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PATH30001 > Lecture 23 - Cancer Stem Cells > Flashcards

Lecture 23 - Cancer Stem Cells Flashcards

1
Q

What is a cancer stem cell?

A

A cancer stem cell has the ability to generate heterogeneous tumours with higher efficiency once injected at high dilution (down to single cells) in recipient animals

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2
Q

What are the core properties of cancer stem cells?

A

Self-renewal: ability to go through infinite cycles of cell division while maintaining at least one stem cell

Multipotency: potential for differentiation into progeny that can’t self-renew

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3
Q

What are the features similar and different between cancer stem cells and adult tissue stem cells?

A

Other similar features:
* Expression of markers that enrich cells with tumorigenic potential
* Overlapping regulatory pathways

Difference: differentiation is regulated in normal adult tissue stem cells but is aberrant in cancer stem cells

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4
Q

What is the relationship between cancer stem cells and the cell of origin?

A
  • The cancer stem cell and the cell of origin are different BUT related concepts
  • The cell of origin is not always a stem cell
  • The cell of origin varies depending on cancer types and subtypes, (may play a role in inter-tumour heterogeneity) – patient specific concept
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5
Q

What are the markers for tissue stem cells and cancer stem cells

A

High concentration of CD44+ but low concentration of CD24 will promote breast cancer – you can enrich for the tumour initiating population

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6
Q

What pathways involved in self-renewal are deregulated in cancer cells?

A

Wnt pathway
Hedgehog pathway
Notch pathway

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7
Q

What extrinsic signals regulate the cancer stem cell phenotype?

A

CSC maintenance: Claudin-2 + Cancer cell plasticity
ECM niche and metastatic CSCs
CSCs in circulating tumour cells
CSC and treatment response: PXR/NIR1 and Progastrin
CSC-enriched chemoresistant metastases

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8
Q

What is the role of claudin 2?

A

A tight junction protein that promotes self-renewal of human colorectal cancer stem-like cells

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9
Q

What is the role of Laminin 521?

A

Enhances self-renewal via STAT3 activation and promotes tumour progression in colorectal cancer
Self-renewal capacity is sensitive to extracellular signals

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10
Q

In general, what does tumour initiation stem from?

A

Spontaneous/stochastic
or
Environmentally induced

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11
Q

Is initial genetic damage leading to tumour growth lethal or non-lethal?

A

Must be non-lethal (i.e. bypass cell checkpoints

If the cell dies there is no propagation of the tumour

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12
Q

Describe the role of driver genes in tumour growth

A

Driver genes:
* Oncogenes
* TSGs
* Genes involved in apoptosis
* Genes involved in DNA repair
Tumour development frequently requires alteration in at least two of these driver genes

Alterations usually need to affect both alleles of a driver gene for maximal impact

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13
Q

What are passenger mutations?

A

Do not have an impact on or drive the tumour

They arise because the cells are becoming more and more genetically unstable

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14
Q

What is the role of CSCs in metastasis development?

A
  • Cancer stem cells preserve their multipotency during metastatic dissemination
  • Cancer stemness and epithelial to mesenchymal transition (EMT)
  • Phenotypic plasticity of cancer cells
    E.g., only the CD133+CD44+ can develop primary tumours after cell purification and orthotopic implantation
  • In vivo: only CD133+CD44+CD26+ subpopulation can give rise to liver metastases
  • In vitro: only CD133+CD44+CD26+ subpopulation can display high invasive properties
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15
Q

What is the role of EMT upon CSCs?

A
  • Increases the invasive properties of CSCs
  • Cancer stem cells preserve their multipotency during metastatic development
    o E.g., CSCs in colorectal cancer can be stimulated to re-create enterocytes, enteroendocrine, goblet cells and Paneth cells as long as there is a sufficient amount of growth factors
  • CSCs survive in the patient’s bloodstream
  • Memory of differentiation programs from their organ of origin
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16
Q

What is the phenotypic plasticity of cancer cells?

A
  • Two major types of phenotypic plasticity exist in cancer: initiating plasticity and maintaining plasticity.
  • Initiating plasticity is generated by the influence of the cell of origin and the specific driver mutations that occur during tumorigenesis. These two forces collaborate to generate the tumour phenotypes that are varied even within the same tissue
  • Homeostatic equilibrium of tumourigenic cells
  • Non-tumourigenic cells can generate CSCs
17
Q

What is the role of CSCs in therapeutic resistance?

A
  • CSCs are often enriched following chemotherapy
    o After chemotherapy, these cells have the capacity to re-generate a tumour that is likely to be more aggressive than the original
    o Dominant cells within subclones survive chemotherapy, while the remaining cells are lost  increasing the PROPORTION of CSCs
    o Tumour with re-established sub clonal diversity
  • CSCs are involved in post-treatment tumour relapse
18
Q

What are the mechanisms of CSCs to resist anti-cancer therapy?

