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Summary SSA10 Cell immortalization and tumorigenesis
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Summary and WG answers of SSA10 Cell immortalization and tumorigenesis of the course MBO (molecular biology and oncology) at University of Leiden.
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SSA10 Cell immortalization andtumorigenesis
Chapter 10 Weinberg
Human cells normally can only replicate a few times and after this they either go into
senescence or apoptosis. In order to form tumors, cells thus need to breach this barrier.
10.1 Normal cell populations register the number of cell
generations separating them from their ancestors in the
early embryo
After a series of passages/replications, a cell will go into senescence and not proliferate
anymore. These cells stay metabolically active, but their capability to enter the cell cycle is
irreversibly lost. These cells will stay alive as long as they get enough nutrients and growth
factors. The growth factors then do not stimulate proliferation, but just viability. They work via
the same receptors, but downstream signaling pathways are altered.
Stem cells from the embryo can replicate more times than stem cells from elderly. This
suggests that these cells already have used up some of their replicative doublings. However,
it can also be due to long term exposure to ROS. Embryonic stem cells are not limited in their
proliferation and show unlimited replicative potential in culture. Therefore, these cells are
said to be immortal.
HeLa cells are a cancer cell line that also have replicative immortality and these are often
used in experiments.
10.2 Cancer cells need to become immortal in order to form
tumors
The body probably developed such a limit to cell proliferation as an anti-cancer defense
mechanism. It can be that cells accidently acquire oncogenes or that they lose tumor
suppressor genes, but when they keep their limited replicative potential, the cells can
become exhausted. However, this is not entirely true as some cells in our body can go
through enough cycles to create a great tumor. Still, they need to circumvent other defense
mechanism like deprivation of growth factors, adequate oxygen and ability to eliminate waste
via vasculature. There are also many defense mechanisms to eliminate cells with
deregulated signaling.
Still, the idea of the limited proliferation as a cancer defense mechanism makes sense as
may cells in our body have already used up many of their cycles. Cancer cells thus need to
erase this history.
Cells thus have a sort of replicative history that is tracked somewhere. This needs to be cell
autonomous, so intrinsic to a cell. The most logical mechanism for this is that there is a sort
of cumulative stress in the cells and that this leads to senescence when cells reach a certain
threshold and when it goes above the threshold, it can lead to a crisis in which cells go into
apoptosis.
, 10.3 Cell-physiological stresses impose a limitation on
replication
The onset of senescence is accompanied by increase in expression of two CDK inhibitors;
p16 and p21. These are able to halt cell cycle advance. Inducing expression of p16 in cells
leads to a similar cell state which looks like senescence. p53 probably also plays a role as its
levels also increase. Increase in p53 can lead to increase in p21.
The prominent role of p16 is supported by experiments in which they shut down p16
expression or overexpress its target CDK4. However, this still gives no clue about how p16 is
then activated.
It was seen that oxygen levels were related to the replicative life span; the lower the oxygen
tension, the more doubling was seen. This suggests that ROS plays a role. Cells in which
p53 and pRb are inactivated, show replicative immortality (large T antigen in SV40).
There are only few markers for senescent cells in the G0 state. One marker is the enzyme
senescence associated acidic Beta-galactosidase. There are also chromatin alterations that
can be used as a marker for senescent cells; senescence associated heterochromatin foci
(SAHF). The formation of SAFH depends on active participation of pRb which associated
with E2F target genes to attract proteins that cause histone modification and chromatin
remodelling. The SHAFs can be detected by antibodies that recognize H3K9me. The
important histone writer that causes these modifications is Suv29h1.
Another marker is γ-H2AX which is a modified histone that is formed after dsDNA breaks
have formed. This histone functions to attract DNA repair enzymes. After the breaks is
repaired, these disappear. However, in senescent cells they persist indicating a irreparable
break.
Things that can induce senescence; hyperoxia and DNA damage. The DNA damage can be
caused by exogeneous agents but also endogenous agents like ROS, dysfunctional
telomeres and oncoprotein signaling. Ras oncogene can thus also induce senescence.
Paradoxically, cell senescence can also promote tumorigenesis. This is because there is a
specific senescence associated secretory phenotype (SASP) with inflammatory cytokines
like interleukins, IGFPs and TGF-Beta.
10.4 The proliferation of cultured cells is also limited by the
telomeres of their chromosome
Cells need to overcome the replicative senescence and the crisis. The large T antigen can
bypass the senescence, but even though it inactivates p53 it does not avoid crisis.
Senescent cells have reasonably stable karyotype, but cells in crisis that will undergo
apoptosis have many abnormalities.
The generational clock that controls the crisis is in the chromosomal DNA. These are the
telomeres which also causes our linear DNA to be stable so that chromosomes will not fuse.
End-to-end fusion of chromosomes without good telomeres would lead to chromosomes with
multiple centromeres.
Each telomere is composed of a 5'-TTAGGG-3' hexanucleotide sequence that is tandemly
repeated thousands of times. This sequence, together with associated proteins, form the
telomeres. Telomeric DNA shortens progressively over each growth-and-division cycle until
they become so short that they can no longer really protect the chromosome. Then, a crisis
will occur as chromosomes will start to fuse. Telomere shortening thus registers the number
of cell generations.
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