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ATU3 > Molecular Oncology > Flashcards

Molecular Oncology Flashcards

1
Q

Why was p53 originally thought as an oncogene?

A

Link with oncogenic viral proteins and high expression levels in tumour cells
In the mid 1980s it was cloned from tumour cells and shown to efficiently transform primary cells

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2
Q

How did p53 then become recognised as a tumour suppressor protein?

A

Gene was inactivated by a retroviral insertion
Virtually deleted in human leukaemia derived cell line
1989 - new clone of p53 that could not transform primary cells
Two groups suggested it was a tumour suppressor:
- vogelstein lab
- Levine and oren labs

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3
Q

What is the most frequently mutated gene in human cancers?

A

P53

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4
Q

What are the two other features required to be classed as a tumour suppressor gene?

A
  1. Humans carrying germline mutations should exhibit increased cancer susceptibility
  2. Loss should confer a cancer prone phenotype in mice studies
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5
Q

What syndrome increases children’s likelihood of getting cancer?

A

Li-fraumeni syndrome

- breast, osteosarcoma, brain, soft tissue, leukaemias, and adrenocorticotropic carcinoma

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6
Q

What is the second fundamental feature required for be a tumour suppressor and how was this shown?

A

Absence of p53 should confer cancer prone phenotype

- in mouse when you knock out p53 you get large increases in death

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7
Q

What is the temperature sensitive version of p53?

A

P53Val135

- inactive at 37 degrees

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8
Q

What did the temperature sensitive p53 show?

A

When performed at 32 degrees there was suppression of oncogenic mediated transformation and imposed cell growth arrest at both G1 and G2/M
Inactive version - 37 degrees - oncogenic mediated transformation and cells continued dividing

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9
Q

What happened when p53 was reactivated (32degrees)?

A

Apoptosis of cells showing p53 to have a role as a mediator of apoptosis

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10
Q

What is the third proposed mechanism of p53?

A

Induces cellular senescence - cells lose the ability to divide

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11
Q

What is the most prominent property of p53?

A

Acts as a transcription factor
When needed to be switched on - activated and forms a tetramer (to p53 response elements) - then can be translocated into the nucleus and up regulate gene expression (cell cycle control, apoptosis, DNA repair, differentiation and senescence)

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12
Q

What link does p53 have with cellular senescence?

A

P53 activation leads to p53 mediated transactivation of p21
- p21 inhibits cyclinD / CDk phosphorylation of rb
Inhibits dissociation of rb from E2F - can’t move into s phase
Rb recruits repressors complexes onto E2F responsive promoters

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13
Q

What is the name of a repressors component recruited by Rb?

A

SUV39H1

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14
Q

What does nuclear p53 induce the expression of?

A

Apoptosis genes - Bax and PUMA

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15
Q

What does PUMA do?

A

Releases cytosolic p53 held inactive in the cytoplasm by bcl-X

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16
Q

What does cytosolic p53 induced in the apoptosis pathway?

A

Bax oligomerisation and mitochondrial translocation

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17
Q

Why is p53 accumulated in the cytosolic and what does this induce?

A

Stable monoubiquination
Induces Bax and Bak oligomerisation, antagonises the bcl-2 and bel-X antiapoptopic effect and forms a complex with cyclophilin D

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18
Q

What do the changes in the apoptosis cascade result in?

A

Marked disruption of mitochondrial membranes and subsequent release of both soluble and insoluble apoptogenic factors

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19
Q

What do p53 and MDM2 form?

A

An auto regulatory feedback loop

P53 stimulates the expression of MDM2

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20
Q

What does MDM2 do?

A

Binds to p53 - blocks in transcriptional activity, favours its nuclear export and stimulated its ubiquitin meditated degradation

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21
Q

What does MDMX do?

A

Binds p53 and inhibits transcriptional activity

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22
Q

What do p53 activating signals do?

A

They cause the phosphorylation of p53 and hence prevent association with MDM2

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23
Q

What happens when oncogenes activate ARF protein?

A

ARF protein binds MDM2 promoting its relocation to the nucleus and hence p53 stabilisation

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24
Q

What effect does mutant p53 binding to its family members have?

