Biology Reference
In-Depth Information
over-expression of genes such as MDR1 that encode an
ATP-dependent efflux pump, P-glycoprotein (P-gp),
which effectively pumps out a broad range of cytotoxins
[31,32]
. Trials to mitigate the function of P-gp using
verapamil and ciclosporin its derivative PSC833 have
been disappointing
[33]
.
Host
Internal
Perturbations
External
Perturbations
host
interactions as well as remodeling and control of the tumor
microenvironment. Tumor
tumor entrainment includes various tumor
e
e
Flight Control Surfaces &
Engines
Instructions
Flight Path
host interactions play major
roles in tumor growth and metastasis
[34]
. When tumor
growth is not balanced by vascular growth, a hypoxic
condition emerges in tumor clusters
[35]
. This triggers
HIF-1 upregulation, which induces a series of reactions that
maintain normal physiological conditions
[36]
. Upregula-
tion of HIF-1 induces upregulation of VEGF, which facil-
itates angiogenesis, and uPAR and other genes that enhance
cell motility
[35]
. These responses solve the restriction of
hypoxia for tumor cells, either by providing oxygen to the
tumor cluster or by moving tumor cells to a new environ-
ment
e
Flight Control
Computers
System Control
Fault Torelance
Flight
control
computer
#1
Flight
control
computer
#2
Flight
control
computer
#3
Modularity
resulting in further tumor growth or metastasis.
Interestingly, macrophages are found to move via chemo-
taxis into a tumor cluster. Such a macrophage is called
a tumor associated macrophage (TAM), and is found to
over-express HIF-1
[37]
. This means that a macrophage that
is supposed to remove tumor cells may instead be built-in to
feedback loops to facilitate tumor growth and metastasis.
In addition, tumor cells may evolve through self-
extending symbiosis
[38]
. In this case, tumor cells can
enhance their robustness against various perturbations
through horizontal gene transfer and uptake of chromo-
somes, leading to symbiosis with other cells in the form of
cell fusion, and the formation of symbiotic relationships
with surrounding environments
[39
e
Digital Circuits
FIGURE 24.2
Robustness mechanisms in an airplane.
robust: intratumoral heterogeneity, intracellular feedback
loops, and host
tumor entrainment.
Intratumoral genetic heterogeneity is a major source of
robustness in cancer. Chromosome instability facilitates the
generation of intratumoral genetic heterogeneity through
gene amplification, chromosomal
e
translocation, point
mutations, aneuploidy, etc.
[21
24]
Intratumoral genetic
heterogeneity is one of the most important features of
cancer that provides fault tolerance for the tumor to survive
and grow again despite various therapies, because some
tumor cells may have genetic profiles that are resistant to
these therapies. Whereas there are only a few studies on
intertumor genetic heterogeneity, available observations in
certain types of solid tumor indicate that there are multiple
sub-clusters of tumor cells within one tumor cluster in
which each sub-cluster has different chromosomal aberra-
tions
[25
e
42]
. This implies that
tumor cells may be considered as a group of cells that have
become somewhat detached from the host system and begin
evolving independently, so that a wide range of
phenomena, such as self-extending symbiosis, occur in
tumor cells, thereby enhancing their robustness against
perturbations. There are arguments that cancer cells can
also carry out cell fusion with macrophages to change their
character to support metastasis
[39,40]
. Furthermore,
macrophages accumulate around a cancer and over-express
genes that may contribute to the growth of a tumor. For
patients who suffer from an immune deficit due to AIDS,
Kaposi sarcomas resulting from AIDS appear with a high
percentage, but the incidence rate of other cancers, such as
breast cancer and lung cancer, are substantially lower than
usual. This seems to indicate that the innate immune
systems are hijacked by cancer cells so as to contribute to
their proliferation and metastasis. If these observations are
correct, the cancer itself seems to evolve to capture the
surrounding host systems as extended cancer systems. So
far, such phenomena have only been reported indepen-
dently,
e
29]
. This implies that each sub-cluster is devel-
oped as a clonal expansion of a single mutant cell. The
creation of a new sub-cluster depends on the emergence of
a new mutant that is viable for clonal expansion. A
computational study demonstrates that the spatial distri-
bution within a tumor cluster enables the coexistence of
multiple sub-clusters
[30]
. The issue of heterogeneity also
applies for cancer stem cells. The heterogeneity of cancer
stem cells provides heterogeneity at genetic and epigenetic
levels.
Multidrug resistance is a cellular-level mechanism that
provides robustness of viable tumor cells against toxic
anticancer drugs. In general, this mechanism involves
e
and
not
placed
in
a
unified
perspective.
