Re: LNT, SNT, or whatever

["Bjorn Cedervall" <bcradsafers@hotmail.com>]

>>functions (due to point mutations, non-disjunction, deletions etc) result 
>>in tumors. There is more along this line.
--------
>	--You are ignoring the factors other than initating events that
affect the development of cancer and may be affected by radiation - like
stimulation of the immune system, stimulated production of repair enzymes
-------------------------------------------------
I am not ignoring these other factors. I am asking for a consistent tumor 
theory where we can get molecular data AND epidemiological data into a model 
that takes all steps into account. This model may be different for different 
histological categories of tumors.

Different tumors arise through different mechanisms & number of underlying 
steps. For the retinoblastoma the penetrance is very high and the immune 
system doesn't matter. For childhood leukemias the number of genetic factors 
to knock out are probably one or two fewer than for many solid tumors.

For chromosomal aberrations (including those scored by the micronucleus 
assay), deletions and point mutations, the repair functions have already 
been included in the studied endpoint - this is exactly why I mentioned 
these lesions.

Furthermore: A tumor seems to develop by a successive series of mutational 
events - at least initially. Say 2-3 point mutations or chromosomal events. 
These events usually disturb two categories of functions (that sometimes 
overlap):
1. The integrity of DNA (repair is an important part of this)
2. Cell cycle regulation.

Once DNA has been damaged in 2-3 of these categories (hundreds of 
possibilities) - the genome becomes instable. The emerging tumor cells may 
not yet leave their tissue origin and invade other tissues but they now 
divide faster and with a higher probability of errors.

Therefore the probability becomes higher (partly because there now are more 
of these cells) that these cells eventually obtain DNA damage in genes 
relating to the invasive properties. More cells... and they get released 
into the blood stream - those that previously were well oxygenated (and 
therefore also dividing rapidly) were perhaps killed by the immune 
mechanisms - eventually some tumor cells will escape immune system detection 
because of mutations relating to the histocompatibility antigen display on 
the cell surface (such mechanisms were studied in the early 70:ies by the 
use of lectins - the Thesis by Sten Friberg (mouse tumors) is an example).

I would guess that if the immune system takes care of released tumor cells 
(not yet fully aggressive in their properties) it is only a matter of time 
before they get the final mutations that give them the invasive properties 
combined with such that will make them escape the immune functions. The 
mechanism here is selection of the worst. The turnover of the tumor cells 
can be very high (many trial and errors for more mutations, chromsomal 
aberrations etc) with a fast division rate within the first 20 micrometers 
or so from a small blood vessel. Those cells that are located further from 
the vessel (the order of 50-100 micrometers) will not divide because they 
are nutrient and oxygen deficient. The cells that are 100-140 micrometers or 
so from the blood vessel are rapidly dying and leaving room for their 
neighbors that will take their place and then also die which in turn leaves 
more room for cell division in the region near the microvessels.

Therefore there is a high turnover of cells with many chances for the last 
and critical metastasis properties to occur. In particular since there 
statistically will be a parallel increase of DNA damages disturbing the cell 
cycle regulation and DNA repair accuracy & efficiency.

My personal interpretations only,

Bjorn Cedervall    bcradsafers@hotmail.com

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