A

family members - p63 and p73

Prevent them from binding to DNA and blocking the activation of p63 and p73 genes

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25
Q

What happens when mutant p53 engages in protein protein interactions with transcription factor X (TFX)?

A

Becomes tethered to the binding site of TFX

Mutant p53 recruits transcriptional ℅-activators (p300) and augments transcription of TFX target genes

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26
Q

What happens in the proposed mechanism of p53 being tethered to DNA through TFY?

A

Recruits ℅ repressors leading to gene inhibition

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27
Q

What might happen when mutant p53 associates with specific DNA elements?

A

Block the recruitment of TFY to an adjacent binding site, resulting in transcriptional inhibition

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28
Q

What is the first reason as to how mutant forms of p53 can cause cancer?

A

Dominant negative effect - they can multimerise with wildtype protein and prevent DNA binding - therefore unable to transactivation specific apoptosis/cell cycle arrest pathways

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29
Q

What is the second mechanism how mutant p53 can cause cancer?

A

Gain of function mutants
Chromosome spreads show various chromosomal translocations in cells expressing mutant p53
1) over ride the interaction between wildtype p53 and p53 binding protein 1 that associate with DNA repair/cell cycle factors
2) interact with other cellular TFs to upregulate genes which promote genomic instability and disruption of spindle checkpoint control

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30
Q

What is the third mechanism for mutant p53 causing cancer?

A

Gain of function mutants - anti-apoptosis
Specific breast cancer cell line - when mutant p53 depleted with siRNA - cells apoptose
Can act to prevent apoptosis - upregulate anti-apoptopic genes and repress pro apoptopic genes

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31
Q

What are the ways behind therapeutically treating cancers by targeting p53?

A

Delivering functional wildtype p53 to tumours (gendicine)
Restoring p53 function by using low molecular weight compound - bind to mutant P53 altering their conformation to restore wildtype function

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32
Q

When was p53 originally identified?

A

1979 - bound to a mouse virus oncogenic protein SV40 T antigen

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33
Q

What are the characteristics of papilloma viruses?

A 
DNA virus
Present in most vertebrate species studied
Particles around 55nm diameter
8kb double stranded circular DNA genome
Difficult to grow in culture
Species specific 
Icosahedral capsid
Non enveloped protein shell
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34
Q

What does papilloma viruses cause?

A

Warts - mainly benign but can progress to malignancy

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35
Q

What are the different genotypes of papilloma viruses?

A

More than 100 types
Cutaneous - cause benign skin warts
Genital - low risk: HPV-6, 11 cause benign warts or condylomata
- high risk: HPV 16, 18 - cause intra-epithelial lesions and ano-genital cancers

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36
Q

How is the HPV genome organised?

A

Early and late expression

  • E1: viral replication
  • E2: viral replication and transcription
  • E4: destabilisation of cytokeratin network
  • E5: mediation of mitogenic signals of growth factors
  • E6/7: cellular transformation
  • L1: major capsid protein
  • L2: minor capsid coat protein
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37
Q

What happens when cells are transformed with HPV?

A

Integration of HPVDNA into cell genome
Integration results in the loss of E1 and E2
E5, E6, E7 are viral oncoproteins (suppressed by E2) hence increased expression in transformed cells
E5 - weak oncoprotein - not expressed in all HPVs

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38
Q

Describe E6 proteins

A

Around 150 amino acids
Contain two zinc fingers
Transcriptional activators
E6 can bind go p53 and direct its degradation

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39
Q

Describe E7 proteins

A

Contains around 100 amino acids
Contains 1 zinc finger
Transcriptional activators
Binds to rb and activates E2F transcription factor

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40
Q

What to forms of HPV are prone to integrate into the host genome?

A

HPV16 and HPV18

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41
Q

What is MDM2?

A

A ubiquitin ligase that targets p53 for degradation

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42
Q

What happens when HPV infects the cell?

A

Recognised as damaged DNA resulting in up regulation of p53

That up regulation leads to the increased activation of p21

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43
Q

What do HPV16 and HPV18 bind to?

A

Ap - a ubiquitin ligase and in order to get degradation of p53 you need a complex of E6 (16/18) - P53 - E6 associated protein - leads to displacement of E6 - ubiquitin action of p53 and degradation

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44
Q

What genes does E6 activate?

