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Cancer Genetics

Cancer Genetics

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Published by Aayudh Das
CLONAL EVOLUTION
Overview of changes in cells that cause cancer,
ENABLING CHARACTERISTICS AND EMERGING HALLMARKS
CLONAL EVOLUTION
Overview of changes in cells that cause cancer,
ENABLING CHARACTERISTICS AND EMERGING HALLMARKS

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Published by: Aayudh Das on Sep 04, 2013
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11/06/2013

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Cancer genetics-©Aayudh Das Page 1
CANCER GENETICS 1
CLONAL EVOLUTION-
In 1976, Peter Nowell proposed a model of 
cancer as an evolutionary process
inwhich a population of cells descended from a
single cell of origin, or ‘clone’ 
, acquires
successive somaticmutations
that allow sequential selection of fitter subclones
an
evolution that underlies tumor progression,metastasis and resistance to therapy.
The gray circle represents a normal cell, and the central dot depicts the initiating somatic mutation that drivesthe founder clone in the tumor. The different colored circles represent subclones that have accumulatedsuccessive mutations. Note that in the primary tumor, several subclones coexist, and although some expand,others remain dormant or become extinct. Metastases can originate from either a major clone in the primarytumor (metastasis 1), or from minor clones (metastasis 2). Metastases can also undergo clonal evolution (asshown in metastasis 1).Each cell, when it divides, generates two identicalnew ones. So, when a
cell acquires a mutation
,
it passes that mutation on to its progeny
duringcell growth and division. Because cells with
cancer-linked mutations tend to proliferate more thannormal cells
, cellular candidates for additionalmutations grow in number.
Mutations continue toaccumulate
and are copied to descendant cells. If 
one cell finally acquires enough mutations
tobecome cancerous, subsequent cancer cells will bederived from that one single transformed cell. So
alltumors are clonal
, which means that they
originate from a single parent cell
, whether that 
first mutant cell was of germline or somaticorigin
.
 
Cancer genetics-©Aayudh Das Page 2A
tumour
(aneoplasm)is a solid or fluid-filled cysticlesionthat may or may not be formed by an abnormal growth of 
neoplastic
cells that appears enlarged in size. a tumor can bebenign,pre-malignant,ormalignant,or can represent a lesion without any cancerous potential whatsoever.
Overview of changes in cells that cause cancer
1) Self-sufficiency in growth signals-
Normal cells require
mitogenic growth signals (GS)
 before they can move from a
quiescent state into anactive proliferative state
. Normal cell can’t proliferate in
the absence of such stimulatory signals. Many of the
oncogenes in the cancer catalog act by mimickingnormal growth signals
and sometimes
tumour cellsgenerate many of their own growth signals
, therebyreducing their dependence on stimulation from theirnormal tissue microenvironment.Most 
soluble mitogenic growth factors (GFs)
are madeby
one cell type
in order to
stimulate proliferation of another
the process of heterotypic signaling
manycancer cells acquire the ability to synthesize GFs to whichthey are responsive, creating a positive feedback signalingloop often termed
autocrine stimulation
(Fedi et al.,1997). Clearly, the manufacture of a GF by a cancer cellobviates dependence on GFs from other cells within thetissue. The production of 
PDGF (platelet-derived growthfactor) and TGF-
α
 
(tumor growth factor α)
byglioblastomas and sarcomas, respectively, are twoillustrative examples.
2) Insensitivity to antigrowth signals-
Within a normal tissue, multiple
anti-proliferative signals
(soluble growth inhibitors and immobilizedinhibitors) operate to
maintain cellular quiescence and tissue homeostasis
. Antigrowth signals can block proliferation.
Incipient cancer cells must evade these anti-proliferative signals
if they are to prosper. All
antiproliferative signals
are funnelled through the
retinoblastoma protein (pRb)
, basically pRb blocksproliferation by sequestering and altering the function of 
E2F transcription factors
that control the expressionof genes progressing from G1 into S phase.
Disruption of the pRb pathway liberates E2F
and allows cell proliferation. The
pRb signalling circuit isgoverned by TGF-
β
and other extrinsic factor
can be disrupted in a variety of ways in different types of humantumors. Some lose TGF-
β responsiveness through
downregulation of their TGF-
β receptors
,
while othersdisplay mutant, dysfunctional receptors.
 
Cancer genetics-©Aayudh Das Page 3
3) Evading Apoptosis
-
The
ability of tumor cell populations
to
expand
in number is
determined
not only by the rate of cellproliferation but also by the rate of 
cell attrition
i.e.
PCD-apoptosis
.
 Acquired resistance toward apoptosis
is ahallmark of most and perhaps all types of cancer.The apoptotic machinery can be broadly divided into two classes of components
sensors and effectors.
This
sensory signal
 
regulates
the second class of components, which function as
effectors of apoptotic death
. Thesentinels include
cell surface receptors
that bind
survival or death factors
. Examples of these ligand/receptorpairs include survival signals conveyed by
IGF1/IGF-2
through their receptor, IGF-1R.Consequent apoptosis could be abrogated by
exogenous survival factors (e.g., IGF-1), by forcedoverexpression of Bcl-2 or the related Bcl-XL protein, or by disruption of the FAS death signaling circuit 
.
4) Limitless Replicative Potential
 
Hayflick demonstrated that cells in culture have a
finite replicative potential
. Once such cell populations have
progressed through a certain number of doublings, they stop growing
a process termed
 senescence
.Provocatively, most types of tumor cells appeared to be immortalized have limitless replicative potential is aphenotype that was acquired in vivo during tumor progression. This is mainly due to the
 progressive shortening(50
100 bp loss of telomeric DNA from the ends of every chromosome) at the telomeric region
that has beenattributed to the
inability of DNA polymerases to completely replicate the 3’ ends of chromosomal DNA
during each S phase
. The
unprotected chromosomal ends
participate in
end-to-end chromosomal fusions
 yielding the
karyotypic disarray associated with crisis
 
and resulting, almost inevitably, in the death of theaffected cell.
 
Telomere maintenance
is evident in virtually all types of 
malignant cells
. 85-90% of them succeed in doing soby
upregulating expression of the telomerase enzyme
, which
adds hexanucleotide repeats
onto the
ends of telomeric DNA
, while the remainder maintain telomeres through
recombination-based interchromosomalexchanges of sequence information
. In this way telomeres are maintained at a length above a criticalthreshold, and this in turn permits
unlimited multiplication of descendant cells
.
5) Sustained Angiogenesis
 
 Angiogenesis
is the physiological process through which new blood vessels form from pre-existing vessels.
Counterbalancing positive and negative signals encourage or block angiogenesis
.
 Angiogenesis-initiatingsignals
are like
vascular endothelial growth factor (VEGF)
that binds to transmembrane tyrosine kinasereceptors. A prototypical
angiogenesis inhibitor
is
thrombospondin-1
, which binds to CD36, atransmembrane receptor on endothelial cells coupled to intracellular Src like tyrosine kinases.Tumors appear to activate the angiogenic switch by changing the balance of angiogenesis inducers andcountervailing inhibitors.
Many tumors evidence
 
increased expression of VEGF 
compared to their normaltissue counterparts. In others,
expression of endogenous inhibitors
(thrombospondin-1)
is downregulated
.
6) Tissue Invasion and Metastasis
 
During the development of most types of human cancer,
primary tumor masses spawn pioneer cells
that 
move out, invade adjacent tissues
, and thence
travel to distant sites where they may succeed in foundingnew colonies
. These distant settlements of tumor cells
metastases
are the cause of 90%of human cancerdeaths.

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