Telomeric Theory - Growth Factors

James james at nospam.com
Tue Sep 29 00:28:21 EST 1998


andrewmason at my-dejanews.com wrote:
> 
> Aubrey de Grey wrote:
> > 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.

James me?  I don't recall syaing that, and if I did I
certainly didn't mean it literally (but probably assumed
that since this type of telomerase thread has been ongoing
for so long that people would know what I meant).  But that
doesn't really reduce the concern much, as I will elaborate
on below.

> > 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.

Correct.

> I agree that this is probably the case, and it also seems likely to me
> (admittedly without any reading or research) that the cells in the body that
> have been shown capable (or are suspected) of expressing telomerase are the
> ones that are the sites of many of the more common cancers.

No.  The cells that most often become cancerous are probably
the ones that can most easily mutate to have inappropriate
response to growth factors - but this is not my area of
expertise.

> 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?

No - as stated above.

> For example,I assume that the only part of the body where telomerase is
> expressed continually is the testes, but we don't all get testicular cancer.
> The presence of telomerase may increase the incidence of cancer when compared
> to other organs, but that doesn't make it certain to occur.

Saying telomerase is expressed in the testes is too
general.  Telomerase is expressed ini germline cells. 
Telomerase is not secreted, so it would have no effect on
the surrounding testicular tissue.  So the only thing that
telomerase could do in the tissues where it is normally
expressed is cause cancer of the spermatocytes.  These cells
are so specialized that it is probably nearly impossible for
them to cause cancer.  The reason you get testicular cancer
is probably because of the presence of testerone acting as a
growth factor - it has nothing to do with telomerase.

> 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.

Good analogy.

> > 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.
> 
> 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.
> 
> I guess the implication for any sort of future telomerase based therapy for
> aging is that a one time activation of telomerase that added a reasonable
> number of bases to the telomeres would be safer than an approach that relied
> on regular expression of just enough telomerase to add a small amount to the
> telomeres prior to each cell division.
> 
> Andrew

All this sounds good except for a few points.  First, I have
heard it said (and I cannot say if this is really true or
not, but I wouldn't doubt it) that statistically speaking
almost all men who make it to the age of 80 (or some such
number) have prostate cancer.  They may never know it, but
that's only because they end up dying fom something else
before it becomes a problem.  That serves to illustrate that
cancer might be a much bigger problem than you might think,
even if we were only to increase lifespan by a little bit.

Second, just a "one time activation of telomerase" could
have much more dire consequences that you seem to think. 
Keep in mind that cell growth is exponential, so if you
lengthen telomeres by enough to permit say just 5 more
divisions, you have allowed a tumor to get 32 times larger
(2 to the 5th power).  So what might have arrested as a tiny
tumor that you never even would have known about can now
become life threatening.

I don't think that there is any question that we need a MUCH
better handle on cancer treatment before any type of
telomerase therapy can be considered (even if it would work,
which remains pure speculation).

Anyway, I think I'm about done on the telomerase topic.  I
think everything has been said many times (as I think Brian
pointed out recently).  Until more experiments are done we
are just rehashing old material to no avail.




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