A

DNA repair
Transcription factors/co-activators
Ubiquitin ligase said
Growth suppressors

45
Q

What proteins does E7 interact with?

A

Ubiquitin ligase
Cell cycle control
Glycolysis
Chromatin remodelling

46
Q

What is the mechanism of action of E7?

A

E2F has an accessory protein - Dp-1
E7 binds to rb - E2F can go and transcribe genes such as cdk2 etc
Mimics phosphorylation - frees up E2F to go and activate genes

47
Q

What are the four sections of keratinised epithelium?

A

Stratum corneum
Stratum granulosum
Stratum spinosum
Stratum basale

48
Q

In a normal cell what happens in the sections of the keratinised epithelium?

A

Stratum corneum - keratin filled sacs
Stratum granulosum - accumulation of kerato-hyalin granules
Stratum spinosum - synthesis of high molecular weight keratin
Stratum basale - DNA synthesis and cell division, stem cells (replicating cells)
Go up you get more differentiation
HPV keeps cells in cycle this is important as required for viral replication

49
Q

What happens in the sections of keratinised epithelium in HPV infected cells?

A

Stratum corneum and granulosum - viral capsid synthesis
Stratum spinosum - induction of viral major late promoter, viral DNA amplification
Stratum basale- infection of stem cell, establishment as multi copy extrachromosomal element, viral gene expression limited to early region (early gene expression)

50
Q

What is the target for HPV infection?

A

Squamous keratinised epithelium
Upper layers contain squams - dead cells for packages of keratin - sloughed off and underneath is stratified epithelium
Target of HPV infection is - basale layer (stem cell type that renews itself) of the keratinised epithelium

51
Q

What is mild dysplasia?

A

Replicating cells
In moderate to severe you have viral replication taking place changing the properties of the cell - eventually break out of the basale layer and establish metastates
Intra epithelial events are very important

52
Q

What are the hallmarks of cancer analysis of HPV associated cervical cancer?

A

Many if not most women are infected by high risk HPVs but many women clear the infection with no adverse events - if low grade lesions are produced they will regress
A small fraction of women will go on to get invasive cancer (1-40 years)
Typically this will range over about twenty years
Placed e6 and e7 in many of the processes associated

53
Q

How does HPV E7 aboragate the control mechanism of the cell cycle?

A

By binding rb - interestingly another virus (adenoviruses E1A it also binds rb)
Conserved motif LxCxE - in both adeno and HPV - this motif was a,so found to be conserved in polyomaviruses large t antigen - evolved a binding site for rb - interesting process

54
Q

What does E6 do in the cell cycle?

A

Arrest cells induced by p53 through interacting with it and degrading it
Analogous mechanism in adenoviruses - much larger (35000bp) - encode a large number of open reading frames that also bind and degrade p53

55
Q

What role does E5 have in virus subversion of the immune system?

A 
Appears to stop MHC class I proteins trafficking through the Golgi to the cell surface - an initial protection 
MHC class I are down regulated in pre-malignant and malignant lesions
56
Q

At what level is MHC class I expression targeted?

A

Level of transcription

57
Q

Describe two polyomaviruses and where they where isolated from

A

Bk virus -from renal infections
JC virus - neurological origin
WI/KU - 2007 from respiratory tract infections
Merkel cell polyomaviruses - 2008 from merkel cell tumours
Small DNA viruses - circular dsDNA genome (5kb)

58
Q

What are the two proteins encoded? Polymaviruses

A

Large t antigen
Small t antigen
Merkel cell Polymaviruses contained large deletions in the large t antigen - needed to transform cells (including binding site for p53 was deleted)

59
Q

What are merkel cell carcinoma?

A

Skin cancers
Increased incidence in the elderly and immunisuppresssed
Poor prognosis
Recurs

60
Q

How was MCPgammaV identified?

A

Digital transcriptome subtraction

- whole transcriptome in MCC sequenced and all human cellular transcripts discarded by bioinformatics

61
Q

What is the possible mechanism of merkel cells transformation?

A

There is a cell type called merkel
- located close to hair follicles
Immunosuppresssed - gives viruses the chance to get into cells and then convert them into cancer cells

62
Q

What therapeutics are there?

