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Lecture 6 - Cancer Stem Cells 1 Flashcards

1
Q

What is a Cancer Stem Cell (CSC)?

A

A cell with the ability to self-renew and differentiate into various cell types, contributing to tumor heterogeneity and recurrence

CSCs are often characterized by specific surface markers such as CD34+ CD38- in AML and CD44+ CD24−/low in breast tumors.

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2
Q

How does cancer arise according to the Cancer Stem Cell Hypothesis?

A

Cancer arises from stem cells due to their long lifespan and ability to accumulate mutations over time

This hypothesis suggests that the asymmetrical reproduction of stem cells contributes to tumor heterogeneity.

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3
Q

What is the role of embryonic stem cells (ESCs) during embryogenesis?

A

ESCs are involved in the formation of different tissues through regulated developmental gene expression

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4
Q

What is the difference between adult stem cells and embryonic stem cells?

A

Adult stem cells are involved in tissue replacement and repair, while embryonic stem cells are involved in tissue formation during development

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5
Q

What is a significant finding from John and Bonnet’s research in 1997?

A

They first identified cells with extensive proliferative potential in acute myeloid leukemia (AML)

This led to the recognition of leukemia stem cells.

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6
Q

What surface markers were identified by Al-Hajj in 2003 in breast tumors?

A

CD44+ CD24−/low

This discovery supported the existence of cancer stem cells in various malignancies.

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7
Q

What is the significance of the WNT signaling pathway in cancer?

A

The WNT pathway is associated with the dedifferentiation of cancer cells into cancer stem cells

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8
Q

What factors can lead to dedifferentiation of cancer cells?

A

Environmental factors, genetic reprogramming, and mutations in signaling pathways

Pathways involved include WNT, NOTCH, TGF-b, JAK/STAT, ERK, and PI3K/PKB.

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9
Q

Fill in the blank: Tumors are often heterogeneous in terms of cellular _______.

A

differentiation

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10
Q

True or False: Most mature differentiated cells have a high rate of proliferation.

A

False

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11
Q

What does the term ‘phenotypic plasticity’ refer to in tumors?

A

The ability of tumors to transform in response to the microenvironment, leading to genetically heterogeneous tumors

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12
Q

How can differentiated cells contribute to cancer development?

A

Differentiated cells may reacquire the ability to self-renew through mutations in growth and developmental pathways

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13
Q

What is the role of hypoxia in cancer stem cell formation?

A

Hypoxia influences dedifferentiation and the formation of cancer stem cells

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14
Q

What is the impact of early pregnancy on breast cancer risk according to hypotheses?

A

Early pregnancy may reduce the risk of breast cancer due to depleted stem cells

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15
Q

What is the function of transcription factors in the differentiation of hematopoietic stem cells (HSCs)?

A

Different transcription factors control various levels of differentiation in HSCs

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16
Q

What genetic mutations are associated with granulocytic acute myeloid leukemia (AML)?

A

Mutant versions of CEBPa involved in granulocyte differentiation

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17
Q

What is the significance of chromosomal translocation in cancer?

A

It affects the genes driving the differentiation of hematopoietic stem cells

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18
Q

How does the tumor microenvironment (TME) influence tumor progression?

A

Components like CAFs, MSCs, and M2/TAMs in the TME influence tumor development

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19
Q

What are the main pathways involved in intestinal signaling?

A

Wnt and Hedgehog (Hh) pathways

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20
Q

What is the role of APC in the Wnt signaling pathway?

A

Loss of function of APC dysregulates Wnt signaling pathway and leads to increased cellular growth

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21
Q

What is the function of Gli in the Hedgehog pathway?

A

Gli is a transcription factor that mediates Hedgehog signaling

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22
Q

Which proteins are involved in the Wnt signaling pathway?

A
  • Frizzled
  • Axin
  • GSK3
  • CKI
  • β-catenin
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23
Q

What is the effect of Wnt signaling on crypt cells?

A

Increases transcription of lgr5, which synergizes with Wnt receptors

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24
Q

How do intestinal stem cells and epithelial progenitors function?

