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BMS336 - Modelling Human Disease and Dysfunction > 7. Cancer 1: Developmental Biology Wnt > Flashcards

7. Cancer 1: Developmental Biology Wnt Flashcards

1
Q

What was found in inbred strains of mice?

A

Particular inbred strains of mice were highly susceptible to mammary tumours ie female mice developed mammary tumours with almost full penetrance

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2
Q

How were the mammary tumours said to form?

A

When an RNA retrovirus (Mouse Mammary Tumour Virus) integrates itself next to a proto-oncogene, resulting in abnormally high levels of expression of this gene

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3
Q

How do RNA retroviruses drive increased proto-oncogene expression?

A
  • RNA retrovirus hijacks the host cell machinery to transform its RNA transcript into DNA which is then randomly inserted into the host’s genome
  • Retrovirus contains strong, constitutively active promoters and if host gene is downstream, read-through can occur from the viral promoter turning on/enhancing expression of host gene
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4
Q

What is a proto-oncogene?

A

Gene that normally regulates cell cycle in controlled manner, but if gene is mutated or overexpressed it can become oncogenic

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5
Q

What was the proto-oncogene found to be unregulated by Mouse Mammary Tumour Virus?

A

Integration Site 1 (Int1)

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6
Q

What did the predicted protein of Int1 show?

What did this suggest?

A
  • Int 1 protein starts with a signal sequence
  • Protein likely to be secreted
  • Protein may be a growth factor - gives growth advantage
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7
Q

How did developmental biology contribute to the understanding of Int1?

A
  • Nusslein-Volhard and Wieschaus performed large-scale mutagenesis screen in Drosophila to identify patterning genes
  • These included segment-polarity genes, 1 of which was Wingless
  • Wingless showed homology with Int1, therefore was renamed to Wnt1
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8
Q

How was the Wnt signalling pathway elucidated?

What is the canonical Wnt signalling pathway?

A
  • Wnt signalling pathway was elucidated in model organisms (Drosophila and Mice) and mammalian cell cultures
    1. In absence of Wnt, B-catenin is degraded in cytoplasm
    2. In presence of Wnt, Wnt binds to its receptor Frizzled resulting in the stabilisation of B-catenin
    3. B-catenin enters nucleus and binds to co-activators and co-TFs to activate target gene expression
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9
Q

What are Wnt signalling target genes?

How do these lead to mammary tumours in mice?

A
  • Genes directly governing cell proliferation (e.g. CmyC and Cyclin D1)
  • In mice, abnormally high levels of Wnt1 in mammary cells leads to increased expression of CmyC and Cyclin D1 which increases cell proliferation
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10
Q

How were components of Wnt signalling identified?

How were these ordered into a pathway?

A
  • In Drosophila, using KO or overexpression studies
  • If KO/overexpress gene and get same phenotype as Wnt KO/overexpression then this tells you the gene is involved in WNt signalling
  • Use epistatic studies to order components into a signalling pathway
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11
Q

Give an example of an epistatic study.

A
  • If think B-catenin is downstream of Frizzled, KO Frizzled and then artificially put in stabilised B-catenin
  • If B-catenin is downstream, this will rescue the effects of the Frizzled KO
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12
Q

What are the 2 ways of activating the Wnt signalling pathway?

A
  1. Increasing activators

2. Removing suppressors

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13
Q

What are oncogenes in the Wnt signalling pathway?

How could they lead to cancer?

A
  • Activators - overexpression leads to increased Wnt signalling activation therefore increased expression of cell cycle regulator genes (CmyC, Cyclin D1)
  • This leads to increased proliferation
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14
Q

What are tumour-suppressor genes in the Wnt signalling pathway?
How could they lead to cancer?

A
  • Suppressors - normally act to suppress activation of Wnt signalling pathway (e.g. APC), but if BOTH copies are mutated/deleted this suppression is lost, leading to increased Wnt signalling activation
  • This leads to increased proliferation
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15
Q

Why is cancer referred to as a multi-step disease?

A

Cancer can take many years to develop

  • If 1 copy of tumour-suppressor gene is mutated/deleted then there is no effect as remaining copy is sufficient
  • When both copies are mutated/deleted then suppressive effect is lost and cancer develops
  • It can be many months, years or never before 2nd copy is mutated/deleted
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16
Q

Does overexpression of Wnt lead to human cancer?

