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Pharmacology of Regenerative Medicine > Edmead Cancer Stem Cell > Flashcards

Edmead Cancer Stem Cell Flashcards

1
Q

What is the cancer stem cell hypothesis?

A

Problems with idea of cancer arising from mature cells.
Cancer is a disease of proliferating cells -> mature cells do not proliferate.
Cancer needs a long time (for life of cell) to occur, accumulation of 3+ mutations - cells normally don’t live long enough to do this.
Tumours are often heterogenous, but cancers are clonal? arising from single cell. Stem cells undergo asymmetrical proliferation.

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2
Q

How could cancer arise from differentiated cells?

A

Induced pluripotency.
Mutations in growth and developmental pathways can account for reactivation of growth pathways in progenitor and differentiated cells.

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3
Q

Mutations to what pathways could lead to induced pluripotency/ ability to self-renew?

A

Wnt pathway.
Beta catenin/Axin
Normally Beta catenin is prevented from acting as a TF. When it is not prevented, then the expression of Cyclin D etc occurs.

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4
Q

B catenin binds and removes the suppression of what?

A

B catenin binds and removes suppression on Tcf by Groucho and then recruits Bcl9 and pygopus.

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5
Q

After B catenin has bound and removed the suppression of Tcf by Groucho, what does it then recruit?

A

B catenin binds and removes suppression on Tcf by Groucho and then recruits Bcl9 and pygopus.

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6
Q

What is Bcl9?

A

Gene/protein cofactor for the transciption factor B-catenin. Clinical significance; Bcl9 is associated with B-cell acute lymphoblastic leukemia.

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7
Q

What is pygopus?

A

Our results suggest that the recruitment of Pygo permits β-catenin to transcriptionally activate Wnt target genes and raise the possibility that a deregulation of these events may play a causal role in the development of B cell malignancies.

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8
Q

What is the Wnt pathway?

A

Wnt binds to Frizzled receptors -> sequestered GSK3 ->B-catenin free to act as transcription factor -> Cyclin D + c-myc -> cell growth.

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9
Q

How are levels of B-catenin normally kept low in the cell?

A

Normally GSK3 + CKI + APC + Axin phosphorylate B-catenin and leads to ubiquitination.

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10
Q

What is the Hedgehog pathway.

A

Normally: Patched inhibits the action of smoothened.

In presence of Hh ligand: Patched no longer inhibits smoothened.

Smoothened then activates Gi which activates gene transcription.

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11
Q

Why is intestinal tissue highly regenerative?

A

Due to the function of the intestine/digestive tract = acidic/breaking down food = need for renewal of epithelial layer.

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12
Q

How does intestinal tissue regeneration occur?

A

SC and epithelial progenitors (transit-amplifying cells) reside in crypts and differentiate as they move up the villi.

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13
Q

What are Polycomb proteins?

A

Epigenetic regulators of gene expression.

Guardians of Stemcell-ness. They control/ drive SR, repress differentiation.

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14
Q

What impact do Polycomb proteins have on TSGenes?

A

Repress TSGenes such as CDKInhibitor INK4.

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15
Q

What impact do Polycomb proteins have on cell growth/renewal?

A

Pro.
Suppress TSGenes, maintains Self-renewal.
Perfect conditions for cancer occuring/oncogenic potential.

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16
Q

Loss of BMI in AML halts cells in G1 and promotes differentiation. What is the normal function of BMI?

A

Normally BMI ubiquitinates H2a, suppressing transcription and compacting chromatin.

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17
Q

What is the in vitro evidence for PcG proteins causing cancer?

A

Loss of the BMI in AML halts cells in G1 and promotes differentiation.

PRC1 is a PcG complex with BMI. Normally BMI ubiquitinates H2a, suppressing transcription and compacting chromatin.

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18
Q

What is the in vivo evidence for PcG proteins in Cancer?

A

BMI knock out in health animals shows depletion of blood cells.

BMI knock out in AML decreases leukaemic cells in circulation.

BMI promotes self-renewal in normal and tumour cells - represses p16 via chromatin remodelling.

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19
Q

BMI has what impact on self-renewal in normal and tumour cells?

A

BMI promotes SR in normal and tumour cells - it represses p16 via chromatin remodelling.

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20
Q

How does BMI promote SR?

A

It represses p16 via chromatin remodelling.

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21
Q

What does AML stand for?

A

Acute myeloid Leukaemia

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22
Q

Why is AML an important model for studying differentiation?

A

HSCs -> differentiated cells through a range of gradually differentiated progenitor cells.

Different TFs control the different levels of differentation.

Mutations in these TF lead to a block on differentation and the development of cancer.

Chromosomal translocation affects the gene driving the differentiation of HSCs.

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23
Q

Pu.1 is responsible for _____ and ______ lineage differentiation and mutations seen in _____ and ________ leukaemias.

A

Pu.1 is responsible for early and late lineage differentiation and mutations seen in early and advanced leukaemias.

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24
Q

CEBPa is involved in granulocyte differentiated and mutant versions associated with _____ AML.

A

Granulocytic AML.

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25
Q

What represses p16 via chromatin remodelling and what impact does this have on SR?

