Cancer stem cells Flashcards
a cell is classified as a stem cell when is satisifes what three criteria?
- Undifferentiated or unspecified.
- Have the ability to self-renew.
- Mature and differentiate
what are transiently amplfying cells?
transit amplifying cells
an undifferentiated population in transition between SCs and differentiated cells
a gradient of what three signals fine tune the differentiation pattern in the intesinal crypt?
Wnt on the proliferation end (crypt) (promoting self renewal capacity of SCs)
BMP and TGFbeta on the differentiation end
what three pathways involved in self renewal are deregulated in cancer cells?
- Wnt
- Shh (sonic hedgehog)
- Notch
give the 6 hallmarks of cancer
- Sustained proliferation
- Invasion
- Metastasis
- Replicative immortality
- Ability to evade growth suppression and apoptosis
- Heterogeneity
how does tumour heterogeneity begin?
wiht one single cell that undergoes genetic or epigenetic alterations
tumour heterogeneity is responsible for what features of cancer
tumour progression, metastasis, resistance to therapy and relapse
what is intratumoural hetergeneity?
heterogeneous expression of different markers among cancer cells
distinct tumor cell populations (with different molecular and phenotypical profiles) within the same tumor specimen
what is intertumoural heterogeneity?
heterogeneity among the tumours arising in different patients with a given cancer
give three mechanisms influencing tumour heterogeneity
- Genomic landscape of individual tumours and their clonal evolution
- Existence of different populations of cancer cells with cancer stem cells (CSCs) residing at the top of the hierarchy
- Tumour microenvironment
give three mechanisms influencing tumour heterogeneity
- Genomic landscape of individual tumours and their clonal evolution
- Existence of different populations of cancer cells with cancer stem cells (CSCs) residing at the top of the hierarchy
- Tumour microenvironment
tumour evolution is affected by what factors
exposure
constituative genetics
systemic regulators (hormones, growth factors, immune/inflammatory response)
local regulators (oxygen metabolism, nutrients, cell-cell/ cell stroma/matrix, space)
architectural constraints (physical compartments, basement membranes, restricted niches)
what is the process by which tumours evolve?
a darwinan process whereby additional somatic mutations confer selective advantages to more fit clones
tumour evolution following the darwinan process is similar to What normal cellular process
similarr to the way stem cells produce transit amplying cells and differentiated cells
why are stem cells the focus of this new cancer stem cell theory?
only stem cells have the ability to self-renew - neoplasia is essentially dysregulated self renewal
stem cells are long lived cells which can acquire the necessay number of sequential mutations to convert a normal cell into a malignant one
what is the origin of the theory of cancer stem cells?
in 1997 Dominique Bonnet discovered an organised hierarchy in human acute myeloid leukemia that originated from primitive hematopoietic cells
what key cell markers are present on long term hematopoietic stem cells but not on its progenitors?
LT-HSCs express CD34+ but are devoid of CD38-
progenitors dont have CD34-
can be Cd34- CD38+ and CD34- CD38-
how did Bonnet discover the leukemic stem cells in human acute myeloid leukemia?
both stem cells (CD34+/Cd38-) and transient amplifying cells (CD34+/CD38+) were injected into mice however only one group of cells resulted in leukemia, the stem cells
isolation of cell types in this mouse found all the intermediate progenitors and mature cells - all lineages - of hematopoeisis in the tumour
Identification of human breast cancer stem cells requires what cell markers
CD44+/CD24-
higher fraction of CD44+/CD24- cells in breast cancer is associated with what three things
- shorter disease free interval
- shorter overall survival
- greater incidence of metastasis
only a fraction of breast cancer cells present the capacity to reform secondary tumours following their transplantation into immunodificient mice, what markers do they possess
CD44+/ CD24-
only leukemic cells expressing the same markers as ________________ were leukemia initiating cells: _________________
hematopoietic stem cells (HSCs: Cd34+CD38-)
leukemic stem cells (LSCs)
what is another name for tumour propagating cells
cancer stem cells
tumour propagating cells in breast cancer possessed what cell markers
CD44+/ CD24- (low)
tumour propagating cells in breast cancer possessed what cell markers
CD44+/ CD24- (low)
tumour propagating cells in breast cancer possessed what cell markers
CD44+/ CD24- (low)
what are the two models for tumour growth and heterogeneity?
- stochastic (conventional) model
- Hierarchal (stem cell) model
describe the stochastic model of tumour growth and heterogeneity
(conventional)
5 points
- All cells are potential cancer cells but have a low probability of proliferation: cells are equally tumorigenic “equipotent”
- Self renewal and differentiation are random
- Cancer cells continue to evolve by virtue of a Darwinian process of genetic drift and natural selection
- Genetic instability within the tumor cell population leads to accumulation of additional mutations within single cells
- A number of genetically divergent clonal subpopulations exist, with the most aggressive cells driving tumor progression
describe the hierarchal model of tumour growth and heterogeneity
(stem cell)
4 points
- Only a small definable subset of cancer cells are CSCs that have the ability to proliferate indefinitely
- CSCs have properties of normal SCs, particularly self-renewal and multipotency
- Upregulated cell growth is due to a disruption in the regulatory mechanisms in stem cell self-renewal
- CSCs participate in “clonal” evolution and drive tumor progression, while the other cells are “evolutionary dead ends”
what intrinsically regulates cancer stem cells?
