Biomedical Engineering Reference
In-Depth Information
the tumor and that no differences in neutrality of interaction or separated time
scales are necessary for different groups.
Although after prolonged evolution tumor systems are likely to tend toward
homogeneity, diversity is the preferred landscape state in most intermediate or
advanced tumors. Homogeneity may be achieved theoretically, but only after
death of the host. Detailed studies of preneoplastic tissues reveal that diversity is
the rule. When tissues at risk for developing a tumor are studied, diversity
within cancer gene loci is commonly found.
Quantitative studies of the frequencies of alleles for different cancer genes
indicate that the normal physiology of tissues includes random fluctuation of
mutated alleles present at very low frequencies. Theoretical work by the group
of Nowak (26) indicates that the best protection against mutations that favor
overgrowth of a clone is a tissue homeostasis that is locally regulated by small
compartments of cells in tissues. The small size of the compartments, which
protects against the emergence of populations harboring a mutated oncogene or
tumor suppressor gene, favors the emergence of genetic instability (e.g., chro-
mosomal instability). If confirmed, these results suggest that genetic instability
is a characteristic of small tumor clones (oncodemes) from the earliest stages of
the neoplastic process. In fact, many expanded oncodemes may coexist in tissue,
at very low frequencies, and a clinically significant malignant neoplasm may
never emerge. Modeling of the preneoplastic states found in tissue is in keeping
with observations of mutated allele frequencies found in somatic cells (27).
The idea that tumors are composed off a heterogeneous ensemble of tumor
cell populations suggests that the biological behavior of tumors depends on the
composition of the tumor tissue rather than on a common characteristic of "the
tumor cell." In very diverse tumors it is most likely that at least one cell type
will harbor a mutation that renders the cell resistant to therapy. Chemotherapy
may in many instances introduce a disturbance in the system, and disturbance,
an external agent of mortality, can modulate the effect of spatial heterogeneity
on biological diversity (28). The relationship of disturbance to diversity could
explain why a drug, if applied too often or too rarely, can cause an increase in
tumor diversity. Another agent of disturbance that is likely to have significant
effects on the natural evolution of a tumor is ischemia. Loss of perfusion in large
areas is likely to modify the degree of diversity in their immediate vicinity, and
such events are not unusual throughout the natural history of tumors. It is of
interest to consider whether additional ecological principles can illuminate tu-
mor pathophysiology. It seems not too risky to speculate that productivity, the
flow of energy through a system, is determined in the case of tumors by the flow
of blood through the tumor tissue. In bacterial systems, productivity is known to
affect diversity in the same way that disturbance does (29).
As more and more therapies are designed to hit specific molecular targets, it
will be important to know the degree of heterogeneity in tumors that are to be
treated. Ideally, one would want to monitor the tumor-cell cell composition as
