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Cancer Lectures > Zebrafish Model of Cancer > Flashcards

Zebrafish Model of Cancer Flashcards

1
Q

What family are zebrafish members of?

A

The minnow family (Cyprinidae)

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2
Q

What is the latin name for zebrafish?

A

Danio rerio

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3
Q

What are zebrafish?

A

Small freshwater fish native to Northern India/Bangladesh

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4
Q

How did Streisinger die in 1984?

A

In a scuba diving accident

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5
Q

What did Streisinger develop methods for?

A

Generating homozygous diploid clones of zebrafish

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6
Q

What year were zebrafish first included in a publication in Nature?

A

1981

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7
Q

Describe the progression of zebrafish studies since the first papers were published on them?

A

Studies using zebrafish have grown exponentially

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8
Q

How long did it take for zebrafish to become the second most widely used model in bioscience research?

A

In around 20 years

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9
Q

Between what years was there development and dissemination of zebrafish methodologies?

A

1984-1992

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10
Q

Describe the pros of using zebrafish as models for human cancers

A

Fast
Large scale
Cheap
High resolution

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11
Q

Describe the pros of using mice as models for human cancers

A

High resolution

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12
Q

Describe the cons of using mice as models for human cancers

A

Time consuming

Expensive

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13
Q

Describe the pros of using bacteria as models for human cancers

A

Fast

Large scale

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14
Q

Describe the cons of using bacteria as models for human cancers

A

Resolution limited

Cheap

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15
Q

What did the Zon lab in March 2011 use zebrafish for?

A

High-throughput screen of chemicals that might suppress melanoma

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16
Q

What was George Streisinger’s hobbies?

A

He was a tropical fish enthusiast who studied his fish in his own collection to find a potentially useful model

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17
Q

Why did George Streisinger want to find a new model organism?

A

He found that mice are too complex and microorganisms are too simple

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18
Q

Where did George Streisinger work?

A

At the University of Oregon

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19
Q

Who is George Streisinger and what did he work on?

A

Geneticist

Worked on T4 bacteriophage genome in the 1960s and 1970s

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20
Q

What did George Streisinger begin to do in the 1980s?

A

Began to look for more complex systems to study genetic regulation of development

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21
Q

Give 4 advantages of the zebrafish life cycle

A

Transparent embryos
Rapid development
Spawn at dawn
100’s of eggs produced per female

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22
Q

What did scientists do prior to Streisinger’s death in order to promote the utility of zebrafish as a genetic model?

A

They ran courses

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23
Q

Give an example of another Oregon scientist who had become interested in harvesting the power of the zebrafish model prior to Streisinger’s death

A

Charles Kimmel

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24
Q

The interest in zebrafish as a model organism gained critical mass and many groups across the US and Europe began working with the fish, true or false?

A

True

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25
Q

Since around what year have many cancer biologists turned their attention to using zebrafish for cancer research?

A

2000

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26
Q

Do immature (embryonic/larval) zebrafish develop tumours?

A

Rarely

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27
Q

How big is a larval fish at 4 days old?

A

~4mm

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28
Q

In immature zebrafish, how can precocious tumours be induced?

A

With transgenic approaches

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29
Q

Can immature zebrafish be readily zenografted with human tumour cells?

A

Yes, the graft is not rejected

30
Q

In immature zebrafish, what does their optical transparency permit?

A

In vivo imaging of tumour growth/metastasis

31
Q

What does the small size of immature zebrafish permit the high throughput chemical screening of?

A

Carcinogens/chemical tumour suppressors

32
Q

In vivo imaging approaches can be used to resolve what in early-stage zebrafish?

A

Intravasation and metastasis

33
Q

Why are fish better for high throughput in vivo screens than mouse models?

A

Once a candidate drug is identified and tested on a mouse model, accurate results cannot be observed until several years later and then there is 98% probability of failure

34
Q

What types of tumour can adult zebrafish spontaneously develop?

A

Almost any type of tumour

35
Q

How can tumours be readily induced in adult zebrafish?

A

Carcinogen exposure
Zenograft
Gene knockout/insertion (fast and easy)

36
Q

Adult fish tissues are opaque so in vivo imaging is not possible, true or false?

A

False, in vivo imaging is still possible to an extent when using pigmentation mutants

37
Q

What have forward genetic screens of zebrafish identified?

A

New oncogenes

38
Q

What did the Hopkins lab develop in 2004 using forward genetics?

