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CANCER STEM CELLS
Stem cells in solid tumours only, not haemapoietic tumours
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ncbi
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nih
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In normal tissues, there is a stem cell (long-term renewal capacity) that gives rise to
progenitor cells (limited renewal capacity) and in turn, those give rise to
differentiated cells of the tissue, and thus lack renewal capacity
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Tumour initiating cells were first isolated in AML in 1997 within the haematopoietic
system by Bonnet and Dick
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- There exists a small population of cells within the tumour that have the ability
to:
o Self-renew
o Give rise to a new tumour with the same heterogeneity of the original
tumour
- Therefore, these cells drive tumour initiation and progression
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A normal cellular hierarchy comprising stem cells, which progressively generate
common and more restricted progenitor cells, ultimately yielding all the mature cell
types that constitute a particular tissue
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In the clonal evolution model all undifferentiated cells have similar tumorigenic
capacity, i
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all progenitor cells have the same chance of ‘hit’
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In the cancer stem cell (CSC) model, only the CSC can generate a tumour, based on
its self-renewal properties and enormous proliferative potential
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Both models of tumour maintenance may underlie tumorigenesis
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With tumour progression, another
distinct CSC (CSC2) may arise due to clonal evolution of CS1
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This more
aggressive CS2 becomes dominant and drives tumour formation
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In the CSC model, normal stem and progenitor cells are the primary targets of
transformation
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o There are exceptions whereby there are some cancers that are hereditary
or environmentally induced
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o Environmental factors play a large factor in developing cancers
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Tumours are made up of different population of cells, some more differentiated
than others
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In many solid tumours, only a rare cell type can give rise to new tumours
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o The idea is that with CSC, there is a small population of cells that can give
rise to new tumours
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This reciprocal signalling may be involved in the maintenance of the cancer stem cell
within that tumour
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Normal niche containing a stem cells
(SC), progenitor cell (P) and
supporting cells
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A series of genetic and epigenetic
changes occur in a stem cell (or
committed progenitor cell), leading
to the generation of a CSC
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c
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d
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Identifying Cancer Stem Cells:
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Functional assays, such as in vitro clonogenic (sphere) assays, transplantation and
lineage-tracing experiments (green), can be used to assess the renewal and
differentiation potential of SCs, committed progenitors and differentiated cells
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- The committed progenitors give rise to colonies or spheres in vitro only
transiently, to secondary tumours on transplantation that cannot be serially
transplanted, and to small and transient clones in lineage-tracing experiments
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- The spheres left are the tumour initiating cells
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In vitro sphere formation:
- Obtained from 4 different breast cancer patients via the plural fluid in the lung as
this is where breast cancer likes to metastasise
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- These cells can differentiate into all cell types (the very definition of cancer stem
cell)
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A combination of a tissue-specific and lineage-negative (LIN-) markers allows
the isolation of tumour cells, which can then be separated in different
subpopulations on the basis of cell surface marker expression or enzymatic
activity
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Transplanting limiting dilutions of tumour cells and assessing the fraction of
transplanted cells giving rise to secondary tumours allows for the estimation
of tumour propagating cell (TPC) frequency – form tumours much later with
a large dose of cells
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Subsets of tumour cells giving rise to secondary tumours more frequently
than unsorted tumour cells are enriched in TPCs
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In certain cases, serial transplantation is required to distinguish a population
of tumour cells with long-term self-renewal potential
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Finally, some tumour cells may not form secondary tumours in the absence
of stromal cells, owing to their strong dependence on the
microenvironment
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Transplantation constitutes a good approach to determine whether certain tumour
cells have long-term self-renewal properties, as well as the capacity to generate all
the cell types that are found in primary tumours
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However, this method does not indicate whether TPCs are responsible for tumour
growth within the primary tumours
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Isolation of human cancer stem cells in tumours other than leukaemia is rather
difficult
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- However, the CD44+CD24- cells (only 200 injected into the mouse) contain the
cancer initiating cells for breast cancer, but it is not clear but makes it quite clear
that not all breast cancers are the same
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o These have been subdivided further because there was an inclusion of gene
expression and chromosome aberration, leading to the development of at
least ten different subtypes
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When we look at the different subtypes together, we see that these subtypes
can have very few markers in common, thus suggesting that perhaps we need to
study them individually instead
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Transgenic mice express the enzyme Cre, which has the ability to cut out pieces
of DNA
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The Cre enzyme could cleave the sequences out of the YFP, removing the stop
signal and get YFP expression
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Placing Cre under a specific promoter and control the YFP expression spatially
and temporally
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Understand the implications of cancer therapy:
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These CSC are resistant because:
- They have a low proliferative rate – most conventional anti-neoplastic agents
target rapidly dividing cells
- Often overexpress anti-apoptotic proteins such as Bcl-2 and survivin that partly
protect from apoptosis induction
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- BMI-1, which is a component of the polycomb repressor proteins (PRC1), and
these seem to be overexpressed in most CSCs, particularly in colon cancer stem
cells
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o CIC frequency is also significantly reduced in mice that are treated with this
small molecule inhibitor
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- a6-integrin negative (expressed in breast cancer) did better than those that
were positive
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Controversies regarding the CSC model:
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- This means that there are 3 models of CSCs:
o Irreversible
o Inefficiently reversible
o Readibly reversible
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- In the hierarchal CSC model with conventional cancer therapy, KO of the bulk but
leaving the CSC leads to relapse
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- In the dynamic CSC model with CSC-specific therapy, there will be relapse due to
no KO of the bulk of the tumour
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- Extension of studies to more patients to account for tumour heterogeneity – this
has happened in breast cancer but not always for other cancer types