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In some the rate is fast; in others, slow; but in all
cancers the cells never stop dividing.
This
distinguishes cancers — malign tumors or malignancies — from
benign growths like moles where their cells eventually stop
dividing.
Cancers are clones. No matter how many
trillions of cells are present in the cancer, they are all
descended from a single ancestral cell. Evidence: Although
normal tissues of a woman are a mosaic of cells in which one X
chromosome or the other has been inactivated [Link], all her
tumor cells — even if from multiple sites — have the same X
chromosome inactivated.
Cancers begin as a primary
tumor. At some point, however, cells break away from the
primary tumor and — traveling in blood and lymph — establish
metastases in other locations of the body. Metastasis is what
usually kills the patient.
Cancer cells are usually
less differentiated than the normal cells of the tissue where
they arose. Many people feel that this reflects a process of
dedifferentiation, but I doubt it. Rather, evidence is
accumulating that cancers arise in precursor cells — stem
cells or "progenitor cells" — of the tissue: cells that are
dividing by mitosis producing daughter cells that are not yet
fully differentiated.
Cancer cells contain many
mutated genes. These almost always include:
mutations
in genes that are involved in mitosis; that is, in genes that
control the cell cycle.
Oncogenes. Their mutated or
over-expressed products stimulate mitosis even though normal
growth signals are absent. Examples:
SIS, the gene for
platelet-derived growth factor (PDGF) and
EGFR, the
gene encoding the receptor for epidermal growth factor (EGF)
(EGFR is also known as HER1.)
These genes act as
dominants; that is, only one of the pair need be mutated to
predispose the cell to cancer.
Tumor suppressor genes.
These genes normally inhibit mitosis.
Example: the p53
gene product normally senses DNA damage and either halts the
cell cycle until it can be repaired or, if the damage is too
massive; triggers apoptosis.
Example: The MAD
(="mitotic arrest defective") gene encodes a protein that
binds to kinetochores until spindle fibers attach to them. If
there is any failure to attach, MAD remains and blocks entry
into anaphase (by inhibiting the anaphase promoting complex
(APC).
Mutations in MAD produce a defective
protein and failure of the checkpoint. The cell finishes
mitosis but produces daughter cells with too many or too few
chromosomes (aneuploidy). Aneuploidy is one of the hallmarks
of cancer cells suggesting that failure of the spindle
checkpoint is a major step in the conversion of a normal cell
into a cancerous one.
Tumor suppressor genes
are recessive; that is, either both copies must be mutated for
their function to be lost or — more commonly — the healthy
copy of the gene has been lost.
Genes that
regulate apoptosis. Mutations in these enable the cell to
ignore signals telling it that it is irreparably damaged and
should commit suicide
Genes that maintain
telomeres (the chromosome tips). Normal cells lose a portion
of their chromosome tips (telomeres) at each mitosis. This
establishes a limit to the number of times they can divide
before the chromosomes become too short and in this way limits
the life span of any cell lineage. Telomere shortening can be
avoided by telomerase, an enzyme that extends the telomeres.
Normal cells do not contain telomerase. Most malignant cells
regain the ability to express telomerase and in this way gain
immortality.
Genes that stimulate
angiogenesis. Tumors, like any tissue, need a blood supply to
bring food and oxygen and to take away wastes. So as it grows,
a developing cancer must be able to stimulate the growth of
new, normal, blood vessels into itself. This is done by the
release of angiogenesis stimulants, e.g., vascular endothelial
growth factor (VEGF), perhaps as an additional effect of
mutated oncogenes or tumor suppressor genes.
Metastasis genes: genes that enable cells of
the tumor to separate from the primary tumor and migrate to
other parts of the body. These can be:
mutations in
genes whose products normally keep the cells of a tissue
adhering to one another.
Example: the E-cadherin genes
that help hold epithelial cells together (the most common
cancers are carcinomas — cancers of epithelial cells).
mutations in genes whose products normally
keep the cells adhering to their substrate.
Example:
integrin genes
elevated expression of genes
that encode proteases which can break down the proteinaceous
extracellular material that normally holds cells in
place.
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