontrib><creatorcontrib>Horner, James W.</creatorcontrib><creatorcontrib>Wang, Y. Alan</creatorcontrib><creatorcontrib>Chin, Lynda</creatorcontrib><creatorcontrib>DePinho, Ronald A.</creatorcontrib><title>Telomerase Reactivation following Telomere Dysfunction Yields Murine Prostate Tumors with Bone Metastases</title><title>Cell</title><addtitle>Cell</addtitle><description>To determine the role of telomere dysfunction and telomerase reactivation in generating pro-oncogenic genomic events and in carcinoma progression, an inducible telomerase reverse transcriptase (mTert) allele was crossed onto a prostate cancer-prone mouse model null for Pten and p53 tumor suppressors. Constitutive telomerase deficiency and associated telomere dysfunction constrained cancer progression. In contrast, telomerase reactivation in the setting of telomere dysfunction alleviated intratumoral DNA-damage signaling and generated aggressive cancers with rearranged genomes and new tumor biological properties (bone metastases). Comparative oncogenomic analysis revealed numerous recurrent amplifications and deletions of relevance to human prostate cancer. Murine tumors show enrichment of the TGF-β/SMAD4 network, and genetic validation studies confirmed the cooperative roles of Pten, p53, and Smad4 deficiencies in prostate cancer progression, including skeletal metastases. Thus, telomerase reactivation in tumor cells experiencing telomere dysfunction enables full malignant progression and provides a mechanism for acquisition of cancer-relevant genomic events endowing new tumor biological capabilities.
[Display omitted]
► Telomerase reactivation in murine prostate cancer model promotes malignant progression ► The malignancies acquire capabilities, such as bone metastases, typical of human disease ► The telomere-based genome instability generates human-relevant genomic aberrations ► Comparative genomic analysis identifies a prognosis signature with clinical potential
Tumors cells that initially acquire dysfunctional telomeres do not exhibit genomic instability until telomerase becomes reactivated. Genetically engineering this sequence of events in mice promotes a malignant progression in prostate cancer that reproduces features of the human disease and generates a genetic signature with potential prognostic value.</description><subject>alleles</subject><subject>Animal models</subject><subject>Animals</subject><subject>Bone Neoplasms - secondary</subject><subject>Bone tumors</subject><subject>Carcinoma</subject><subject>Cell Line, Tumor</subject><subject>Crosses, Genetic</subject><subject>Disease Models, Animal</subject><subject>DNA Copy Number Variations</subject><subject>DNA damage</subject><subject>Female</subject><subject>Genomes</subject><subject>Genomic Instability</subject><subject>genomics</subject><subject>Humans</subject><subject>Male</subject><subject>Metastases</subject><subject>metastasis</subject><subject>Mice</subject><subject>neoplasm cells</subject><subject>p53 protein</subject><subject>prostate</subject><subject>Prostate cancer</subject><subject>prostatic neoplasms</subject><subject>Prostatic Neoplasms - genetics</subject><subject>Prostatic Neoplasms - pathology</subject><subject>PTEN protein</subject><subject>Smad4 protein</subject><subject>telomerase</subject><subject>Telomerase - metabolism</subject><subject>telomerase reverse transcriptase</subject><subject>Telomere - metabolism</subject><subject>Telomeres</subject><subject>Transforming growth factor- beta</subject><subject>Tumor cells</subject><subject>Tumor suppressor genes</subject><subject>Tumor Suppressor Protein p53 - metabolism</subject><subject>Tumors</subject><subject>yields</subject><issn>0092-8674</issn><issn>1097-4172</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2012</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqFkU9v1DAQxS0EokvhC3CA3OglYezYSSxxgZZ_UisQbA-cLMcZF6-SuNhOq357HHbhWOSDD_N7TzPvEfKcQkWBNq93lcFxrBhQVgGtoJYPyIaCbEtOW_aQbAAkK7um5UfkSYw7AOiEEI_JEWM1p1yIDXFbHP2EQUcsvqE2yd3o5PxcWD-O_tbNV8WBwOLsLtplNn_GPxyOQywuluBmLL4GH5NOWGyXyYdY3Lr0s3jn8-QCk86jiPEpeWT1GPHZ4T8mlx_eb08_ledfPn4-fXteGt7JVHILPXDQwBqtTdNpKehQM4kaB06NZX1vWuRD1_UdgjBGWCEbUdeM9hKprY_Jq73vdfC_FoxJTS6uQekZ_RKVZI0A2fAmkyf3kiwHBky2LfsvSnO0XZ2fzCjboyaHEgNadR3cpMNdhtTam9qpVanW3hRQlXvLohcH_6WfcPgn-VtUBl7uAau90lfBRXX5PTs0646yFus1b_YE5nBvHAYVjcPZ4OACmqQG7-7b4DcwC7OF</recordid><startdate>20120302</startdate><enddate>20120302</enddate><creator>Ding, Zhihu</creator><creator>Wu, Chang-Jiun</creator><creator>Jaskelioff, Mariela</creator><creator>Ivanova, Elena</creator><creator>Kost-Alimova, Maria</creator><creator>Protopopov, Alexei</creator><creator>Chu, Gerald C.</creator><creator>Wang, Guocan</creator><creator>Lu, Xin</creator><creator>Labrot, Emma S.</creator><creator>Hu, Jian</creator><creator>Wang, Wei</creator><creator>Xiao, Yonghong</creator><creator>Zhang, Hailei</creator><creator>Zhang, Jianhua</creator><creator>Zhang, Jingfang</creator><creator>Gan, Boyi</creator><creator>Perry, Samuel R.