A

Vaccines - hepatitis B - surface antigen vaccine
HPV vaccine
Men should be vaccinated against HPV
Men are the carriers of HPVs and transmitted by sexual contact
Vaccine is very expensive
Other cancers - no vaccine for hepatitis C
Want to be able to eradicate Epstein Barr virus
Some viruses like HTLV are susceptible to AZT (anti viral drugs)

63
Q

How much of cancer associated mortality is metastasis associated with?

A

Around 90%

64
Q

What is the multistage process of metastasis?

A

1) local invasion
2) intravasation - travel through the storms and get into the blood stream
3) survival in circulation
4) extra assign into parenchyma of distant organs
5) adaptation to new environment
6) outgrowth of secondary tumours

65
Q

What are the the two models for cells acquiring metastatic properties?

A

Linear model

Parallel model

66
Q

Describe the linear model of metastasis

A

Primary tumour goes into primary metastasis then onto secondary metastasis
Primary tumour undergoes successive rounds of mutation and selection
Giving rise to a heterogenous population - subset of cells have accumulated sufficient alterations necessary for metastasis

67
Q

What evidence supports the idea of the linear model?

A

Reduction in metastatic rate upon primary tumour removal

Direct correlation between size of primary tumour and metastatic events

68
Q

Describe the parallel model of metastasis

A

Tumour cells may disseminate very early in malignant progression
Colonies multiple secondary sites at different times and acquire mutations independent to primary tumour

69
Q

What evidence supports the parallel model idea?

A

Studies have compared growth rates of primary tumour and metastasis - metastasis were too big to have been initiated at advanced stage of primary tumour
Animal breast cancer - models have observed early dissemination of tumour cells from primary source

70
Q

How did scientists investigate which model was true?

A

Molecular genealogy - exploring the genetic and temporal relationship between the primary tumours and metastatic lesions

71
Q

What did whole genome sequencing of primary breast tumours and secondary brain metastases show?

A

Copy number alterations and overall mutation spectra were not very different
Prevalence of specific mutations from within a subset of primary tissue was concentrated in metastases

72
Q

Which model did the molecular genealogy experiments favour?

A

Linear progression model - metastatic tumours are clonal in nature but have driver mutations that are not found in primary tumour

73
Q

What does EMT stand for?

A

Epithelial mesenchymal transition

74
Q

What does EMT require?

A

Complex changes in cell architecture and behaviour

75
Q

When and why is EMT essential for?

A

During morphogenesis - without mesenchymal cells tissues and organs will never be formed

76
Q

What differences are there between mesenchymal and epithelial cells?

A

Epithelial cells form tight junctions - mesenchymal cells do not form an organised layer, nor do they have the same apical-basolateral organisation and polarisation of the cell surface molecules and the actin cytoskeleton as epithelial cells

77
Q

What does alterations in EMT control mechanisms allow for?

A

Transformed cells to acquire the ability to invade, resist apoptosis and to disassemble

78
Q

What are the traits for metastasis?

A

Loss of adherents junctions
Expression of matrix degrading enzyme
Increased motility
Repression of E-Catherine gene expression

79
Q

Which genes if over expressed lead to dramatic changes in gene expression profiles and cellular behaviour?

A

Twist
Snail
SNAL2

80
Q

What do twist, snail and SNAL2 do physiologically?

A

Lead down regulation of E-cadherin expression and trigger expression of an entire EMT transcriptional program

81
Q

What does loss of E-Cadherin result in?

A

Loss of cell to cell contacts and cell scattering

82
Q

What do metastasis initiation genes do?

A

Promote EMT

83
Q

What specialised activities does infiltration of distant organs require?

A

Cancer cell passage through capillary walls
Survival in newly invaded parenchyma
All of which differs based on the target organ

84
Q

What does epiregulin (EREG) and prostaglandin G/H synthase 2 (PTGS2) do?

A

Metastasis progression genes

Increase the ability of cancer cells to pass through endothelial barriers

85
Q

What does angiopoietin-like 4 do?

A

Dissociated vascular endothelial cell to cell junctions - increases the infiltration of ANGPLT4 secreting cancer cells into the parenchyma

86
Q

What does LOX do?