A

They reside in crypts, differentiate as they move up the villi, and eventually die by apoptosis

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25
What is the role of NF-κB in colorectal cancer?
Activation of NF-κB enhances Wnt signaling, supporting dedifferentiation of intestinal villus cells
26
What role does TGF-β play in colorectal cancer?
Activates signaling pathways that convert colorectal cancer cells into CSCs, dependent on TWIST1
27
Fill in the blank: Activation of the WNT pathway and loss of _______ drive differentiated intestinal epithelium to stem cell-like status.
Smad4
28
What is the impact of mutating APC in crypt cells?
Causes tumors but not in progenitor or differentiated cells
29
What happens when APC function is restored?
Restores crypt cell function even in the presence of other mutations
30
What do Polycomb (PcG) proteins do?
Regulate gene expression as epigenetic regulators, repress differentiation, and drive stemness
31
List components of PRC1 and their function.
* PRC1 (Bmi) - ubiquitinates H2a, suppresses transcription, compacts chromatin
32
What is the role of PRC2?
(EZH1, SUZ12)Histone methyltransferase activity targeting histone 3
33
How does BMI-1 contribute to cancer?
Involved in DNA double-strand break repair, promotes stemness, represses p16 via chromatin remodeling
34
True or False: Bmi overexpression is seen in many cancers, including leukemias.
True
35
What is the effect of Bmi knockout in AML?
Halts cells in G1 and promotes differentiation
36
What is the role of PML in Acute Promyelocytic Leukaemia (APL)?
Promotes p53 activity leading to cell cycle arrest and apoptosis
37
What happens to RAR when retinoic acid (RA) is absent?
Recruits HDAC and represses gene expression
38
What is the consequence of the PML-RAR fusion protein?
Recruits HDAC and represses differentiation even in the presence of RA
39
Fill in the blank: The situation regarding differentiation in cancer is probably a continuum of cells at varying stages of _______.
differentiation
40
What factors may influence malignant potential in cancer?
Stage of differentiation and acquisition of different mutations
41
What is cancer?
Cancer is a disease of uncontrolled proliferation by transformed cells subject to evolution by natural selection. ## Footnote * Caused by the accumulation of mutations in a single cell * Cancer tumours are often heterogenous in terms of cellular differentiation but cancers are often clonal * Only a small number of tumour cells (<1%) can recolonise
42
Cancer stem cell hypothesis
* Expansion of normal stem cell niches which can support more cancer stem cells arising from normal stem cells. * Cancer stem cells that arise can adapt to different niches following their expansion * Cancer stem cells can become niche independent and self-renewal is cell-autonomous * Shift in the programmed declined in replication potential * Elements of all of these in the cancer stem cell hypothesis, however difficult to prove.
43
What is homeostasis?
Homeostasis relies on a balance between cell growth, differentiation and cell death.
44
What are some continually active adult stem cells?
* HSCs (restriected progenitors * BMw * Intestinal stem cells in villi
45
Examples of stem cells that are activated as required
* Hair follicle stem cells responding to a wound * Breast gland stem cell responding to pregnancy hormones ## Footnote Early breast cancer has been shown to reduce risk of breast cancer, which is hypothesised to be due to depleted stem cells.
46
What phenotype did isolated CSCs possess that John and Bonnet identified in 1997?
Isolated CSCs characterised by their stem cell CD34+ CD38- phenotype. ## Footnote Proliferative capability with these markers.
47
What markers were shown to have tumour-initiating potential?
Both CD34+CD38- and CD34+CD38+ ## Footnote Vast heterogeneity in surface marker expression - not one consistent marker.
48
What are the population of stem vs differentiation cells?
Tumours have differing populations of stem vs differentiation cells. There is a considerable range of stemness vs differentiation. Less than 1% will be CSCs therefore, difficult to isolate.
49
What methods are used to indentify cancer stem cells?
* FACS * MACS * Staining * WB
50
