Telomeric Theory - Growth Factors

Aubrey de Grey ag24 at mole.bio.cam.ac.uk
Mon Sep 28 07:32:12 EST 1998

Andrew Mason wrote:

> James, can you cite the research that shows that adding telomerase
> to normal cells makes them cancerous. My impression was that the
> experiments done by Geron immortalized human fibroblasts and did not
> turn them cancerous.
> Just because most (not all) cancer cells express telomerase, it does
> not mean that all cells that express telomerase are cancerous.

I see that James has not got round to replying; apologies to him if he
is doing so as I write :-)  Note first that James said that constitutive
telomerase expression would "cause cancer", not "make cells cancerous":
this distinction is important.

It is necessary to consider cells in vivo and in vitro separately.  In
vivo, we know (from very many studies, of which I believe the first was
Counter et al, EMBO J 11(5):1921-1929) that telomerase is expressed in
most human tumours at levels a good deal higher than in any non-cancerous
somatic tissue yet found.  This has been taken to indicate that activation
of telomerase, though not absolutely necessary for tumour progression, is
a big step towards it, ie a telomerase-positive cell needs fewer other
mutations to become a full-blown tumour than a telomerase-negative one.
Since mutations are stochastic, this implies that a human all of whose
cells are telomerase-positive from birth will get cancer sooner than a
normal human.

So to the in vitro case.  The experiments by Geron are just as you say:
in fact, the whole reason why they are interesting is that the cells are
not cancerous, since cancerous cells already have indefinite replicative
capacity.  But this does not conflict with the in vivo argument above.
Why not?  Because non-cancerous normal human cells NEVER spontaneously
become cancerous in vitro.  When I say "never" I of course can only mean
"not in the finite number of cultures examined so far", but that finite
number is quite large.  This is not actually much of a surprise, because
(a) people are bigger than cultures, and (b) the environment of a cell in
culture may be a good deal less mutagenic than that of a cell in the body.
So this means that Geron's cells may be a lot more prone to cancer than
telomerase-negative cells, but not prone enough to have become cancerous
in the time (and in the number of cultures) yet examined.

Aubrey de Grey

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