A
  • Slow cycling cells: less sensitive to proliferation-targeting treatments (long term as opposed to rapid short term)
    o It is the progenitor cell which is sensitive to chemotherapy not CSCs
  • Lower sensitivity to pro-apoptotic signals
  • High capacity for drug metabolism(detoxification)
  • Less prone and less sensitive to DNA damage:
    o Low levels of ROS
    o Very active DNA repair machinery
19
Q

Describe the two models for cancer heterogeneity

A

Stochastic model / clonal evolution
* Self renewal and differentiation are random
* Extrinsic factors (environmental) that determine the differences between the cells
* Any cell type can be taken from the tumour, and a new tumour can be generated from it (i.e. all cells have equal but low probability of initiating the tumour growth)
* Strong influence of the microenvironment
Cancer stem cell model
* Intrinsic factors are most important (as opposed to extrinsic microenvironment)
* No matter what the external environment, most cells are unable to generate a tumour
* Distinct classes of cells within a tumour (CSCs, and the rest)
* Only a small definable subset has intrinsic ability to initiate tumour growth (CSCs)
* These cells will again generate a tumour that is heterogeneous (not unlike tumour of origin)
* Hierarchical organisation with cancer stem cells (CSCs) as the source of other cells

20
Q

Describe detection of cancer stem cells in leukaemias

A

Suspicion that some cells were different from the others and had special markers that differentiated them

FACS: (flow activated cell sorting aka flow cytometry)
* Separates cells based on surface markers
* Surface markers detected with Abs specific for them
* FACS plot generated

In leukaemia:
* Two sub populations of cells observed:

CD34+
* CSC, stem cell potential
* These cells were put into irradiated mice (no BM)
* Bone marrow reconstituted from the CSCs
* Mice will have leukaemia
* Whole haematopoietic system regenerated from these cells, thus, they must have some stem cell characteristics
CD34-
* When injected into irradiated mice, the cells were unable to reconstitute the haematopoietic system

21
Q

Describe detection of cancer stem cells in solid tumours

A

Derivation of cells from solid tumour to create a cell suspension
FACS
Two sub-population of cells identified:
a. CD24+CD44+
* No tumour in mouse
b. CD24-CD44+
* Tumour generated in mouse

Thus, CD24-CD44+ cells in solid tumours are the stem cells, capable of self-renewal and tumourigenesis

22
Q

Describe how the following are determined experimentally:
* Tumourigenicity
* Self-renewal
* Differentiation potential

A

– Tumourigenicity –

FACS separation of cells into groups depending on surface markers
* CD133+
* CD133-
Comparison of the two sub-populations
* Cell culture of the two sub-populations in vitro in suspension (cells cannot attach to plate)
(Clonogenic sphere assay)
a. CD133+
* Stem cells start dividing and forming spheres
* i.e. a tumour forms

b. CD133-
* No formation of spheres

– Self-renewal –

Seropassaging of spheres:
Dissociation of cells into single cell suspension
Continuous rounds of clonogenic sphere assays
Only stem cells will be able to continue generating spheres time after time etc
NB Some progenitors may be able to regenerate for a short time, then conk out
– Differentiation potential –

Look for differentiated cells in the tumours
Differentiation assay:
* Growth of cells in particular conditions that force differentiation
CD133+ populations:
* Evidence of differentiation

CD133- populations:
* No evidence of differentiation

23
Q

Compare surface markers for healthy tissue cells and tissue cancer cells, using the example of the gut

A

Colon cancer
* EpCAM
* LGR5
* CD166
* CD133
* CD44
* ALDH1
* EphB2

Healthy intestinal epithelium
* Bmi1
* LGR5
* Acsl2
* EphB2
* Lrig1

24
Q

What is different about melanoma and the CSC model?

A

Melanoma
* There are no marker that enriches tumorigenic potential
* No matter which marker was used, they couldn’t separate out the CSC
* Thus, melanoma does not conform to the cancer stem cell model
* Tumorigenicity is random
* Any cell has the potential to generate a new tumour
Implication:
Some cancers conform to the CSC model, and some (like melanoma) do not

25
Q

What is the clinical implication of tumour cell plasticity?

A

Tumour cell plasticity is the ability of cancer cells to switch between different phenotypes and adapt to changing microenvironments, allowing them to survive and thrive even under stressful conditions. The clinical implications of tumour cell plasticity are significant because it can contribute to treatment resistance and disease progression

26
Q

What are challenges to the cancer stem cell model?

A
  • How best to combine CSC targeting with targeting of other tumour cells?
  • Minimise targeting of adult tissue stem cells!!
  • Possible genetic variability of Cancer Stem cells: do they display a shared sensitivity to common therapeutic compounds?
  • What are appropriate biological responses to measure in preclinical and clinical trials? (what time-course, which CSC markers…?)
27
Q

Why is combination therapy a hope for anti-cancer therapy?

A

Primary tumour –> metastasis initiating cells –> metastases –> anti-proliferative therapy (e.g., chemotherapy) or CSC-targeted therapy or combination therapy
* Anti-proliferative therapy (chemo) –> tumour relapse
* CSC-targeted therapy –> plasticity –> tumour relapse
* Combination therapy (e.g. chemo + CSC-targetted –> tumour regression !!

PATH30001 (9 decks)

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