Biomedical Engineering Reference
In-Depth Information
investigators conducting molecular analysis of tumor tissue have described a
significant degree of genetic heterogeneity in tumors of various types (21-23).
It is significant that the heterogeneity at the molecular level involves genes
that play a important role in the pathogenesis of the tumor state and in the main-
tenance of the neoplastic phenotype. Because of this, one may argue that alleles
at these loci should be under selective pressure, so that one would expect to find
the allele present in every cell of the tumor. Many studies that have been inter-
preted as demonstrating clonality of cancer genes in tumors do not deal with the
caveat that they examined large mixed populations in aggregate and that, given
the sensitivity of the detection technologies used in most cases, the results are
likely to show a dominant allele, but do not critically exclude the presence of a
quilted pattern of cell populations harboring allelic diversity in cancer genes.
Most recent studies demonstrating genetic heterogeneity are predicated on using
microdissection as a means of procuring relatively small and well-defined cell
populations.
In attempting to generate models that will illuminate the phenomenology of
tumor cell heterogeneity, it is crucial to simplify by focusing, sometimes arbi-
trarily, on a subset of biological characteristics of the tumor cell. Some key
properties of cancerous tissues result in the increased mutational rate of tumor
cells. These include their increased proliferative activity (which can overcome
elevated rates of cell death) and prolongation of the lifespan of a cell by a vari-
ety of mechanisms that include avoidance of senescence. Other properties of
tumors, such as the capacity to invade or stimulation of tumor angiogenesis, are
undoubtedly of crucial importance to tumor pathophysiology and will need to be
incorporated in more refined versions of metapopulation models of tumor
growth. Is there an ecologic analogue for the two strategies found in tumor cells,
e.g., high replicative rate and avoidance of death? The answer is affirmative,
given the fact that two negatively correlated strategies for space occupation and
persistence are observed in a community. The first, high colonization, is simply
a strategy of effectively occupying available space. In tumors this stems from
the high replication rate of tumor cells compared to normal cells. The second
involves local extinction. It is known that some plants will be more tolerant to
existing local conditions than others because they have developed mechanisms
to tolerate such adverse conditions as shading from their neighbors. Inability to
trigger apoptosis or independence of the need for survival signals from the envi-
ronment are documented strategies evolved by tumor cells during tumor forma-
tion. In many cases there may be a tradeoff between both strategies: good
colonizers are less able to persist, whereas poor colonizers are best adapted to
local conditions, less prone to extinction, and thus better competitors.
A simple metapopulation model can be constructed to illustrate the impor-
tance of each ingredient. Let
p
be the fraction of patches occupied by a given
species; the Levins model will describe the evolution in time of the metapopula-
tion by
