Cancer stem cells Flashcards
1
Q
What is a stem cell
A
- self-renewal
- differentiation
2
Q
What is cell differentiation?
A
- less specialised cells becomes more specialised
- stable, complex change in gene expression with change in cell type
3
Q
What is the relationship between stem cell-renewal and differentiation?
A
2 types
- symmetrical SC renewal = 2 of same cells
- asymmetrical cell division = 2 diff cells (1 SC and 1 committed progenitor cell)
4
Q
Describe SC differentiation
A
- long term SC –> short term SC –> early progenitors –> late progenitors –> differentiating cells –> differentiated cells
5
Q
What is a cancer stem cell?
A
- rare immortal cells within a tumour that can both self-renew by dividing and give rise to many cell types that constitute the tumour - forming tumours
6
Q
What are the key points of cancer stem cells (CSC)?
A
- not al cells are equally capable of regenerating the tumour
- CSC are only cells within the tumour with the capacity to maintain and regenerate the tumour
- tumours are stem-cell maintained tissue
- CSC-specific therapies should complement current anticancer treatments - mainly aimed at the reduction of the tumour mass
7
Q
When were CSCs first discovered?
A
- 1994 by Dick - used cell-surface protein markers to identify a relatively rare population of stem-like cells in AML
- present in peripheral blood of persons with leukaemia
- able to initiate human AML when transplanted into mice with compromised immune systems
- relatively immature in terms of differentiation - stem like
8
Q
What are the properties shared by normal stem cells and CSCs?
A
- self-renewal - tissue-specific SC must self-renew throughout lifetime = maintain organs
- differentiation - give rise to a heterogenous population of cells that compose the organ
- asymmetric cell division - all SC are capable of symmetric and symmetric cell division
- cellular signalling - pathways that regulate self-renewal
9
Q
What signalling pathways are related to CSCs?
A
- hedgehog
- notch
- Wnt
- NK-kb
- c-myc
10
Q
How is the epithelial-mesenchymal transition and CSCs linked?
A
- epithelial cells are more proliferative while mesenchymal cells are more migratory
- cancer-associates EMTs enhance stemness
- EMT and stemness has been observed in pancreatic, prostate, breast cancer
- mesenchymal properties = breast cancer cell lines with high CD44+ cells show high stem/progenitor properties
11
Q
Describe tumour cell heterogeneity?
A
clonal evolution model
- non-hierarchical model where mutations arising in tumour cells confer a selective growth advantage
- cell acquires a series of mutations and produced a dominant clone
- tumour cells arising from this clone have similar tumourigenic capacity
- other cells may lack tumourigenicity due to stochastic events
- tumour heterogeneity results from the diversity of cells present within the tumour
12
Q
Describe the cancer stem cell model
A
- hierarchical organisation of cells where a small subset of cells has the ability to sustain tumourigenesis and generated heterogeneity
- mutations in a progenitor cell endows the tumour cells with stem cell like properties
- these cells have self-renewing capability and give rise to a range of tumour cells- accounting for tumour heterogeneity
13
Q
What was the method used to show CSCs in vivo?
A
- genetic lineage tracing approaches
14
Q
How do CSCs arise?
A
3 types
- cancer cells arise from stem cells
- cancer cells arise from progenitor cells - partly differentiated cells retain a partial capacity for self-renewal, divide to produce mature cells
- cancer cells arise from differentiated cells = dedifferentiation
15
Q
Describe reciprocal interactions between the CSC and its niche
A
- normal niche contains a SC, progenitor cell and supporting cells
- genetic or epigenetic changes in SC = generation of CSC - expansion of cells in niche
- genetic epigenetic changes in a cell within the niche = inappropriate production of a growth factor = generation of CSC
- niche adapts to presence of CSCs with cells changing properties and recruitment of cells that would be normally present
16
Q
Describe cancer stem cell assays
A
- limiting-dilution transplant are used to determine the freq of CSCs
- ideally tumours that form in primary hosts are again tested for their content of cells with CSC activity to conform initial CSC have self-replicating ability
- most sensitive assays are those in which there is no immunological difference between host and tumour
17
Q
Xenograft assays to measure CSCs
A
- human tumour containing CSC and other cancer cells is dissociated then injected into mouse
- causes tumour growth
- tumour dissociates again
- results in a regenerated human CSC population
- injected into secondary mouse
- leads to tumour growth
18
Q
Do multiple CSC pools exist in individual tumours?
A
- yes
- can have distinct leukemic SC populations defined by CD34, CD38
- heterogenous CSC compartments have been describes in solid tumours where distinct CSC populations regenerate the phenotypic and functional heterogeneity of parental tumour
- phenotypic conversion among distinct CSC subsets of tumour
19
Q
Describe models of tumour propagation by CSCs
A
- one CSC subset may be present in tumour, non-CSCs are incapable of regenerating tumour
- multiple distinct CSC pools each capable
- long-lived dormant CSCs may produce local and or distant tumour recurrence after activation many years after therapy
- as tumour progresses, second distinct CSC may arise as a result of clonal evolution = acquisition of additional mutation or epigenetic modification
- CSC phenotype may be unstable - phenotypic reversion of cell surface markers = switching of CSC phenotype - response to cell-intrinsic or micro-environment
20
Q
Describe tumour propagation - metastatic cancer stem cells
A
- metastatic CSCs may be the same or distinct from the primary CSC
- CSC is responsible for both local and disseminated tumour progression
- CSC enters the vasculature and metastasises to distant organ
- a metastatic CSC is responsible for disseminated tumour propagation
- genetic or epigenetic mechanisms acting in the primary CSC could lead to the emergence of a self-renewing metastatic CSC = distinct markers from original CSC –> secondary tumour
21
Q
What is the CSC concept?
A
- CSC is a functional definition - should be defined in assays by their ability to generate serially transplantable tumours. simple marker expression and in vitro assays are not sufficient to define any cancer cells as CSCs
- CSCs may or may not originate from normal SC
- Metastatic CSCs may the same or distinct from the primary CSCs
- CSCs may or may not be rare, and their relative abundance likely varies between tumours
- CSCs are transformed cells with complex genetic mutations and epigenetic alterations - should not be equated to normal SCs
- like normal SC, CSCs are heterogenous and their progeny may also possess plasticity
22
Q
Evolution of CSCs and tumour cell plasticity
A
- CSC and clonal evolution concepts are not mutually exclusive
- tumour cell plasticity may contribute to phenotypic and functional heterogeneity
- CSC function may be induced by specific micro-environmental cues from growth factors or stress-related contexts
23
Q
What is the implication of CSC in cancer therapy?
A
- therapy is used for primary tumour
- cancer cells that are resistant to therapy survive
- can have : tumour relapse driven by non-CSCs, additional mutations or tumour relapse driven by CSCs
- therefore require - alternative therapeutic strategies, specific strategies against resistant cells
24
Q
What therapies are used to target CSCs?
A
- targeting surface markers = targeting CD44, CD90, CD33
- targeting ABC cassette = verapamil, MS-209, VX-710
- targeting microenvironment = CXCL12/CXCR4, VEGF
- targeting signal cascades = Notch, Wnt
25
Q
What are some drugs that target CSCs?
A
- WZB117 targets GLUT1 in pancreatic CSC = regulates metabolism
- Rituximab targets CD20 in melanomas by inhibiting self-renewal
- Transtuzumab targets HER2 in breast cancer by inhibiting self-renewal
