L3: Transformed cells and replicative immunity Flashcards
immortalised cells lacking telomerase
Some immortalised cells can maintain telomeres without telomerase.
A subset of cancers lacking telomerase maintain their telomeres by engaging the alternative lengthening of telomeres (ALT) pathway.
ALT is now an established telomere maintenance mechanism in human cancers.
Telomere elongation during ALT is triggered by spontaneous double-stranded DNA (dsDNA) damage, chronic replication stress and/or simple telomere erosion
ALT is maintained through a homology-directed DNA repair mechanism
Discovered that there is an alternative pathway that can change the length of the telomeres.
Not driven by telomerase but having the same outcome of lengthening and maintenance of telomerase. Triggered by dna damage response. Maintained through dna damage repair mechanisms.
targeting telomerase
Can we target telomerase?
inhibition/activation of gene transcription, e.g: inactivate promoter activation?
inhibition/activation of protein synthesis
Inhibition of enzymatic activity e.g: through small molecule inhibitors
+ve not active in normal cells
-ve ALT could confer resistance
To date, imetelstat is the only direct inhibitor of telomerase that has entered clinical trials, which have shown that imetelstat may be effective in patients with certain rare hematologic cancers.
Cancer-specific. No adverse effect on normal biology as no telomerase activity. No off-target effects in normal cells.
The issue is that we know there is an alternative pathway which was partly discovered as people would try to inhibit telomerase and found it was not ineffective.
Shows that cancer cells have a high level of plasticity. Good at switching pathways and finding alternative routes.
This lecture focused on two
characteristics of the hallmarks
of a cancer cell
Sustained proliferative signalling
Introduced concept of oncogenes > follow up lecture growth factors and receptors
Replicative immortality
Role of telomere shortening in the regulation of normal cell proliferation
Loss of telomere shortening in cancer cells
Shows the textbook at the end - look at that!!
But quite detailed