A

BMI represses p16 via chromatin remodelling - promoting self-renewal in normal and tumour cells.

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26
Q

APL

A

Acute Promyelocytic Leukaemia.

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27
Q

In normal cells, what is the role of PML?

A

PML promotes p53 activity - cell cycle arrest, apoptosis.

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28
Q

APL is characterised by what?

A

Chromosomal translocation involving the retinoic acid receptor alpha gene on chromosome 17 (RARa).

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29
Q

What does RAR stand for?

A

Retinoic acid receptor.

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30
Q

The RAR receptor is dependent on what for the regulation of transcription?

A

RAR is dependent on retinoic acid for the regulation of transcription.

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31
Q

What is PML?

A

Promyelocytic leukaemia gene (PML) on C15 fuses with RAR.

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32
Q

The fusion of PML and RAR results in what?

A

The expression of a hybrid protein with altered functions.

Blocks transcription and differentiation of granulocytes by enhancing the interaction of nuclear co-repressor (NCOR) molecule and histone deacetylase (HDAC).

33
Q

How does PML/RAR fused hybrid protein block transcription and differentiation of granulocytes?

A

It enhances the interaction of nuclear co-repressor (NCOR) molecule and histone deacetylase (HDAC).

34
Q

In the absence of RA (retinoic acid) what is the relationship between RAR, RXR and HDAC, and what is the outcome?

A

In the absence of RA: RAR + RXR are dimerised. HDAC is recruited and gene repression occurs/no gene expression.

35
Q

In the presence of RA (retinoic acid) what is the relationship between RAR, RXR and HDAC, and what is the outcome?

A

RA present: RAR + RXR dimerised, coactivator recruited (not HDAC) - > expression of genes for differentiation.

36
Q

In APL, what is the relationship between RAR, RXR, HDAC and RA?

A

RXR not present, APL: fusion of PML+RAR.

PML+RAR recruits HDAC even in presence of RA, hence represses differentiation.

Also, the P53 function of PML is disrupted = no cell cycle arrest etc. Oncogenesis.

37
Q

Loss of what normal function of PML in APL can lead to oncogenesis?

A

p53 function: no cell cycle arrest or apoptosis.

38
Q

Pregnancy early in life has shown to lead to a reduction in the risk of developing breast cancer. Why is this?

A

Hypothesis:
Mammary SCs differentiate into milk producing breast cells during pregnancy.

This depletes the Mammary SCs meaning they are not present in later life in sufficient numbers to become malignant.

39
Q

Why are teratocarcinomas evidence for CSCs?

A

Despite being clonal, CSCs can give rise to a range of cells in various stages of differentiation. eg. teratocarcinomas.

40
Q

Two features critical to cancer progression and prognosis are:

A

Ability of the tumour to grow:

Ability of the tumour to spread to secondary sites.

41
Q

What is angiogenesis?

A

Growth of new blood vessels to provide tumour with oxygen and nutrients.

42
Q

What is metastasis?

A

Ability of tumour cells to break away from primary tumour, travel through the body and recolonise at a distant site.

43
Q

Hypoxia is a strong signal for

A

Angiogenesis

44
Q

What is the function of a stem cell niche?

A

To suppress self-renewal but to to maintain them in an undifferentiated state - primed for if we need them for wound repair.

45
Q

If we take stem cells aware from the stem cell niche what occurs?

A

They will no longer be suppressed by the regulatory signals released by nurse cells, can lead to uncontrolled stem cell growth/renewal/differentiation.

46
Q

Avoidance of immune destruction is a hallmark of

A

Hallmark of cancer.
Involves:
loss of tumour antigens.
Downregulation of MHC
Overexpression of immune checkpoint proteins (PD-L1)
Overexpression of anti apoptotic molecules.

47
Q

What are the mechanisms of tumour-mediated immune evasion?

A

Loss of tumour antigens
Downregulation of MHC
Overexpression of immune checkpoint proteins (PD-L1)
Overexpression of anti apoptotic molecules
Secrete immunosuppressive molecules (TGF-b, IL-10, VEGF)

Switching of macrophages to M2 (tumour promoting) phenotype

48
Q

Why does loss of tumour antigens result in evasion of the immune system?

A

Immune system cannot recognise abhorrent cells for destruction.

49
Q

Why does downregulation of MHC result in evasion of the immune system?

A

Normally their function is to display peptide fragments of non-self proteins from within the cell to cytotoxic T cells; this will trigger an immediate response from the immune system against a particular non-self antigen displayed with the help of an MHC class I protein.

50
Q

Why does overexpression of immune checkpoint proteins like PD-L1 cause evasion of the immune system?

A

Halts the immune system

51
Q

TGF-B, IL-10 and VEGF are examples of what?

A

Immunosuppresive molecules which tumours can secrete to evade the immune system.

52
Q

Switching of macrophages to __ phenotype results in immune system evasion.

A

M2 is the tumour promoting/permitting phenotype of macrophages.

53
Q

What is EMT?

A

Epithelial-mesenchymal transition:

The way that epithelial cancer cells move to distant sites.

