Progressive Telomere Attrition
trigger
Because conventional DNA polymerases cannot fully replicate chromosome ends (the end-replication problem), telomeres shorten with each cell division in cells lacking active telomerase. As a premalignant clone expands, telomeres erode toward a critically short length, which normally signals a DNA-damage response and engages the replicative-senescence or crisis barrier.
Downstream
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Replicative Senescence and Crisis Barrier
Critically short telomeres engage the senescence/crisis barrier that limits replicative potential.
Show evidence (1 reference)
"The repression of telomerase and shorter telomeres in humans may have evolved, in part, as an anticancer protection mechanism."
Establishes telomere shortening and telomerase repression as a tumor-suppressive barrier, the trigger condition this module addresses. Evidence source is OTHER because this is a review article.
Replicative Senescence and Crisis Barrier
effector
Critically short, uncapped telomeres are recognized as DNA double-strand breaks, activating p53/RB-dependent replicative senescence (the Hayflick limit) or, if those checkpoints are bypassed, a crisis state marked by chromosome end-to-end fusions and massive cell death. This barrier limits the number of divisions a lineage can complete and must be overcome for a clone to become immortal.
Downstream
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Telomere Maintenance Reactivation
Rare clones that reactivate a telomere-maintenance mechanism escape the senescence/crisis barrier.
Telomere Maintenance Reactivation
central effector
A rare clone reactivates a telomere-maintenance mechanism, stabilizing telomere length and escaping the senescence/crisis barrier. In the great majority of human cancers this occurs through reactivation of telomerase (TERT) - via TERT promoter mutations, amplification, or rearrangement - while a minority use the recombination-based alternative lengthening of telomeres (ALT) pathway, frequently associated with ATRX/DAXX loss. This is the conserved central node disorder-specific lesions converge upon.
Used by disorders
Glioma
as TERT Promoter Mutation and Telomere Maintenance Reactivation
Show evidence (1 reference)
"A hallmark of advanced malignancies is the ability for continuous cell divisions that almost universally correlates with the stabilization of telomere length by the reactivation of telomerase."
Directly states that telomerase reactivation stabilizing telomere length underlies the continuous cell division of advanced malignancies, the central effector of this module. Evidence source is OTHER because this is a review article.
Replicative Immortality
consequence
With telomeres stabilized, the cancer cell lineage acquires unlimited proliferative capacity - replicative immortality - decoupling division number from the telomere clock. This sustains the extensive clonal expansion required for macroscopic tumor growth and progression.
Show evidence (1 reference)
"They include sustaining proliferative signaling, evading growth suppressors, resisting cell death, enabling replicative immortality, inducing angiogenesis, and activating invasion and metastasis."
Hanahan & Weinberg list enabling replicative immortality as a core hallmark capability, the consequence modeled here. Evidence source is OTHER because this is a review article.