</creator><creator>Jiang, Shan</creator><creator>Li, Liren</creator><creator>Horner, James W.</creator><creator>Wang, Y. Alan</creator><creator>Chin, Lynda</creator><creator>DePinho, Ronald A.</creator><general>Elsevier Inc</general><scope>6I.</scope><scope>AAFTH</scope><scope>FBQ</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7QP</scope><scope>7TM</scope><scope>7TO</scope><scope>8FD</scope><scope>FR3</scope><scope>H94</scope><scope>P64</scope><scope>RC3</scope><scope>7S9</scope><scope>L.6</scope><scope>7X8</scope></search><sort><creationdate>20120302</creationdate><title>Telomerase Reactivation following Telomere Dysfunction Yields Murine Prostate Tumors with Bone Metastases</title><author>Ding, Zhihu ; Wu, Chang-Jiun ; Jaskelioff, Mariela ; Ivanova, Elena ; Kost-Alimova, Maria ; Protopopov, Alexei ; Chu, Gerald C. ; Wang, Guocan ; Lu, Xin ; Labrot, Emma S. ; Hu, Jian ; Wang, Wei ; Xiao, Yonghong ; Zhang, Hailei ; Zhang, Jianhua ; Zhang, Jingfang ; Gan, Boyi ; Perry, Samuel R. ; Jiang, Shan ; Li, Liren ; Horner, James W. ; Wang, Y. 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Alan</au><au>Chin, Lynda</au><au>DePinho, Ronald A.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Telomerase Reactivation following Telomere Dysfunction Yields Murine Prostate Tumors with Bone Metastases</atitle><jtitle>Cell</jtitle><addtitle>Cell</addtitle><date>2012-03-02</date><risdate>2012</risdate><volume>148</volume><issue>5</issue><spage>896</spage><epage>907</epage><pages>896-907</pages><issn>0092-8674</issn><eissn>1097-4172</eissn><abstract>To determine the role of telomere dysfunction and telomerase reactivation in generating pro-oncogenic genomic events and in carcinoma progression, an inducible telomerase reverse transcriptase (mTert) allele was crossed onto a prostate cancer-prone mouse model null for Pten and p53 tumor suppressors. Constitutive telomerase deficiency and associated telomere dysfunction constrained cancer progression. In contrast, telomerase reactivation in the setting of telomere dysfunction alleviated intratumoral DNA-damage signaling and generated aggressive cancers with rearranged genomes and new tumor biological properties (bone metastases). Comparative oncogenomic analysis revealed numerous recurrent amplifications and deletions of relevance to human prostate cancer. Murine tumors show enrichment of the TGF-β/SMAD4 network, and genetic validation studies confirmed the cooperative roles of Pten, p53, and Smad4 deficiencies in prostate cancer progression, including skeletal metastases. Thus, telomerase reactivation in tumor cells experiencing telomere dysfunction enables full malignant progression and provides a mechanism for acquisition of cancer-relevant genomic events endowing new tumor biological capabilities.
[Display omitted]
► Telomerase reactivation in murine prostate cancer model promotes malignant progression ► The malignancies acquire capabilities, such as bone metastases, typical of human disease ► The telomere-based genome instability generates human-relevant genomic aberrations ► Comparative genomic analysis identifies a prognosis signature with clinical potential
Tumors cells that initially acquire dysfunctional telomeres do not exhibit genomic instability until telomerase becomes reactivated. Genetically engineering this sequence of events in mice promotes a malignant progression in prostate cancer that reproduces features of the human disease and generates a genetic signature with potential prognostic value.</abstract><cop>United States</cop><pub>Elsevier Inc</pub><pmid>22341455</pmid><doi>10.1016/j.cell.2012.01.039</doi><tpages>12</tpages><oa>free_for_read</oa></addata></record> |
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| ispartof | Cell, 2012-03, Vol.148 (5), p.896-907 |
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| source | MEDLINE; Cell Press Archives; Elsevier ScienceDirect Journals; EZB Electronic Journals Library |
| subjects | alleles Animal models Animals Bone Neoplasms - secondary Bone tumors Carcinoma Cell Line, Tumor Crosses, Genetic Disease Models, Animal DNA Copy Number Variations DNA damage Female Genomes Genomic Instability genomics Humans Male Metastases metastasis Mice neoplasm cells p53 protein prostate Prostate cancer prostatic neoplasms Prostatic Neoplasms - genetics Prostatic Neoplasms - pathology PTEN protein Smad4 protein telomerase Telomerase - metabolism telomerase reverse transcriptase Telomere - metabolism Telomeres Transforming growth factor- beta Tumor cells Tumor suppressor genes Tumor Suppressor Protein p53 - metabolism Tumors yields |
| title | Telomerase Reactivation following Telomere Dysfunction Yields Murine Prostate Tumors with Bone Metastases |
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