54
Q

How do epithelial cells differ from mesenchymal cells?

A 
EP vs MC
Cell polarity vs no cell polarity. 
Cell adhesion vs no cell adhesion. 
Stationary vs ability to migrate. 
High E-cadherin vs low E-cadherin. 
Low N-cadherin vs high N-cadherin.
55
Q

How is EMT intitiated?

A

It is initiated by HGF/TGF-B (signals from tumour stroma/microenvironment)

56
Q

Why can we target EMT?

A

Doesn’t normally happen in adults - mostly occurs during embryogenesis.

57
Q

EMT results in what?

A

acquisition of migratory and SR capabilities.

58
Q

What do HGF/TGF-B released from the tumour stroma etc, bind to?

A

They bind to tyrosine kinase receptors on neighbouring tumour cells.

Activate MAPK/PI3K.

TGF-B activates Smad complex.

Activates EMT TF - Twist/Snail/Slug/Zeb-1

Repress epithelial genes by PcG epigentetic mechanisms

59
Q

What does HGF stand for?

A

Hepatic growth factor?

60
Q

What does PcG refer to?

A

Polycomb proteins

61
Q

Broadly speaking, what is the outcome of HGF/TGF-B release by tumour stroma WRT EMT?

A

They activate a range of signalling pathways that result in the repression of epithelial gene expression via PcG epigenetic mechanisms.

This results in the acquisition of migratory and SR capabilities.

62
Q

Why could the targeting of integrins be useful?

A

They are responsible for tethering cells to the ECM.

There is differential expression of integrins on metastatic melanoma cells.

Currently, not well understood or utilised.

Reduce the motility of the cancer cells.

63
Q

Why might targeting of proteases be useful?

A

They are responsible for the degredation of the ECM and release of cancer cells.

Examples: serine proteases, MMPs.

Tumour cells induce upregulation of MMPs in neighbouring cells.
They cleave E-cadherins, mediate intravasation.

64
Q

WRT recolonisation, what does is the first pass organ theory?

A

That tumour cells metastasise in the first organ they pass through following release from site of origin, get trapped in the capillaries.

65
Q

WRT recolonisation, what is the seed and soil theory?

A

Tumour cells grow in locations where particular selectins are expressed.

66
Q

Kaplan et al 2006 preposed what theory with regard to tumour recolonisation?

A

That tumour preparation of pre metastatic niche can occur.

67
Q

What are micrometastases?

A

Dormant pre colonistion disseminated tumour cells.

68
Q

What are exosomes?

A

“Here, we show that PDAC-derived exosomes induce liver pre-metastatic niche formation in naive mice and consequently increase liver metastatic burden. Uptake of PDAC-derived exosomes by Kupffer cells caused transforming growth factor β secretion and upregulation of fibronectin production by hepatic stellate cells. This fibrotic microenvironment enhanced recruitment of bone marrow-derived macrophages.”

69
Q

If cancer cells do originate from stem cells, what does this mean for the development of therapies?

A

We must be able to target the small population of tumour-initiating cancer cells in addition to the non-stem cells that make up the bulk of the tumour.

But we must not affect normal stem cells - we need to target the differentiaal gene expression.

70
Q

What problems are there currently with developing treatments for cancer stem cells?

A

Cancer stem cells are present in very low numbers so it is hard to isolate them for use in high throughput screening drug strategies.

Need to not target normal stem cells.

71
Q

Gupta 2009 stated what with regard to drug screening models for cancer stem cells?

A

The process of EMT can induce SC-like properties which can be utilised in order to screen for new drugs.

72
Q

Why have ABC inhibitors been developed as adjuvant cancer therapy? What are ABC transporters?

A

Presence of ABC transporters (P-glycoprotein) MDR family to protect
SC against foreign toxins

Expression is lost on differentiation

In tumour cells this manifests as drug resistance and has lead to the
development of ABC inhibitors as adjuvant therapy.

73
Q

BRAF targeting occurs in

A

Melanoma.

74
Q

Wnt has what effect on B-catenin?

A

Upregulated (downregulated by APC - tumour suppressor).

75
Q

Truncating mutations in APC remove all the binding sites for Axin. What is axin?

A

A scaffold that also binds B-catenin and recruites the Kinases GSK3 and CKI which are essential for marking B-catenin for destruction via E3 ubiquitin ligase B-TRCP.

76
Q

Axins bind directly to both ____ and ______ and are essential for the downregulation of ________.

A

Axins bind directly to both APC and β-catenin and are essential for the downregulation of β-catenin.

77
Q

Downregulation of Wnt signalling is a driver in the majority of _______ _______

A

Colorectal cancers.

78
Q

How can we inhibit Wnt signalling?

A
  1. Targeting B-catenin protein-protein interactions.
  2. Targeting kinases in the Wnt pathway.
  3. Unconventional approaches: Lytic virures engineered to replicate selectively in the background of enhanced B-catenin signalling. Directly eliminating β-catenin by mRNA interference is also conceptually appealing. Silencing of β-catenin by transfection or local administration of small interfering RNA retards the growth of preclinical tumour models.

Pharmacology of Regenerative Medicine (14 decks)

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