What factors are used to genetically reprogram differentiated cells into stem cells?
Oct4, Nanog, Sox2, KLF4 (cf iPSCs with conditioned media)
51
How can hepatocellular cancer cells be dedifferentiated?
Promoter demethylation of transcription factors.
52
What pathways are involved in the regulation of dedifferentiation?
* WNT * NOTCH * TGF-b * JAK/STAT * ERK * PI3K/PKB ## Footnote Therefore, mutations in these pathways likely to lead to cancer stem cells.
53
What cancers is WNT pathway associated with?
* Dedifferentiation of breast cancer bone metastases into CSCs * Intestinal villi in colorectal cancer
54
What does activation of HIF-1a/Notch pathway lead to?
Dedifferentiation of pancreatic cancer cells and formation of stem-like cells. Causes centre of tumour to become hypoxic.
55
What does ERK inhibition lead to?
Promotes cancer cell dedifferentiation and expands the CSC population in non-small cell lung cancer (NSCLC)
56
What does induction of STAT3 and Smad activation cause?
Activates WNT, Notch, and hedgehof pathways and induces dedifferentiation of lung carcinoma cells.
57
What is AML?
Acute myeloid leukemia (AML) ## Footnote Important model for studying differentiation.
58
Role of transcription factors in differentiation
Different transcription factor controls different levels of differentiation.
59
Mutations in transcription factors
Mutations in TFs lead to a block on differentiation and the development of cancer. ## Footnote Heterogeneity seen as mutation at different stages.
60
Role of Pu.1
Pu.1 responsible for eary and late lineage differentiation and mutations seen in early and advnces leukaemias.
61
Regeneration of intestinal tissues
Intestinal tissue is highly regenerative. Stem cells and epithelial progenitors called transit-amplifying cells residue in crypts and differentiate as they move up the villi, eventually dying by apoptosis.
62
63
Dedifferentiation of villi cells
Activation of Wnt pathway / loss of Smad4 drive differentiated intestinal epithelium to stem cell-like status and initiation colon cancer growth. Activation of NF-kB leads to enhancement of Wnt signalling, which further supports dedifferentiation of intestinal villus cells.
64
What other methods can colorectal cancer cells be converted into CSCs (dedifferentiation)
Activation of Transforming Growth Factor b 9TGF-b) signalling pathway can also convert colorectal cancer cells into CSCs, which is dependent on TWIST1.
65
Mutation of APC
Mutating APC in crypt cells caused tumours but not in progenitor or differentiated cells (too much b-catenin)
66
What happens when APC function is restored?
Restores crypt cell function even in presence of other mutations. ## Footnote APC is early 'trigger' mutation driving toward CSCs.
67
What are polycomb (PcG) proteins?
Epigenetic regulators of gene expression. Represses differentiation.
68
Effect of BMI-1 knockout?
In healthy animals, there is a depletion of blood cells. In AML, theres a decrease in leukaemic cells in circulation.
69
What is APL?
Acute promyelocytic leukaemia
70
What is PML?
Tumour suppressor protein that regulates cellular processes (cell cyle arrest, apoptosis, genome stability). Promotes P53 activity.
71
What is RAR?
Retinoic acid receptor. Type of nuclear receptor that can also act as ligand-activated trnascription factor. RAR dimerises with RXR (retinoid X receptor)
72
RAR in presence of RA
Recruitment of co-activator and expression of genes for differentiation. ## Footnote Proliferation decreases, differentiation increases.
73
What is APL caused by?
Fusion of PML protein to RAR. PML-RAR recruits HDAC and represses even in presence of RA - repression of differentiation. P53 function of PML disrupted and no cell cycle arrest or apotosis which leads to oncogenesis.
74
What is likely to be the actual cause of CSCs?
* Probably continuum of cells at varying stages of differentiatin. * Accumulated mutations and epigenetic changes so differentiation pathways likely altered * Stage of differentiation may influence malignant potential and severity/progression of cancer * Acquision of different mutations in cells at different stages of differentiation could alter outcome

Regenerative Medicine (11 decks)

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