Telomeric Theory - Growth Factors

Aubrey de Grey ag24 at mole.bio.cam.ac.uk
Tue Sep 29 07:55:21 EST 1998

Andrew Mason wrote:

> I think however that there is a subtle difference between increasing the
> likelihood of cancer and "causing cancer".  Without getting into a semantic
> agument I felt that James' use of 'cause' implied some measure of certainty
> that it was going to occur, as opposed to a simple causal link that may
> have had a low rate of occurrence. If cancer can occur without telomerase
> initially being present, and telomerase can be present without cancer
> occurring, does telomerase 'cause' cancer?

I think James was on pretty solid ground there, given the large numbers
involved.  Since we are composed of so many cells, and just one becoming
cancerous is enough, each cell has a really tiny chance of becoming mutant
for a relevant gene (and must be mutant for several such genes in order to
become cancerous).  If we reduce that "several" by one (or possibly more,
since there may be multiple telomerase-inhibition systems), we therefore
raise the chance of a given cell becoming cancerous by a big factor.  That
translates to virtual certainty that the first such event will be sooner.

> It may be that in telomerase expression may not occur in cells other than
> those that require high turnover rates as a way of reducing the possibility
> of cancers getting a foothold. The natural limiting of telomere length may
> be like putting an aggressive dog on a chain - at least if it goes beserk
> it won't get far or do much damage before it chokes.

This is indeed the standard argument.  It is also held to explain why mice
are so profligate with their telomeres: mice are small enough that a tumour
would reach a fatal size before reaching replicative senescence, so turning
off telomerase would be of no benefit, so they don't bother with a complex
system for giving cells just the minimal amount (usually none).

> So I guess the next step is to expose Geron's immortalised cells to a
> mutagen and see how the incidence of cancerous transformation compares to
> normal cells exposed to the same mutagen. That may at least confirm your
> hypothesis that telomerase activity would increase the incidence of
> cancer.

That seems like a realistic experiment, yes.  (I can't claim the hypothesis
as mine, though.)  As James mentioned, it's the sort of experiment we would
expect to be already underway, and published very soon if it goes according
to plan.

Aubrey de Grey

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