Abstract B32: Telomerase activity confers growth and DNA damage survival advantages in telomerase-negative transformed human cells
Bibliographic record
Abstract
Abstract Constitutively high telomerase activity is detected in more than 85% of human cancers. Together with the activation of oncogenic growth through RAS-oncogene-associated signal transduction pathways and the inactivation of tumor suppressor pathways regulated by p53 and Rb, telomerase reverse transcriptase expression promotes tumorigenic transformation of human cells. The prevalence of telomerase, rather than a homologous recombination-based mechanism, for telomere length maintenance in human cancers, suggests that telomerase has auxiliary roles in tumorigenesis. Here, we investigate growth advantages provided by the telomerase enzyme in oncogene-transformed human cells that do not require telomerase activity for telomere length control. We employed retroviral vector directed expression of telomerase components in human cell models that utilize the alternate lengthening of telomeres (ALT) mechanism for telomere maintenance. Forced expression of telomerase in ALT cells did not abolish the ALT mechanism, and ALT molecular characteristics were maintained in the resultant cell lines. Our data indicates that in these oncogene-transformed ALT cells, telomerase activity accelerates cell growth kinetics and promotes anchorage-independent growth. Co-culture experiments demonstrated that this growth advantage conferred by telomerase activity is not transferable by cytokine exchange and not likely the result of increased cellular crosstalk. Growth advantages provided by telomerase required all functional aspects of the enzyme. Dissociation-of-activities telomerase mutants and other functionally defective versions of telomerase were unable to promote oncogene-transformed cell growth, implying that canonical telomerase activities may be involved. Telomerase-positive ALT cells pass through the cell division phases of the cell cycle with increased kinetics, suggesting that the observed cell growth advantage is cumulative over cycles of proliferation. In addition, telomerase-positive ALT cells displayed an increased tolerance to the cytotoxic effects of DNA damaging agents that cause double-stranded DNA breaks. We conclude that telomerase expression provides growth and survival advantages to oncogene-transformed human cells; this supports the development of telomerase-based anticancer chemotherapies targeting these growth-promoting effects. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the Second AACR International Conference on Frontiers in Basic Cancer Research; 2011 Sep 14-18; San Francisco, CA. Philadelphia (PA): AACR; Cancer Res 2011;71(18 Suppl):Abstract nr B32.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.004 | 0.001 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".