Biomedical Engineering Reference
In-Depth Information
4.5. Cancer Cells Can Be Defined by a Set of IF/THEN
Rules of Varying Complexity
A fundamental property of complex adaptive systems is flow—the ability to
model much of its actions as a set of IF/THEN rules. Previously, we and others
have demonstrated how the cell-signaling cascades of cells can be modeled as a
series of biocircuits within the cell that can be perturbed by mutation (6,8,46). A
classic circuit consists of wires leading to switches and/or circuits that guide
electricity. For example, the electrical wiring of a house is connected to the
power company, which feeds into the main junction box of the house, which
then sends electricity to several main circuits. Each of these circuits in turn split
to turn on appliances and plugs. These circuits are often termed "nodes." A
prime example of a biocircuit in a cancer cell is hypoxia-inducible factor 1
(HIF-1 ) (see Figure 3). As a tumor grows, it cannot extend beyond a millimeter
in size before it outstrips its blood supply and the cells are starved for oxygen.
Hypoxia serves as a tag to turn on HIF-1 . HIF-1 then turns on more than 40
different pathways to promote cell survival (47). Cell survival is accomplished
by turning on pathways that promote cell energy metabolism in anoxic environ-
ments, blood vessel growth to decrease hypoxia, and a series of genes that pro-
mote metastasis—allowing the cell to migrate to areas of normal oxygenation. In
this manner, HIF-1 functions as a "hypernode" in the biocircuit. If HIF-1 is
mutated, the pathways to promote survival are never turned on and the cells un-
dergo programmed cell death, or apoptosis. If the HIF-1 is counteracted by
cytostatic factors, the tumor may exist in a quiescent steady state. If other
growth factors are present fueling the cancer cells, proliferation is allowed to
occur and the tumor mass grows. If HIF-1 is turned on, growth factors are pre-
sent and the immune system escape mechanisms are in place, the cancer cells
can metastasize. IF/THEN rules can also be applied at the level of the cells
themselves. For example, IF a cell produces proteases, THEN it will break down
the surrounding tissue matrix environment. These rules can be applied to each of
the fundamental alterations that are necessary to form a lethal cancer cell (Ta-
ble 2).
4.6. Genetic Instability Gives Rise to the Diversity of Cancer Cells:
Tumor Cell Heterogeneity
The mutations that lead to formation of a tumor facilitate further changes in
the cancer cells' genetic makeup. The genetic instability inherent in a tumor al-
lows populations of cells to adapt rapidly to new conditions (see chapter 6.2, by
Solé, Gonzales Garcia, and Costa (Part III, this volume)). This helps explain
how cancers avoid the immune system, become resistant to certain drugs, and
how they are able to metastasize. The strategy undertaken by a tumor appears to
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