From: Robert J. Bradbury (bradbury@aeiveos.com)
Date: Sat Sep 13 2003 - 07:36:55 MDT
On Fri, 12 Sep 2003, matus wrote:
> It takes *at least* five mutations for a cell to become
> cancerous, 50% of cancerous cells have a mutation in the p53 gene, if
> one of your parents gamete cells has that mutation, you are far more
> likely to get cancer throughout your lifetime then people without that
> mutation.
Actually Michael, this may not be strictly true -- yes the p53 gene
and retinoblastoma (RB gene) mutations do certainly bias cells towards
cancer. The standard "5 mutations" model is used mainly with colon
cancer I believe. But there are other types of cancer, esp. leukemia
where the primary culprit is chromosome rearrangements (do a google
on "Philadelphia Chromosome"). These are due to faulty DNA double
strand break repair processes (i.e. 2 chromosomes break and they
mismatched in the repair process). One could call this a "mutation"
but it generally isn't identified as such.
I think the counts at this point are something like 15-20 tumor suppressor
genes (like p53 and RB) and perhaps 50-100 tumor promoter genes. One
generally has to get mutations in several of the tumor promoter genes
and 1 or more of the tumor supressor genes before the cell becomes
cancerous. The p53 gene is a particular weak point because it seems
it plays a critical part of deciding whether the cell should commit apoptosis
(suicide) if things get too messed up.
> Its not just any five mutations, but a whole score of
> mutations can occur in different places in the genome.
Yes, but I would probably say that each specific type of cancer
results from an accumulation of a specific set of mutations
(or genomic changes) that cause the normal cellular control
processes to become defective. That is why you can view aging
in part of the flip side of the coin from cancer. We *know* from
cancer research that mutations and chromosomal rearrangements
are taking place. One has to ask what kind of damage results
from the same types of mutations and rearrangements taking place
in those genes that are not involved in tumor suppression or
tumor promotion? If one has a few hundred genes involved in
regulating cell division then one has 30,000+ genes involved
in dealing with other stuff. What happens as they gradually
go bad?
> At least five of the target areas have to be mutation.
Not strictly true as pointed out above.
> Eventually, all cells in
> your body (with the exception of nuerons) are child cells of parents,
Not quite accurate. Obviously all the cells in your body are the child cells
of parent cells. Different cells in your body have different regenerative
schedules. The way I like to describe it is to consider the human body
to be organized like a doughnut. The cells on the surface of the doughnut
are exposed to the environment -- these are primarily biased to renew
themselves on a regular basis (these are epithelial cells of one form
or another and are found in the skin, stomach, intestine, lung). The
other major system biased towards cellular renewal are the blood and
immune systems. These are the systems that are the primary sites where
cancer develops. The other systems are biased towards reproduction
are those involved in reproduction (breast, ovary, prostate, etc.).
There are many systems biased against reproduction (heart, other muscles,
brain, kidney, etc.). In these cancer is much less common. The liver
appears to be the odd organ in that it is normally in non-cell-division
mode but can be shifted into cell-division mode if it is damaged enough.
So one can view tissues that are biased towards cellular division
as already having a genetic program with a few "mutations" that
can lead down the path to cancer. (When was the last time you
heard of someone getting "heart cancer"?)
Now, dealing with Robbie's claims -- I would suggest that you go
do a google on "aflatoxin grain cancer". Aflatoxin is a toxin
produced by a natural fungus that is known to cause a specific
mutation(s) in the p53 gene. It is a primary source of liver cancer
in China which has few or no constraints on the levels of aflatoxin
that may be present in grains or peanuts (which are particularly
susceptible to the fungus). Now could you please explain how a toxin
produced by a natural fungus can be considered a "pollutant"?
The rise in exposure to aflatoxin is a consequence of the fact that
over the last several thousand years humans learned to store food
sources to allow them to survive years when crop harvests are poor.
So you can die from starvation or you may eventually die from cancer
due to long term aflatoxin exposure. Take your pick.
I am not saying that there is not any evidence that pollutants do
not contribute to cancer. For example, there is overwhelming evidence
that some of the substances in tobacco smoke -- which one can probably
consider to be a pollutant -- do contribute to mutations and cancer
in a significant subset of the human population (in large part due
to their genetic makeup most probably). However other pollutants,
such as lead, may have little relation to cancer but may instead
impact other functions such a neuronal development or activity.
And in fact it *is* possible using chelation therapy to treat
overexposure to metals. It is much more difficult to deal with
the mutations to the genomic DNA caused by plant toxins.
Robert
Some references:
Tumor Supressor Genes:
http://users.rcn.com/jkimball.ma.ultranet/BiologyPages/T/TumorSuppressorGenes.html
Loss of Tumor Suppressor Gene Triggers Colon Cancer
http://www.hhmi.org/news/vogelstein.html
p53 - tumor suppressor protein
http://www.ncbi.nlm.nih.gov/disease/p53.html
Tumor Suppressor Genes
http://envirocancer.cornell.edu/FactSheet/Genetics/fs6.TSgenes.cfm
This archive was generated by hypermail 2.1.5 : Sat Sep 13 2003 - 07:47:50 MDT