A

Mass mutagenic screening

39
Q

Outline the mass mutagenic screening approach to identify new oncogenes

A
  1. Inject 1000s of eggs with a retrovirus
  2. Virus randomly inserts into the genome
  3. Outcross and screen for mutant phenotypes
  4. Sequence mutated genes
40
Q

What did Amsterdam et al. use the mass mutagenic screening approach in 2004 to identify?

A

12 mutant lines that had increased incidence of cancer

11 of these were mutations in ribosomal genes, which had not been previously associated with cancer

41
Q

Give an example of a zebrafish liver oncogene

A

apc

42
Q

Give an example of a zebrafish intestine oncogene

A

apc

43
Q

Give an example of a zebrafish ocular oncogene

A

pten

44
Q

Give examples of a zebrafish nerve sheath oncogene

A

tp53

msh

45
Q

Give an example of a zebrafish leukemia oncogene

A

c-myc

46
Q

Give an example of a zebrafish melanoma oncogene

A

BRAF

47
Q

Give an example of a zebrafish neuroendocrine oncogene

A

MYCN

48
Q

Adult zebrafish can shed new clues on the formation of what?

A

Melanoma

49
Q

Imaging metastases in vivo with zebrafish has shown that what compounds work together to cause metastases?

A

VEGF and RhoC

50
Q

Over the past 20 years the zebrafish has become a credible and powerful model for studying cancer, true or false?

A

False, only over the past 12 years

51
Q

Give an example of a rapid, reliable method for studying cancer in zebrafish

A

The insertion of transgenes

52
Q

Outline the method for the easy insertion of transgenes in zebrafish

A
  1. Inject one-cell stage eggs with DNA
  2. Raise to adulthood (3 months)
  3. Outcross and test for germline transmission
  4. Widely used technique for introducing oncogenes (e.g. RNUX1/c-myc/bcl2/Notch/BRAF) into fish
53
Q

What is c-myc?

A

A transcriptional regulator

54
Q

What are mutations in c-myc associated with?

A

Cancer (highly prevalent in Burkitt’s lymphoma)

55
Q

What is BRAF a member of?

A

The RAF kinase family

56
Q

What is BRAF?

A

A serine/threonine kinase that participates in the RAS/RAF sigalling pathway

57
Q

What is BRAF critical for?

A

Normal development

58
Q

Without BRAF, what syndrome develops?

A

Cardio-facio-cutaneous (CFC) syndrome

59
Q

What are the symptoms of CFC?

A

Metal retardation
Heart defects
Distinct facial features

60
Q

What are gain of function mutations in BRAF during later life often associated with?

A

Melanoma (but only in around ~50% of cases)

61
Q

What substitution is present in 90% of cancers involving BRAF?

A

Valine is substituted with glutamine at codon 600

62
Q

In 2005, what did Leonard Zon and colleagues used zebrafish to ask?

A

Whether the mutation of BRAF alone was sufficient to induce melanoma

63
Q

What must BRAF work cooperatively with?

A

Other gene mutations

64
Q

What locus other than BRAF is also commonly associated with melanoma?

A

CDKN2A

65
Q

What does the CDKN2A locus contain coding regions for?

A

p16 and p19 which are components of the Rb and p53 tumour suppressor pathways

66
Q

How did Patton et al. produce a fish with the melanoma in 2005?

A

Generated BRAF-V600E/p53 double mutants by injecting mutated BRAF DNA into loss-of-function p53 mutant embryos and then raised until adulthood

67
Q

What did Patton et al. conclude from their research in 2005?

A

That melanoma depends on a gain of function mutation in BRAF coincident with the loss of p53 tumour suppressor pathway

68
Q

What is the role of methyltransferases?

A

They regulate the methylation of chromatin

69
Q

Outlined the methods and findings of the experiment conducted by White et al. in 2001 in which chemical agents that inhibited neural crest formation in developing zebrafish embryos were screened

A

Used mitf:GFP line which expresses GFP in precursors of melanocytes and carried out a mass screen tested on around 2000 compounds and then tested efficacy of leflunomide in a mouse xenograft model
Found that leflunomide, an anti-arthritic drug suppressed proliferation of neural crest cells and suppresses tumour growth

70
Q

What happens to melanoma progression when leflunomide is administered in combination with the BRAF inhibitor PLX4720?

A

Melanoma progression is completely arrested

71
Q

What type of cancer has zebrafish research provided new insights into?

A

The metastasis of breast cancer

Cancer Lectures (24 decks)

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