Telomeres and Cancer

Aubrey de Grey ag24 at mole.bio.cam.ac.uk
Tue Mar 9 08:36:04 EST 1999


Tom Mahoney wrote:

> By introducing telomerase prior to a cells encounter with the p-53 process
> of senescence/apoptosis then the cells can retain a "phenotypically youthful 
> state" (see; Science 1998 Jan 16;279(5349):349-352 "Extension of life-span by 
> introduction of telomerase into normal human cells.", Bodnar AG, et al), and 
> avoid the dangers of the crisis stage of cellular development.  This should 
> have the effect of avoiding many of the late age developments of p-53 
> defective cancers.

Your last sentence is not implied.  The main "late age development" to which
you refer is presumably (please correct me if I misunderstand) the activation
of telomerase during crisis.  I can only repeat what I've explained in the
past:

> > If the mutated p-53 gene is the cause of the cell proceeding to crisis
> > and the uncontrolled growth of cancer is a result of the same type of
> > mutations that currently activate telomerase in cancer, post senescence,
> > then avoidance of both senescence and crisis will *decrease* the number
> > of these types of cancers.
> 
> OK, now we're getting somewhere.  What do you mean by "the same type of
> mutations"?  Do you mean "mutations that effectively never happen except
> in crisis"?  OK, so we know that the mutation in p53 itself is not such
> a mutation, since non-mutant p53 precludes crisis.  Why do you think that
> mutations that cause escape from quiescence should need crisis?  I fully
> agree with you that IF THEY DID need crisis then telomere maintenance
> would indeed reduce the number of these types of cancers.  But we're
> back to the very beginning of the whole thread: just as I said on Oct.
> 11th, I know of no evidence for this assertion.  Rather, I think that
> the number of cells which reach crisis without mutating anything except
> p53 will be tiny, because such cells will have divided at a dignified
> pace (if at all) throughout adult life and will thus not get critically
> short telomeres, whereas the number of cells that reach senescence without
> mutating anything except the system that was meant to keep them quiescent
> (and in particular, not mutating p53) will be much larger.  That larger
> category of cells will be allowed to proceed to arbitrarily large tumours
> by telomerase therapy, whereas if there were no telomerase then they would
> be stopped in their tracks by p53.  Thus, telomerase therapy will increase
> the number of [otherwise] p53-mutation-dependent tumours.

In other words, both p53-mutation-dependent and p53-mutation-independent
tumours are predicted to be increased.

Having said that, there is in fact some evidence that the above prediction
is wrong.  One of the many results reported in the recent Cell paper on the
knockout mice is that they get MORE tumours.  The numbers are small, but
the crucial point is that an effect (not quite statistically significant,
but nearly so) is seen in the early-generation mice, so it can't be put
down to the general dysfunction of many tissues which doesn't appear (in
unstressed animals) until the last producible generation.  This result is
quite tantalising enough to merit a lot of research on what type of cancer
actually happens (e.g. whether p53 mutations are present); even better, of
course, will be if the knock-in mice show reduced tumour incidence.

Aubrey de Grey




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