General Cytology
Inactivation of p53 seems to be very important for malignant
progression to be possible. pRb is a key regulator of cell cycle
progression by controlling the E2F protein. The majority of
cancers show inactivation of these TGSs themselves. However,
specific cellular functions can be abrogated by attacking dif-
ferent components of the respective functional pathway. Thus
functional pathways that represent a complex network of differ-
ent gene functions may be hit on various levels in order to pro-
mote tumor development. Many different functional pathways
that explain the heterogeneity of the genes affected in sporadic
cancers have been described.7
malignant progression cannot be achieved at the standard
mutation rates (1 mutation/million bases) observed in pro-
liferating cells. It seems clear now that this baseline mutation
rate is not sufficient for carcinogenesis and that some kind of
genetic instability must occur in order to allow for the nec-
essary mutations in cancer cells. This can only be achieved
if central pathways that maintain the genetic integrity of a
cell are hit. If such cells succeed to survive, they may rapidly
accumulate a sufficient number of mutations that permit the
neoplastic growth properties. Thus, carcinogenesis can for-
mally be subdivided into three major pathways depending
on the molecular mechanism that makes it possible for a
sufficient number of mutations or other genetic alterations
of oncogenes and tumor suppressor genes that initiate and
maintain the neoplastic conversion and progression to be
The Major Pathways of Carcinogenesis
Alterations of mechanisms that maintain the genetic integrity of
the cell's genome thus constitute the least common denomina-
tor. Consequently, neoplasia emerges as the failure of genetic
functions that control either the composition of whole chromo-
somes, their number, structure, and distribution during mitosis
or, alternatively, the integrity of the genetic information encom-
passed in the chromosome even if they do not undergo gross
numerical or structural alterations. Consequently, cancer is the
result of three major mechanisms that destroy the integrity of
the genetic information:
Chromosomal instability (CI)
—Induced by failure of
mechanisms that guarantee the even distribution
of chromosomes to the daughter cells that emerge
during mitosis;
Microsatellite instability (MSI)
—Induced by failure of
DNA mismatch repair enzymes that proofread and
repair errors that occur during the de novo synthesis
of DNA in the S-phase of the cell cycle; and finally
CpG island methylator phenotype (CIMP)
—Induced by
failure of the epigenetic control of genes that regulate
critical steps in these processes and is often associated
with the later development of MSI-induced cancers.
The vast majority of cancers occur via the CIN pathway. The
major underlying mechanisms of carcinogenesis mediated
by CIN is induced by disturbances of the bipolar character of
the mitotic spindle during mitosis and the desegregation of
chromosomes during mitosis (Fig. 1.10).8 During the normal
M phase of the cell cycle the chromosomes line up in a plane,
the metaphase plate, and associate with spindle fibers of micro-
tubule proteins. The fibers together form a metaphase spindle.
They are connected to the kinetochores on the chromosomes,
nucleoprotein bodies
associated with the centromeric
DNA of the chromosomes, and the centrosomes at the poles
of the mitotic cell. In a normal dividing cell the spindle fibers
pull each sister chromatid apart toward the centrosomes. This
ensures that each emerging daughter cell will get exactly one
copy of the sister chromatids to form exactly one new copy of
the respective chromosomes in the emerging new daughter cells.
This complex mechanism is controlled by various checkpoints
that monitor that before the process proceeds to the next step
exactly two centrosomes and microtubules spindle apparatus
have been formed, each chromatid in a pair associates with its
own distinct half of the spindle. Chromatid separation is not
allowed to proceed until all pairs of chromatids are lined up in
the metaphase plate. If these checkpoint controls fail, chromo-
somal segregation may fail and both chromatids may be pulled
to one chromosome (non-disjunction). As consequence one of
the daughter cells may become haploid for the respective chro-
mosome and the other triploid. Alternatively, one chromosome
is completely lost, if the attachment between microtubules and
kinetochores fails.
Fig. 1.10 Influence of centrosome aberrations
on chromosomal instability.
(A) Normal
centrosomal distribution with two spindle poles
results in equal distribution of the chromosomal
material to the daughter cells. (B) aberrant spindle
pole formation leads to unequal distribution of the
chromosomal material; as a result, most cells die
while some can acquire genetic alterations that
lead to a growth advantage and the development
of malignant cell clones.
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