From: Robert J. Bradbury (bradbury@aeiveos.com)
Date: Sat Sep 13 2003 - 10:37:05 MDT
On Sat, 13 Sep 2003, matus wrote:
> I did not
> think the 'five mutation' model was completely accurate in all cases,
> but from the rest of your descriptions, it seems it, or something very
> similar, is the case in most forms of cancer with the exception being
> luekemia.
You have to realize that cancer goes through 3 stages. First,
uncontrolled cell division. Second, production of angiogenisis
factors to increase blood supply (and therefore nutrient availability).
Third, metastasis where the cancer spreads throughout the body.
If you can limit it to the first stage it is less probable
that cancer can kill an individual. The progression through
each of the stages involves the expansion of cells with a
greater number of specific mutations or chromosome rearrangements.
There is a fairly large debate right now within the cancer researcher
community if chromosome rearrangements might not be the start of the
problem followed by mutations rather than the other way around.
I suspect it will turn out to be a mix perhaps depending on cancer
type.
> So the five mutation model may not describe every form of cellular
> cancer, there are probably four mutation or eight mutation variants?
> The number of mutations may differ, but is seems safe to say the
> principle and the requirement for certain number of certain mutations to
> take place is still valid.
Sure. The problem is that "mutations" tends to be a general term
and one has to get down to specifics -- these can include things
like "point mutations" (i.e. the change of a specific base so the
protein does not function as it is supposed to), deletions (i.e.
a section of the gene gets deleted), insertions (i.e. some extra
code gets inserted into the DNA), and chromosome segment exchanges
(that produce cases where genes that are supposed to be off get turned
on or genes that are supposed to be on get turned off).
Its a mess when you get into the details.
> My main point was that once a cell gets a mutation, all of its offspring
> have that same mutation (unless some are lucky enough to have that
> mutation reversed accidently).
Yes, that is why most cancers occur in cells that are significantly biased
to divide -- they probably need fewer mutations to run amok. Reversal
is unlikely -- it is more likely that your immune system just might
be able to recognize the signs of cancerous (malformed) proteins within
a cell and take out the offending cells. This is difficult but serves
as an interesting explanation behind the remission of some cancers.
> Thus the older you get, the more likely
> you are to have more of your cells have more and more mutations, even in
> the absence of pollution or radiation.
I would guess that free radicals and radiation are the primary sources.
That would explain why cancer remains relatively constant across people
with a wide variety of diets that may or may not contain various toxins.
Free radicals would also explain in part why CR is effective in extending
longevity -- fewer free radicals leads to less DNA damage leads to less
cancer (as well as other causes of "aging").
The problem, IMO, is that it appears cells use various pro-oxidant
molecules (e.g. nitric oxide, perhaps superoxide, etc.) as signal
molecules and so they compensate for the amount of anti-oxidant molecules
that may be available. That explains why massive supplementation of
anti-oxidants only has limited effectiveness in extending lifespan.
I think that natural toxins may play only a limted role.
For example several types of cancer have been linked to viruses
(e.g. HPV). Others are linked to numbers of hormonal cycles that
promote cell division (e.g. breast cancer).
Some individuals clearly have molecular signal systems where
natural toxins actually help more than they hurt. This makes the
whole process of attempting to adopt a useful strategy a nightmare
because we don't currently relatively inexpensive genotyping that
would allow one to determine whether such toxins help more than
they hurt. As a side note -- the systems that metabolize the
plant toxins are relatively the same as those that metabolize
drugs. So it is effectively impossible for physicians to prescribe
drug doses that work well without a complete understanding of
ones genetic systems that remove toxins/drugs from ones body.
The variations in rates and processes of metabolizing toxins/drugs
can be quite significant from individual to individual. There
are probably 50 or more genes involved. Each gene may have
multiple variations within a population because they only impact
reproductive and survival capacity to a very limited extent --
so natural evolution will allow the accumulation of many variations.
Some of us may deal with toxins/drugs quite well (perhaps a good
sitation for toxins but a not-so-good situation for drugs where
one might want effects to last longer). Some of us may have the
reverse situation (poor toxin removal but drugs are more effective).
Its a real mess at this time.
Robert
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