Telomere-based crisis: functional differences between telomerase activation and ALT in tumor progression
Open accessAbstract
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 mTerc−/−Ink4a/Arf−/−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 mTerc-transduced cultures maintained intact chromosomes and stable genomes. Despite a high degree of telomere dysfunction and genomic instability, transformed late passage mTerc−/−Ink4a/Arf−/−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 mTerc reconstitution alone conferred robust metastatic activity in these cells. Finally, serial subcutaneous tumor formation using late passage transformed mTerc−/−Ink4a/Arf−/−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.
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The activation of ALT in tumors with telomere dysfunction may serve as another avenue toward alleviating the antitumorigenic effects of telomere dysfunction, as observed previously in murine cell-based transformation systems.
“Furthermore, the activation of ALT in tumors with telomere dysfunction may serve as another avenue toward alleviating the antitumorigenic effects of telomere dysfunction, as we have observed previously in murine cell-based transformation systems (52).”
From <i>Ink4a</i> / <i>Arf</i> tumor suppressor does not modulate the degenerative conditions or tumor spectrum of the telomerase-deficient mouse (2007) · cites this paper as [52]
In both the squamous cell carcinoma and breast adenocarcinoma models, emergent cancers showed activation of endogenous telomerase activity.
“Importantly, in both the squamous cell carcinoma model and the breast adenocarcinoma model, the emergent cancers show activation of endogenous telomerase activity.”
From Telomeres and telomerase in cancer (2010) · cites this paper as [98]
In most cases, enforced expression of exogenous TERT was required for transformation of human cells, with exceptions such as keratinocytes transformed by IκBα and activated H-RAS.
“In the vast majority of cases, enforced expression of exogenous TERT was required for transformation, although there are some exceptions such as human keratinocytes wherein Inhibitor NFjB a (IjBa) and activated H-RAS can drive transformation to squamous cell carcinoma (98).”
From Telomeres and telomerase in cancer (2010) · cites this paper as [98]
TERT promotes tumor development even in settings of ample telomere reserve.
“Moreover, recent findings indicate that TERT promotes tumor development even in settings of ample telomere reserve, although the mechanisms underlying these telomere length-independent activities of TERT remain unclear9–13.”
From Conditional telomerase induction causes proliferation of hair follicle stem cells (2005) · cites this paper as [12]
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References 72 · Cited by 183
Research works printed but not linked: 8
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- Authors
- Chang, S., Khoo, C. M., Naylor, M. L., Maser, R. S., & DePinho, R. A.
- Affiliations
- Brigham and Women's Hospital (US)
- Venue
- Genes & Development
- Publisher
- Cold Spring Harbor Laboratory
- Published
- 2003-01-01
- Volume
- 17
- Issue
- 1
- Pages
- 88-100
- ISSN
- 0890-9369 (ISSN-L)
- 1549-5477
- PMC
- PMC195968
- OpenAlex
- W2137023032
- Cited by
- 183
- References
- 72
- Citations by year
- 2025: 2 · 2024: 1 · 2023: 2 · 2022: 1 · 2021: 5 · 2019: 3 · 2017: 2 · 2016: 6 · 2015: 6 · 2014: 2 · 2013: 7 · 2012: 12
- Type
- posted content
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Genes & Development (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Ellison Medical Foundation
- Damon Runyon Cancer Research Foundation
- National Institute on Aging (1KO8AG01019-01, K08AG001019)
- Topics
- Health Sciences › Medicine › Physiology › Telomeres, Telomerase, and Senescence
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Aging › Genetics, Aging, and Longevity in Model Organisms
- Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
- Keywords
- telomere crisis, telomerase activation, alternative lengthening of telomeres, telomere dysfunction, genomic instability, chromosome fusion, dicentric chromosomes, non-reciprocal translocation, tumor progression, metastasis, lung metastasis, telomere maintenance, Ink4a/Arf, mouse embryonic fibroblasts, carcinogenesis
- MeSH terms
- Animals, Cell Line, Transformed, Chromosome Aberrations, Chromosomes, Embryo, Mammalian, Fibroblasts, Lung Neoplasms, Neoplasm Proteins, Neoplasm Transplantation, RNA, Mice, SCID, Telomere, In Situ Hybridization, Fluorescence, Mice, Knockout, Telomerase, Cyclin-Dependent Kinase Inhibitor p16, Chromosome Painting, Mice
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