{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T08:20:19Z","timestamp":1791274819771,"version":"4.1.0"},"reference-count":72,"publisher":"Cold Spring Harbor Laboratory","issue":"1","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Genes Dev."],"published-print":{"date-parts":[[2003,1,1]]},"abstract":"<jats:p>Telomerase activation is a common feature of most advanced human cancers and is postulated to restore genomic stability to a level permissive for cell viability and tumor progression. Here, we used genetically defined transformed mouse embryonic fibroblast (MEF) cultures derived from late generation<jats:italic>mTerc<\/jats:italic><jats:sup><jats:italic>\u2212\/\u2212<\/jats:italic><\/jats:sup><jats:italic>Ink4a\/Arf<\/jats:italic><jats:sup><jats:italic>\u2212\/\u2212<\/jats:italic><\/jats:sup>mice to explore more directly how telomere-based crisis relates to the evolution of cancer cell genomes and to tumor biology. An exhaustive serial analysis of cytogenetic profiles over extensive passage in culture revealed that the emergence of chromosomal fusions (including dicentrics) coincided with onset of deletions and complex nonreciprocal translocations (NRTs), whereas<jats:italic>mTerc<\/jats:italic>-transduced cultures maintained intact chromosomes and stable genomes. Despite a high degree of telomere dysfunction and genomic instability, transformed late passage<jats:italic>mTerc<\/jats:italic><jats:sup><jats:italic>\u2212\/\u2212<\/jats:italic><\/jats:sup><jats:italic>Ink4a\/Arf<\/jats:italic><jats:sup><jats:italic>\u2212\/\u2212<\/jats:italic><\/jats:sup>cultures retained the capacity to form subcutaneous tumors in immunocompromised mice. However, even moderate levels of telomere dysfunction completely abrogated the capacity of these cells to form lung metastases after tail-vein injection, whereas<jats:italic>mTerc<\/jats:italic>reconstitution alone conferred robust metastatic activity in these cells. Finally, serial subcutaneous tumor formation using late passage transformed<jats:italic>mTerc<\/jats:italic><jats:sup><jats:italic>\u2212\/\u2212<\/jats:italic><\/jats:sup><jats:italic>Ink4a\/Arf<\/jats:italic><jats:sup><jats:italic>\u2212\/\u2212<\/jats:italic><\/jats:sup>cultures revealed clear evidence of telomerase-independent alternative lengthening of telomeres (ALT). Significantly, despite a marked increase in telomere reserve, cells derived from the ALT+ subcutaneous tumors were unable to generate lung metastases, indicating in vivo functional differences in these principal mechanisms of telomere maintenance. Together, these results are consistent with the model that although telomere dysfunction provokes chromosomal aberrations that initiate carcinogenesis, telomerase-mediated telomere maintenance enables such initiated cells to efficiently achieve a fully malignant endpoint, including metastasis.<\/jats:p>","DOI":"10.1101\/gad.1029903","type":"journal-article","created":{"date-parts":[[2003,1,3]],"date-time":"2003-01-03T18:03:13Z","timestamp":1041616993000},"page":"88-100","source":"Crossref","is-referenced-by-count":148,"title":["Telomere-based crisis: functional differences between telomerase activation and ALT in tumor progression"],"prefix":"10.1101","volume":"17","author":[{"given":"Sandy","family":"Chang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christine M.","family":"Khoo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria L.","family":"Naylor","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Richard S.","family":"Maser","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ronald A.","family":"DePinho","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"246","published-online":{"date-parts":[[2003,1,1]]},"reference":[{"key":"2021111519023260000_17.1.88.1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.89.21.10114"},{"key":"2021111519023260000_17.1.88.2","doi-asserted-by":"publisher","DOI":"10.1038\/35020592"},{"key":"2021111519023260000_17.1.88.3","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.112515399"},{"key":"2021111519023260000_17.1.88.4","doi-asserted-by":"publisher","DOI":"10.1097\/00000658-200109000-00008"},{"key":"2021111519023260000_17.1.88.5","doi-asserted-by":"publisher","DOI":"10.1016\/S0092-8674(01)00492-5"},{"key":"2021111519023260000_17.1.88.6","doi-asserted-by":"publisher","DOI":"10.1016\/S0092-8674(01)80006-4"},{"key":"2021111519023260000_17.1.88.7","doi-asserted-by":"publisher","DOI":"10.1126\/science.279.5349.349"},{"key":"2021111519023260000_17.1.88.8","doi-asserted-by":"crossref","first-page":"155","DOI":"10.1016\/S0300-9084(99)80048-0","article-title":"Oxidative DNA damage processing in nuclear and mitochondrial DNA.","volume":"81","author":"Bohr","year":"1999","journal-title":"Biochimie"},{"key":"2021111519023260000_17.1.88.9","first-page":"2104","article-title":"Limited proliferation and telomere dysfunction following telomerase inhibition in immortal murine fibroblasts.","volume":"62","author":"Boklan","year":"2002","journal-title":"Cancer Res."},{"key":"2021111519023260000_17.1.88.10","doi-asserted-by":"publisher","DOI":"10.1038\/nm1197-1271"},{"key":"2021111519023260000_17.1.88.11","first-page":"2533","article-title":"Telomerase activity associated with acquisition of malignancy in human colorectal cancer.","volume":"55","author":"Chadeneau","year":"1995","journal-title":"Cancer Res."},{"key":"2021111519023260000_17.1.88.12","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.212514699"},{"key":"2021111519023260000_17.1.88.13","doi-asserted-by":"publisher","DOI":"10.1016\/S0092-8674(00)80762-X"},{"key":"2021111519023260000_17.1.88.14","doi-asserted-by":"crossref","first-page":"1921","DOI":"10.1002\/j.1460-2075.1992.tb05245.x","article-title":"Telomere shortening associated with chromosome instability is arrested in immortal cells which express telomerase activity.","volume":"11","author":"Counter","year":"1992","journal-title":"EMBO J."},{"key":"2021111519023260000_17.1.88.15","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.91.8.2900"},{"key":"2021111519023260000_17.1.88.16","unstructured":"de Lange T. 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