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The Cell: Basic Structure and Function
cells that are selected in an ongoing Darwinian selection
process. Specific modifications of the gene expression signature
trigger the next step of selection.
Given the complex alterations required to achieve the signa-
ture of a full-blown cancer cell and given the many individual
selection steps required to transform a normal cell into a can-
cer cell, transformation cannot be achieved by a linear selection
process but depends on higher level mechanisms that allow
for major modifications of the genetic code in a relatively brief
period of time or restricted number of cell divisions. The integ-
rity of the number and structure of chromosomes, for example,
is one particularly important aspect herein. If the mechanisms
that maintain the integrity of the chromosomes fail, major
genomic modifications may rapidly occur. Since most of these
are non-viable, most cells that experience these failures will die
in a process called genomic catastrophe. However, some cells
may survive the complex modifications induced by malfunction
of the mechanisms that preserve chromosomal homeostasis.
If the gene signatures of the surviving cells allow for continu-
ous autonomous growth eventually even at distant anatomical
sites, the respective cell clones may be selected and their sus-
tained growth may then clinically manifest itself as metastasiz-
ing cancer.
To preserve the ordered function of cells in higher order
organisms a number of redundant genome protective mecha-
nisms that prevent consequences of genetic catastrophes have
evolved. They primarily constitute organized suicide mecha-
nisms called apoptosis that become activated once major
modification of the cellular genome in distinct genetically
damaged cells occur. They assure that most cells that undergo
genetic catastrophes undergo apoptosis before they can grow
out as transformed cancer cell. Thus, outgrowth of a cancer
cell still is the rare exception in view of the many billions
of proliferating cells that constitute the human body and the
many events that trigger genomic catastrophes in damaged
cells.
Principles of Malignant Transformation
The development of a cancer cell from a normal cell goes
through three basic steps:
(1)
Immortalization:
In contrast to normal cells, immor-
talized cells can divide indefinitely, as long as they
are supported with nutrients. They still have the
same shape as normal cells, and they stop growing
when they reach other cells (contact inhibition).
(2)
Transformation:
Transformed cells are independent of
tissue-specific growth factors; they lose their contact
inhibition and may grow invasively. Their shape is
altered; the specific differentiation is lost.
(3)
Metastasis:
Metastasizing cells acquire the potential
to migrate to distant sites and grow out to tumors.
These paramount changes occur on the level of the individ-
ual cancer cell. Subsequently, the establishment of tumors larger
than 1-2 mm*
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requires the development of a vascular system
that can support the growing tumor with nutrients. In order to
achieve this, tumors induce angiogenesis via angiogenic factors
such as vascular angiogenic growth factor (VEGF), fibroblast
growth factor (FGF), and platelet-derived endothelial growth
factor (PDGF).
Tumor growth is based on a complex interplay between the
transformed cells and the surrounding tissue: invasive growth
is associated with the expression of proteolytic enzymes that
degrade the peritumoral stroma, most importantly matrix-
metallo-proteinases (MMPs). Furthermore, the immune system
is involved in the local control of growing cancers. It is esti-
mated that the majority of malignant cell clones that develop in
the human body are eliminated by immune system components
directed against the transformed cells, a process called immune-
surveillance. Invasive tumor development needs to evade these
immune control mechanisms. A number of immune evasion
strategies, including loss of antigen presentation machinery
components, induction of suppressive T cells, and induction of
apoptosis in attacking lymphocytes, have been analyzed.
Cancer-related Genes
Three major groups of genes are involved in carcinogenesis:
oncogenes, tumor suppressor genes, and genes that are respon-
sible for DNA repair and stability.7 Oncogenes are mostly activa-
tors of the cell cycle that are strictly controlled in non-malignant
cells. Activation can occur by chromosomal translocations that
bring an active promoter close to an oncogene that is usually
not expressed (e.g. BCR-ABL translocation in leukemia). Gene
amplifications frequently lead to overexpression of oncogenes,
as it is the case for the MYC gene. In addition, point mutations
can lead to continuous activation of oncogenes, e.g. activating
BRAF or RET mutations. In general, mono-allelic activation of
oncogenes is sufficient for malignant transformation. In con-
trast, tumor suppressor genes (TSGs) usually require two hits,
since the unaffected allele can substitute in part for the mutated
allele. Still, in some cases, a partial effect (haploinsufficiency)
conferred by the loss of one allele has been described. TSGs can
be altered by point mutations or by larger chromosomal losses.
Typically genes involved in cell cycle control, regulation of pre-
programmed cellular suicide (apoptosis), or the maintenance
of genomic integrity may serve as TSGs. Repair/stability genes
comprise a specific subgroup of TSGs in that they maintain the
genetic integrity of the cell. Their loss of function is a prerequi-
site for the rapid acquisition of the critical mutations required
for neoplastic transformation. To the latter group belong among
others the mismatch repair genes (MMR), nucleotide excision
repair genes, base excision repair genes, and genes involved in
chromosomal recombination and segregation, such as BRCA1
and ATM. Germ line mutations of many of the TSGs have
been identified as the cause of inherited cancer predisposition
genes in familial cancer syndromes (e.g. hereditary nonpoly-
posis colon cancer (HNPCC), familiar adenomatous polyposis
(FAP), multiple endocrine neoplasia II (MENII), BRCA1 and 2
for familial forms of breast cancer, and p53 for the Li-Fraumeni
syndrome). In hereditary cancer syndromes, a tumor suppressor
gene is inactivated in the germ line and a second hit is necessary
to abrogate the function of the respective tumor suppressor gene
in individual somatic cells (two-hit-hypothesis). Frequently, the
initial gene alteration induces uncontrolled proliferation of the
affected cells. In the course of accelerated cell divisions, genetic
errors are accumulated and finally lead to malignant transfor-
mation of the cells. For many cancer entities, specific pathways
of consecutive gene alterations have been described. Two cen-
tral tumor suppressor genes are affected in many cancers: p53
is a central protein in the control of programmed cell death.
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