A

Acts on extracellular matrix proteins to establish a permissive niche for infiltrating cancer cells

87
Q

What are the two stages metastasis can be broken down into?

A

1) dissemination from primary tumour to distant cells

2) adaptation of these cells to foreign tissue environment resulting in colonisation

88
Q

What are micro-metastases?

A

Successfully disseminated but never progress to form a metastatic tumour

89
Q

What so systemic suppressor factors do?

A

Sent out by the primary tumour to keep the micro-metastases dormant - if the primary tumour is removed they might explode

90
Q

What might macroscopic metastases do?

A

Erupt decades after primary tumour was removed

91
Q

What does metastatic dormancy suggest?

A

Micro-metastases lack all the cancer hallmarks for vigorous growth, in particular activating angiogenesis
Also nutrient starvation
Anti-growth signals
Tumour suppressor actions of immune system

92
Q

What phenotype a do metastases require to overcome colonisation issues?

A

Tumour propagating phenotype or cancer stem cell phenotype
- leads to increased interactions with tumour cell and tumour micro environment
Also acquire or activate metastatic virulence genes - up regulation of inhibitor of differentiation leads to metastatic growth

93
Q

What are ID1 and ID3 proposed to do?

A

Although they have a motile phenotype they are involved in colonisation as KO prevents tumour spreading

94
Q

What do bone metastasis virulence genes do?

A

Confer essential activities for the metastatic colonisation of a certain organ - expression increases the tendency of disseminated cancer cells to form successful metastases in distant organs

95
Q

What does parathyroid hormone related protein do?

A

Enables osteolytic metastases in bone
Can reabsorb bone and release growth factors which in turn can’t act in a paracrine manner to further enhance PTHrP production

96
Q

What are cancer stem cells?

A 
Subclass of neoplastic cells which have the ability to self-renew
- regeneration after chemotherapy 
- ability to trans differentiate into different cell types to aid tumour growth 
E.g endothelial cells to form tumour associated neovasculture
97
Q

Where is much of the heterogeneity of a tumour found?

A

The stroma - the supportive tissue surrounding the cancer cells

98
Q

What cell types are found in the tumour micro environment?

A

Endothelial cells
Pericytes - (specialised mesenchymal cells) wrap around blood vessels (help to cope with high blood pressure)
Immune inflammatory cells - tumour antagonising and promoting leukocytes
- secrete enhances that enhance tumour growth
Cancer associated fibroblasts -
Stem and progenitor cells of the tumour stroma - key source is the bone marrow

99
Q

What role do tumour associated macrophages play?

A

Foster local invasion by supplying matrix degrading enzymes

Important in spreading of tumour cells into vessels but also have a role in metastasis

100
Q

What do TAMS do?

A

Enhance metastasis

Cancer cells activate tams by expressing IL-4 etc

101
Q

What role do cancer associated fibroblasts play?

A

Foster local invasion by supplying matrix degrading enzymes

Enhance angiogenesis to allow blood vessels to form around cancers

102
Q

What are myofibroblasts activated by?

A

Cancer cells secreting TGFbeta

103
Q

What does MMP3 expression do?

A

Lead to cleavage of E-Cadherin - leading to tight junction dissociation
Highly expressed in myofibroblasts
Cancer cells then undergo EMT

104
Q

What is a promising approach for metastatic therapeutics?

A

Targeting dormant metastatic cells and preventing their outgrowth
More preferable to interfere with the tumour micro environment or CSC niche permissive for outgrowth of metastases

105
Q

What do the present metastatic approaches target?

A

Both the primary tumour and metastases simultaneously by blocking tumour cell proliferation and survival of tumour vascularisation

106
Q

What does denosumab do?

A

Mops up RANK-L

  • causes eating of the bone for the tumour cell to colonise
  • secretion by tumour cell stimulates RANK-L production
107
Q

How does RANK-L work?

A

Binds to its receptor on osteoblAsts

  • leads to differentiation and activation creating osteolytic lesions
  • bone resorption factors in turn stimulate production of PTHrP from tumour cells
  • increased src activity leads to activation of osteoclasts and bone resorption
108
Q

Which drugs interrupt this cycle and reduce osteoclast activity?

A

Denosumab, bisphosphonates and dasatinib

ATU3 (2 decks)

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