Biomedical Engineering Reference
In-Depth Information
genetic instability (15-20). There are multiple ways that genetic instability can
be generated (chromosomal instability and microsatellite instability) and ob-
served. For example, tumor cells exhibit karyotypes that are grossly changed in
quantity and quality from the complement of normal cell chromosomes.
Radman and colleagues have suggested that two different models can ex-
plain mutations in evolution (1). In one model, there is a low mutation rate in a
very large population. In the second model, there is a high mutation rate in a
limited population with coincident intense recombination, permitting a rare
adaptive mutation to become separated from frequent deleterious mutations (1).
The latter type of evolution can be seen in bacterial populations under stress. It
is likely that the evolution of cancer is a combination of these two models. The
initial mutations within a cell destined to become cancer happen as a result of a
low mutation rate within a large population of cells. These mutations occur as a
result of the interplay between susceptibility alleles and the environment, as
outlined above. Within the expanding clone, a mutation eventually occurs that
induces a "mutator phenotype" with coincident high mutation rates and the gen-
eration of tumor cell populations with a heterogeneous set of properties over a
relatively short period of time. While this mutator phenotype may occur as a
result of chance, it may also be facilitated by the exposure of the cells to
stresses, such as hypoxia, as the size of the tumor increases. Indeed, it has been
demonstrated that hypoxia induces genetic instability in cancer cell populations
(21,22). The emergence of the mutator phenotype rapidly selects cells with the
most robust survival advantages. This robust phenotype can be observed clini-
cally. A cancer can be in remission for many years and then present with metas-
tatic disease that quickly kills the patient over a matter of weeks or months (23).
3.3. Protection from Death
There are multiple redundant pathways in place to maintain the fidelity of
cellular systems to prevent mutation and damage. More often than not, deleteri-
ous mutations lead to initiation of programmed cell death. Teleologically, this is
built into systems to protect the rest of the cell population. There are multiple
apoptotic pathways within cells in response to different types of cellular damage
(24,25). Cancer cells have acquired mutations that allow damage to occur and
accumulate without activating apoptotic pathways. It is almost unbelievable, the
amount of genetic ruin, mutation, and rearrangement that a cancer cell can ac-
cumulate and still be viable, functional, and robust (26).
3.4. No Inhibition of Growth
For an organism or organ such as the liver to function in a coordinated fash-
ion, it must control the individual cells that compose it, just as a society must.
But for a human population to grow and expand, it must outfit groups to leave
the population base and find new areas to populate. In cancer cells, this growth