A
  • No evidence that overexpression of Wnt itself leads to human cancer
  • But mutations in Wnt signalling pathway components leads to constitutive stabilisation of B-catenin which is clearly implicated in many human cancers
17
Q

What are the 2 categories of mutations in Wnt signalling pathway?

A
  1. Activating mutations - B-catenin is always stabilised and in nucleus
  2. Loss of suppression - both copies of suppressor gene are lost so B-catenin is always stabilised and in nucleus
18
Q

What is the most common cancer linked to mutations of Wnt signalling pathway components?

A

Colorectal cancer

19
Q

What does the finding of signalling pathway components allow in cancer?

A
  • Pathways have important predictive values in cancer
  • By establishing how genes control signalling (e.g. act as activators or suppressors) can make educated guesses how these genes may contribute to human cancer
  • Activator = oncogene
  • Suppressor = Tumour-suppressor gene
20
Q

How can signalling pathway components be used in assessing cancer risk?

A
  • Signalling pathway components can be used as biomarkers for cancer risk
  • E.g. if increased nuclear B-catenin causes increased proliferation can biopsy tissue and analyse levels of nuclear B-catenin to assess cancer risk
21
Q

How can we see what cells in the body respond to Wnt?

A

Using Wnt-responsive transgenic reporter lines (e.g. take Axin promoter (Axin gene unregulated by Wnt signalling activation) and clone reporter protein (GFP) downstream of this promoter)

22
Q

What did transgenic reporter lines show about Wnt-responsive cells?

A

In many parts of body, Wnt-responsive cells were tissue-specific stem cells

23
Q

How might Wnt signalling activation lead to cancer?

A

Activation of Wnt signalling pathway in stem cells promotes self renewal therefore abnormal activation may cause uncontrolled self-renewal

24
Q

Describe the gut crypt stem cell niche.

A

Gut crypt made up of columnar epithelial cells

  • At base of crypt is the stem cell niche
  • At top of crypt is differentiating/ed cells
  • Stem cells at base of crypt are surrounded by supporting Paneth cells
  • When stem cell divides give rise to progenitor which rapidly amplifies this cell type (Trans Amplifying cells)
  • As TA cells migrate up crypt they begin to differentiate into villus cells
25
Q

What signalling occurs in the gut crypt?

A
  • At crypt base, high levels of Wnt and Notch promote stemness/proliferation in stem cells
  • At top of crypt, high levels of BMP promotes differentiation
26
Q

What is an adenoma?

A
  • Pre-cancerous growth

- In colon adenomas, detect high levels of nuclear B-catenin in stem cells leading to increased proliferation

27
Q

How are inbred/genetically engineered mice used in cancer study?

A
  1. Identify oncogenes/tumour-suppressor genes
  2. Identify signalling pathways that lead to specific cancer types
  3. Understand basic biology at a cellular level (e.g. uncontrolled stem cell self-renewal)
  4. Impact of diagnostics and treatment
28
Q

What has been found about breast cancer treatment?

A
  • In BC many cells respond to oestrogen and therefore treat with anti-oestrogen Herceptin to target HER2
  • However, BC often returns due to breast cancer stem cells (BCSC) which are resistant to anti-oestrogens
  • New rationale is to treat BC with a combination of anti-oestrogens and anti-Wnt/Notch/Shh to target BCSCs
29
Q

What is linked to the progression of cancers?

A

Inflammatory pathways

30
Q

How is tumorigenesis thought to occur following loss of APC?

A
  • APC gene is mutated in majority of colorectal cancers and loss of APC leads to constitutively active Wnt signalling and activation of CmyC
  • This leads to increased RAC1 expression which causes hyper-poliferation
  • RAC1 mediates this effect by driving NFkB and ROS signalling - indicates role of inflammatory pathways in tumorigenesis
31
Q

What are NFkB and ROS?

A
  • NFkB is a pro-inflammatory factor that positively regulates the expression of pro-inflammatory genes e.g. cytokines
  • Reactive Oxygen Species are key signalling molecules that are important in the progression of inflammatory disorders
32
Q

What is the potential mechanism of action how inflammatory pathways promote cancer progression?

A
  1. As tumour grows, its need for oxygen and nutrients outstrips its supply
  2. Cancer cells secrete pro-inflammatory signals (e.g. cytokines)
  3. Macrophages invade tumour and secrete more cytokines to kick-start angiogenesis to increase nutrient and oxygen supply
  4. Inflammatory cells break down ECM to promote metastasis

BMS336 - Modelling Human Disease and Dysfunction (14 decks)

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