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Cell differentiation is a measure of the maturity of a
cell. Cells that are fully differentiated (fully mature)
resemble their parent cells in form and function, and
they proliferate very slowly, if at all. In contrast, immature
cells are poorly differentiated, do not yet resemble
their parents, and are able to proliferate at a higher rate.
Most cancer cells are less differentiated, less mature,
than normal cells, allowing cancer cells to proliferate
readily. The degree to which a cell differentiates is
regulated by gene expression. Therefore, by manipulating
gene expression, one can alter the degree of differentiation.
A number of natural compounds, discussed
below, can induce differentiation in cancer cells, thereby
decreasing their proliferation rate and causing them to
display fewer malignant characteristics.
Stem Cells
The least differentiated and most prolific cells within
the body are called stem cells. In a healthy organism,
stem cells act as a source of new cells during tissue repair.
Stem cells are capable of
both self-renewal (self-replacement) and clonal expansion
and so are virtually immortal. Not surprisingly,
stem cells are present in high numbers in tissues that
constantly renew their population, such as the bone marrow
and intestinal lining. Bone marrow cells have a
turnover rate of approximately five days, as opposed to
several years for some vascular cells. Although stem
cells in normal tissues have a high ability to proliferate,
their proliferation is tightly regulated, occurring only
under specific circumstances.
Small numbers of stem cells are also present in malignant
tumors. Unlike stem cell proliferation in normal
tissues, that in cancerous tissue is largely unregulated.
Furthermore, the daughter cells do not fully differentiate
(i.e., acquire the functions of more mature cells), and so
the proliferation rate of the offspring remains high. For
these reasons, stem cells are the prime targets of cytotoxic
chemotherapy and radiotherapy.
Tumors can be described by the degree to which their
cells have undergone differentiation; this is referred to
as the “grade” of a tumor. Tumors that are poorly differentiated
generally grow faster and are assigned a
higher grade. The opposite is true for tumors that are
well differentiated. If tumor cells do not differentiate at
all, the tumor is called anaplastic (literally, not formed).
The grading system usually uses a scale of 1 to 3 or 1 to
4, with anaplastic tumors having the highest grade. For
example, a well-differentiated tumor may be classified
as grade 1, whereas a poorly differentiated one may be
grade 4. Most tumors, except perhaps the most anaplastic,
contain enough cells that sufficiently differentiate so
that a pathologist can determine the tissue of origin. For
example, at least a few cells from a bone cancer will
differentiate into mature and identifiable bone cells.
Natural Compounds That Induce
Differentiation
The cells of most cancers have the potential to differentiate
into more mature cells. In other words, many, if
not all, cancer cells retain the capacity to express some
normal characteristics and, under some circumstances,
to suppress malignant behavior.2 Natural compounds
and certain drugs can induce differentiation in cancer
cells, although some cancers are more easily induced to
differentiate than others. The greatest successes so far
have been in inducing leukemia cells to differentiate.3
Cells must be in the cell cycle before they will respond
to differentiating agents; that is, they must be actively
dividing and not in the G0 resting phase .
Leukemia cells are particularly sensitive to differentiating
agents in large part because they have a high rate of
proliferation relative to cells of other cancers. In contrast
to leukemia and other fast-growing cancers, success
in inducing the cells of most solid tumors to differentiate
has been more sporadic.
We note here that, contrary to popular belief, cancer
cells do not generally proliferate at a high rate relative to
normal cells. Fast-growing cancers such as leukemias
proliferate at roughly the rate of fast-growing normal
cells such as bone marrow or hair cells. Fast-growing
cancer cells and fast growing normal cells enter the cell
cycle about once every two weeks or less, and in some
cases once every few days. The cells of other cancers
and those of most normal tissues proliferate much more
slowly. Often, the rate of a tumor’s growth is measured
as its doubling time, the time required for it to double in
volume. To provide some examples, the doubling rate
of breast cancer is generally about 40 to 100 days, that
of lung cancer about 60 to 270 days, of colorectal cancer
about 630 days on the average, and that of prostate cancer
is commonly greater than 740 days. In general,
tumors in younger patients have a faster doubling rate
than those in older patients; likewise, tumors arising
from metastases tend to have a faster doubling rate than
primary tumors. All of these relatively slow-growing
cancers are less susceptible to differentiating agents than
the faster-growing ones.
We have then the seemingly contradictory result that
drugs or other compounds that increase cancer cell proliferation
can, when used in combination with differentiating
agents, increase cell differentiation and in so
doing, ultimately reduce proliferation. As we will later
see, some chemotherapy drugs and natural compounds,
apart from those that induce differentiation, may also be
more effective at inhibiting cancer when cells are actively
proliferating; agents that increase proliferation
may therefore make these more effective too.
NATURAL COMPOUNDS THAT INDUCE DIFFERENTIATION IN VITRO
Arctigenin
ATRA (vitamin A)
Boswellic acid
Bromelain and other proteolytic enzymes
CAPE
Flavonoids (including apigenin, luteolin, quercetin, genistein,
and daidzein)
Emodin
EPA and DHA
Monoterpenes
Resveratrol
1,25-D3 (vitamin D3)
Not surprisingly, most of the differentiation studies using
natural compounds have been conducted on leukemia
cells. Still, melanoma, colon, breast, lung, bladder,
and brain cancer cells have also been reported to differentiate
in some cases.8,_9 Natural compounds that induce
differentiation in vitro are listed above.
Of the compounds listed, ATRA (an active metabolite of vitamin
A) and 1,25-D3 (the active metabolite of vitamin
D3) have received the most research attention. The majority
of compounds listed in Table 3.1 induce differentiation
within the concentration range of roughly 1 to 50
mM, the exceptions being ATRA and 1,25-D3, which
induce differentiation within the concentration range of
about 0.01 to 1 mM. This is still above the normal
plasma concentrations for these two compounds, however.
Some of the compounds listed have also been reported
to induce differentiation in vivo. For example, intraperitoneal
administration of daidzein (at 25 to 50 mg/kg per
day) reduced tumor volume and induced differentiation
of leukemia cells held in chambers in mice.10 The
equivalent human oral dose is about 1.1 to 2.3 grams per
day. The same intraperitoneal dose of boswellic acid
also induced differentiation of leukemia cells in
mice.11,_12 The equivalent human oral dose is about 340
to 680 milligrams per day. Combinations of ATRA and
vitamin D3 at high doses have also been reported to be
effective in animals |
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