- epithelial to mesenchymal transition: the hybrid EMT state
what things extrinsically regulate cancer stem cells?
regulation by their niche through cell-cell interactions, secreted factors, cell-matrix interactions and biophysical properties of the niche
* Endothelial cells: The important role of the perivascular niche (VEGF signalling) - EMT and invasiveness
* Hypoxia: The rapid proliferation of cancer cells and aberrant angiogenesis lead to hypoxic regions within tumors (induction of Hypoxia-inducible factors Hif1a and Hif2a) - EMT and invasiveness
* Inflammation: The inflammatory component of the tumor microenvironment. CSCs physically interact with tumor-associated macrophages (TAMs) to form a metastatic niche - EMT and invasiveness
* Fibroblasts and Myofibroblasts: synthesize the extracellular matrix, supporting the functions of cancer cells via cell-cell and paracrine interactions - EMT and invasiveness
how does EMT intrinsically regulate Cancer stem cells
EMT is not a binary process, during EMT cells make a gradual transition from one state to the other along a continuous spectrum of change in which cells lose epithelial characteristics and concurrently gain mesenchymal ones.
- the hybrid EMT state is a partial EMT/ metastable state where individual cells express both epithelial and mesenchymal markers
- the hybrid state is at the heat of the most aggressive and metastatic cancers - this intermediate state is where they have stem cell like features meaning they are more metastatic
EMT cell subpopulations display differences in what features
differences in cellular plasticity, invasiveness and metastatic potential
EMT cell subpopulations display differences in what features
differences in cellular plasticity, invasiveness and metastatic potential
why are there tumour subpopulations with different EMT stages?
- These tumour subpopulations are localized in different niches that differentially regulate EMT transition states.
- Differential transcriptional and epigenetic mechanisms of regulation
Different niches influences a myriad of states
how does the cancer stem cell theory feed into metastasis?
- Only a subset of long-term self-renewing CSCs can drive metastasis
- Both metastatic dissemination and the acquisition of CSC properties are promoted by EMT
- The metastatic SCs are characterized by additional features such as dormancy and plasticity. Metastases can occur years after a successful treatment of the initial tumor
- Metastatic cancer cells shut down EMT transcription factors undergo MET, and regain epithelial traits in order to colonize the distant organs
- Interactions of metastatic SCs with the microenvironment govern metastatic seeding, survival, dormancy, colonization, and growth
how would novel targetted therapy of cancer stem cells differ to the conventional therapy
in the conventional therapy rapid growing cellls are killed but the tumour can grow back because there are essential survivors eg cancer stem cells
in novel targetted therapy, kill stem cells, and the tumour degenerates because the non-tumourigenic cells die off
cancer stem cells - slow duplication,, but potentially unlimited
non-tumorigenesis - fast duplication, but for few cycles
Wnt is involved in stem/progenitor cell self renewal of what three cell types
Haematopoetic, Epidermal, Gut
Shh is involved in stem/progenitor cell self renewal of what three cell types
Haematopoietic, Neural, Germ line
Shh is involved in stem/progenitor cell self renewal of what three cell types
Haematopoietic, Neural, Germ line
Notch is involved in stem/progenitor cell self renewal of what three cell types
Haematopoietic, Neural, Germ line
Wnt is involved in tumourigenesis of what tumour types
2 examples
Colon carcinoma
Epidermal tumours
Shh is involved in tumourigenesis of what types of tumours
2 examples
Medulloblastoma
Basal cell carcinoma
Notch is involved in tumourigenesis of what types of tumours
2 examples
Leukaemia
Mammary tumours
what is multiplex imaging
Multiplex imaging methods enable the quantification of numerous proteins in tissues while retaining spatial and morphological information
It could facilitate the mapping of the heterogeneity of primary and metastatic tumours, where the different expression of key biomarkers is informative for patient stratification into different treatment arms
what are the markers of cancer stem cells in colon cancer
CD133+ Lgr5+
what are the cancer stem cell markers in Glioma
CD133+ CD15+
what are the cancer stem cell markers of melanoma?
ABCB5+
what are the markers of cancer stem cells in skin cancer?
CD34+
at what state during the epithelial to mesenchymal transition are cancer cells the most metastatic?
an intermediate hyrid state where they have stem cell like features which means they are more metastatic.
what research do we still need to do into cancer stem cells
- Identify novel stem cell markers – various stem cell subpopulations
- Better evaluate the number of CSCs and the size of their respective progeny/units at different stages of tumor progression and metastasis
- Better evaluate how CSCs compete or collaborate during tumor growth
what is cell plasticity?
ability of a cell to change from one identity to another
who described the landscape of differentiation?
when? what does it depict?
Waddington’s (1957) landscape of differentiation
Depicting the process of differentiation of a stem cell into distinct cell types, visualized as a ball rolling down a hill – differentiation is a not a unidimentional process
define differentiation
process by which a less specialised cell acquires properties of a more specialised cell, usually a mature functioning cell
define differentiation
process by which a less specialised cell acquires properties of a more specialised cell, usually a mature functioning cell
define dedifferentiation
process by which a specialised cell converts to a less specialisesd phenotype, sometime to a stem/ progenitor cell
define transdifferentiation
conversion of a cell from one differentiated state to an alternative differentiated fate
define reprogramming
experimental manipulation that results in dedifferentiation or transdifferentiation; often refers to process of generating induced pluripotent stem cells (adipocytes in breast into epitheial cell)
