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Summary SSA11 Multistep tumorigenesis and cancer stem cells
Summary and WG answers SSA11 Multistep tumorigenesis and cancer stem cells of the course MBO (molecular biology and oncology) at University of Leiden.
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SSA11 Multi-step tumorigenesisand cancer stem cells
Chapter 11 Weinberg
Tumor progression is when cells evolve into increasingly neoplastic phenotypes. It is driven
by a sequence of randomly occurring mutations and epigenetic alterations that affect genes
controlling proliferation, survival and other traits of a malignant phenotype.
11.1 Most human cancers develop over many decades
Cancer risk increases massively with age. However, some critical steps of the tumor
progression might occur much earlier, but then the rate-limiting steps that really lead to a
tumor much later. Later steps in tumor progression probably take less time because then
cells often already have acquired oncogenes that allow the cell to proliferate faster and the
genomes are often more mutable.
The conclusion that tumorigenesis is a multi-step process hints to that (1) in order to develop
a tumor there is a sequence of unlikely events that need to happen and (2) many of these
events happen in all of us with similar frequency. Many of us will carry tumors at a later age,
but these may not be diagnosed.
Some will really develop neoplastic disease. The rate-limiting pathogenic can occur with
different speed in people and may depend on hereditary predisposition diet, lifestyle etc.
Often the duration of exposure to a carcinogen, rather than the age, influences when a tumor
will develop.
11.2 Histopathology provides evidence of multi-step tumor
formation
Most cancers are of epithelial origin. Biopsies have shown different degrees of abnormality in
for example colon cancer. Cells classified as hyperplastic have normal histology, but the rate
of division is increased. Dysplastic growths show abnormal morphology. These growths can
become bigger to form polyps or adenomas which are both still benign. Growths that invade
through the basement membrane are malignant and can eventually metastasize to the liver.
However, this still is no evidence for the precursor-product relationship. Evidence is: (1)
Sometimes you see a malignant carcinoma growing out of an adenoma in a biopsy. (2) In
patients that had polyps removed via colonoscopy, the incidence of colon cancer was
reduced massively. (3) Longitudinal studies of patients over time.
11.3 Cell accumulate genetic and epigenetic alterations as
tumor progression proceeds
Some steps in the tumor progression might be due to differential expression of genes.
However, most are due to heritable alterations in the genomes. Most is known about the
colon carcinomas as this organ is very accessible.
Early stage adenomas were found to have LOH on the 5q arm. Some larger adenomas also
had K-ras oncogene. Even larger ones has LOH on the 18q arm. Around half of the
carcinomas has LOH on the 17p arm.
On chromosome 5q21 is was found to be a LOH of the APC gene which is a tumor
suppressor gene. On chromosome 18q it was the tumor suppressor gene DPC4/MADH4
,which encodes Smad4 which relies the growth-inhibitory signal of TGF-B. However, it could
also be Smad2 that is affected so the exact TSG on 18q is still a mystery. On the 17q arm
there is a gene for the type II TGF-B receptor. Many tumors also activate K-ras.
However, there is still a lot of variation seen in the different mutations. However, all of them
show a common mechanism. First, there needs to be a mutation in the B-catenin signaling
pathway (far most common is APC). Second, there needs to be oncogene activation in the
Ras-Ras-PI3K pathway. Next, there needs to be an alteration in the TGF-B pathway. Last
the function of p53 has to be affected which occurs most often by inactivating p53 itself of
p14 (ARF). Sometimes multiple mutations need to occur in the same pathway; mutually
exclusive.
The mutations do not always have to occur in this order, but the alteration in the B-catenin
pathway (due to inactivation of APC) almost always occurs first. This is probably because
cells that will first acquire other mutations, will migrate out of the crypts and will die within a
few days. If APC function is lost, this migration does not occur anymore and the cells will live
longer.
It is not only things like mutations and LOH that contribute to the cancer. Epigenetics also
play a role. There is methylation of TSGs and hypomethylation of other genes. This can also
activate endogenous retroviral genomes and their transposable elements. These elements
can then jump around in the genome to cause problems.
The idea of a multi-step progression might lead to the idea that the cell of origin has little to
do anymore with the final tumor cells. However, even though when there is less
differentiation due to loss of pRb and fain of Myc, there are still some markers that enable to
identify the cell of origin. The original differentiation program still persists somewhat. This
differentiation program can also influence the behavior of the neoplastic cells. However,
around 5% of the metastases are classified as cancer of unknown primary origin (CUP).
These cells have lost the markers for the tissue-specific differentiation.
11.4 Multi-step tumor progression helps to explain familial
polyposis and field cancerization
Sometimes, sporadic cancer cells can sprout at the same time only a few centimeters apart
which is called field cancerization. This can occur when these cells already had somatic
mutations that are an early step in the tumorigenesis. These cells can divide and thus form
clones. However, each clone can then acquire its own additional mutations.
, It can also be that someone already had cancer
that is then surgically removed, but if a mutation is
also present in the surrounding tissue, the chance
of developing a new carcinoma is higher (like is
seen with LOH of 3p in breast cancer).
Field cancerization can occur when cells have
earlier genetic alterations and then cause these to
be widespread (proliferation of the cells that have
this). These cells have higher chance of becoming
cancerous as the first steps in the progression
have already occurred, but in itself these genetic
alterations do not lead to abnormal histological
appearance.
11.5 Cancer development seems to follow the rules of
Darwinian evolution
Once a heterogenous population of
tumor cells has developed, there will be
competition and a cells with certain
genetic alterations may outgrow the
other cells; clonal expansion. If this cell
has such an advantage that it can grow
more, it also increases the likelihood of
acquiring other beneficial mutations.
Four to six of these clonal expansions,
which are each triggered by a specific
mutation, explains how cancer
progression actually occurs at the
cellular/genetic level.
Elimination of tumor suppressor genes is often the majority of the alterations that are
involved. Often it is a first mutation and then a LOH. Each clonal expansion, which is
triggered by a specific alteration, may be many years apart. There may be increased
mutability which increases this speed due to exposure to carcinogens or defects in the DNA
repair machinery.
The actual amount of mutations that occur during tumor progression are way higher than the
number of mutations that actually drive the progression (driver mutations). Ones that occur
but are not necessarily beneficial for the tumor are called passenger mutations.
11.6 Tumor stem cells further complicate the Darwinian
model of clonal succession and tumor progression
Only a small minority of all cells in a tumor can lead to new clonal expansions or can lead to
new tumors in experiments. The tumors than then grow out of these cells show the same.
This raises the idea that just like in normal tissue, there are a few self-renewing stem cells in
the tumor. These types of cells also have distinct surface markers as assessed with FACS
(CD133 high in brain tumors). Stem cells are less differentiated and their descendants can
show more differentiation. These more differentiated cells can enter a post-mitotic state.
Stem cells show an asymmetrical division; one daughter cell will stay a stem cell and the
other will become more differentiated. The cell that keeps the stem cell state is called a
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