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To be clear, not all cancers develop exactly as in the
scenario above. This scenario is common, however, and
within it lies the foundation for all our discussions on
cancer inhibition. From it, we can identify seven clusters
of procancer events:
1. Induction of genetic instability. Each cancer cell
carries within itself genetic instability, and this instability
increases the chances the cell will be able to
mutate as needed to adapt to its environment.
2. Abnormal expression of genes. In essence, the function
of genes is to make proteins—a process called
gene expression. When they are expressed, some
genes produce proteins that inhibit cancer progression,
and others produce proteins that facilitate it. In
cancer cells, abnormal expression of genes occurs,
resulting in too few proteins that inhibit cancer and
too many that facilitate it.
3. Abnormal signal transduction. Signal transduction is
the movement of a signal from outside the cell toward
the cell’s nucleus, where it can stimulate proliferation
or other activities. One important source of
external signals comes from growth factors. Growth
factors are soluble molecules that bind to specific receptors
on the cell’s surface and stimulate the cell’s
activities. A second source of external signals comes
from cell adhesion molecules (CAMs). Cells interact
with their environment through CAMs located on
their surface. Cell adhesion molecules are proteins
that act like fingers to regulate the degree of contact
with other cells and tissues and inform cells of their
surroundings. Other factors are also involved in signal
generation and signal transduction. For example,
cancer cells can produce their own growth factors,
thereby allowing self-stimulation; they can produce
extra receptors for growth factors; and they can produce
free radicals, which can make growth factor receptors
more responsive to stimulation.
4. Abnormal cell-to-cell communication. By decreasing
their contact with normal cells, cancer cells are
freed to act independently. As mentioned previously,
cell-to-cell communication occurs via portals
between adjacent cells (gap junctions) and through
cell adhesion molecules. Normal cell-to-cell communication
through gap junctions maintains homeostasis
and discourages cancerlike behavior. Normal
CAM activity keeps cells in place and prevents signal
transduction that may be initiated by abnormal
CAM activity.
5. Induction of angiogenesis. Angiogenesis is the
growth of new blood vessels toward and within tumors
(or other tissues). Solid tumors require angiogenesis
in order to grow. Tumors need blood vessels
to supply oxygen and nutrients, and the blood vessels
created by angiogenesis provide the channel by
which tumor cells metastasize to distant locations.
6. Invasion and metastasis. Tumors can spread both
locally, via invasion of adjacent tissues, and distantly,
via metastasis through the blood and lymph
circulation. The spread of cancer, along with uncontrolled
proliferation, is a central hallmark of malignancy.
7. Immune evasion. Cancer cells shield themselves
from immune attack, thereby evading destruction;
they can hide from immune cells by employing various
camouflaging techniques or can produce immunosuppressive
compounds that impair the ability of
immune cells to function.
Since each of these seven clusters is a target for therapy,
we can identify seven strategies for cancer inhibition.
Keep in mind that natural compounds can be used
to carry out each of these seven strategies and that the
best results will be seen when all seven are used together.
The seven strategies are as follows:
1. Reduce genetic instability. Genetic instability is aggravated
by oxidative stress (stress caused by free
radicals). Cancer cells exist in an oxidative environment,
and although such an environment kills
some cells, many continue to survive. As oxidative
stress increases, the declining population of surviving
cells exhibits greater instability and higher mutation
rates, in theory eventually producing more
aggressive and successful cancers.
Thus one way of reducing genetic instability
is by reducing oxidative
stress.
2. Inhibit abnormal expression of
genes. One way that gene expression
can be normalized is through modifying
the activity of transcription factors.
Transcription factors are
proteins that act as switches in the
nucleus to turn on gene expression.
Genes that inhibit cancer progression
are commonly underexpressed in
cancer cells, and genes that facilitate
cancer are commonly overexpressed.
Therefore, cancer can be inhibited by
normalizing the activity of those
transcription factors that control the
expression of these genes.
3. Inhibit abnormal signal transduction.
The movement of a signal from outside
the cell toward the nucleus relies
on several proteins (including kinase
enzymes and ras proteins, discussed
later), and so signal transduction can be inhibited by
blocking the actions of these proteins;
Signal transduction is a normal process needed by
healthy cells, but in cancer cells the volume of signal
transduction is excessive, and the signals that flow
favor proliferation and spread. Thus the intent is not
to eliminate signal transduction but to bring it down
to normal levels.
4. Encourage normal cell-to-cell communication.
Normal cell-to-cell communication can be fostered
by improving gap junction communication and by
normalizing CAM activity.
5. Inhibit tumor angiogenesis. Like signal transduction,
angiogenesis is a normal process; it is needed
during wound healing and in other situations. Angiogenesis
in tumors, however, unlike that in normal
conditions, is uncontrolled and ongoing. Our intent
then is not to eliminate angiogenesis but to normalize
its occurrence by normalizing the factors that control
it. Angiogenesis is most successful if certain chemicals
called angiogenic factors are present, as well as
certain environmental conditions, such as hypoxic
(low-oxygen) ones. Cancer can be inhibited by
blocking the release or action of angiogenic factors
or by otherwise altering the local environment to inhibit
tumor angiogenesis.
6. Inhibit invasion and metastasis. Invasion requires
enzymatic digestion of the healthy tissue surrounding
the tumor. It also requires the migration of tumor
cells. Invasion can be reduced by inhibiting enzymes
that digest local tissues, by protecting normal tissues
from the enzymes, and by reducing the ability of tumor
cells to migrate. Metastasis requires
that cells detach from the primary tumor, enzymatically
digest blood vessel walls to gain access
to and exit from the blood circulation, and evade the
immune system while in the circulation. Thus metastasis
can be checked by inhibiting any one of these
processes.
7. Increase the immune response. The immune response
against cancer cells can be increased by
stimulating the immune system and by reducing the
ability of cancer cells to evade immune attack. Both
actions are best taken in tandem, since without prevention
of immune evasion, immune stimulation will
have little benefit; healthy, vital immune cells can
destroy cancer cells, but only if the cancer cells can
be recognized as foreign to the body.
When natural compounds are used in these strategies,
some will directly inhibit cancer cells, causing them to
die, revert to normalcy (a process called differentiation),
or just stop proliferating. Others will inhibit cancer progression
indirectly by inducing changes in the local environment
that are unfavorable to angiogenesis,
invasion, or metastasis. This might include, for example,
inhibiting the enzymes produced by cancer cells that
allow invasion. Thus we can group natural compounds
into two broad categories of action: those that act directly
on cancer cells to inhibit proliferation (called direct-
acting compounds) and those that inhibit cancer
progression by affecting tissues or compounds outside
the cancer cell (called indirect-acting compounds). In
addition, we can add a third category: compounds that
inhibit cancer through stimulating the immune system.
Although immune attack produces a direct cytotoxic
effect against cancer cells, immune stimulants themselves
generally do not.a | 
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