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Unit 10 > Week 5: Cancer cell biology 2 > Flashcards

Week 5: Cancer cell biology 2 Flashcards

1
Q

What is meant by tumour heterogeneity?

A

variation in tumours both between individuals and within a tumour in the same individual - tumours should not be considered the same entity

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2
Q

What are the three factors contributing to tumour heterogeneity?

A

Genomic and epigenomic mechanisms - genomic instability and abberent epigenetics
Tumour microenvironment and metastasis - tumour resistance to treatment
Clonal evolution - mimics the stem cell model

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3
Q

What are the different hallmarks of cancer?

A

Deregulating cellular energetics
Resisting cell death
Genome instability and mutation
Inducing angiogenesis
Activating invasion and metastasis
Promote inflammation
Enable repilcative immortality
Avoid immune destruction
Evade growth suppresses
Sustain proliferative signalling

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4
Q

How are protooncogenes implicated in caner?

A

Promote cell surival or proliferation
Gain of function
Dominant mutation
Examples are anti-apoptopic proteins, signalling pathway proteins etc

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5
Q

How are TSG implicated in cancer?

A

Inhibit cell survival or proliferation
Loss of function mutation
Recessive mutation
Examples apoptosis promoting proteins, checkway pathway proteins, DNA damage detectors

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6
Q

How are genome maintenance genes implicated in cancer?

A

Repair or prevent DNA damage
Loss of function mutation
Recessive mutations
Examples are DNA repair enzymes

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7
Q

What types of proteins tend to be mutated in cancer?

A

Extra and intra-cellular signalling molecules
Signal receptors
Signal transducing proteins
Transcription factors
Cell cycle control proteins (restrain cell proliferation)
DNA repair proteins
Apoptopic proteins (anti or pro)

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8
Q

What type of genes are cancer critical?
What conditions must be met for this to be cancer critical?

A

1%
Must occur in the correct cell type and are the correct developmental stage

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9
Q

What genes are considered to be cancer critical in colorectal cancer cells?

A

K-Ras
B-catenin
Apc
p53
TGFbeta receptor
Smad4
MLH1 (and other DNA mismatch repait genes)

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10
Q

What are the oncogenes associted with colorectal cancer?

A

K-Ras - affects tyrosin kinase signalling
Beta catening - affects Wnt signalling

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11
Q

What are the TSG associated with colorectal cancer?
What pathway do they affect?

A

Apc - Wnt signalling
p53 - damage to stress and DNA damage
TGFbeta receptor and Smad4 - TGFbeta signalling
MLH1 - DNA mismatch repair

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12
Q

What are the most common mutations in colorectal cancer?

A

Apc
p53
K-Ras

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13
Q

What type of mutations tend to be associated with protooncogenes?

A

Change in protein sequences - results in hyperactive protein
Regulatory mutation - normal protein greatly overproduced
Gene amplification - overproduced
Chromosome rearrangement
1) behind nearby regulatory sequence - causes DNA to be transcribed more often
2) fusion to transcribed gene results in hypertranscription
Mutations that stabilise the protein e.g Myc

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14
Q

What is the role of Myc in colorectal cancer?

A

Low gain knowledge

Acts as a transcription factor for proteins that allow cell to enter the cell cycle or engage with cell proliferation. Such as cyclin dependent kinases

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14
Q

What is more likley to be caused by epigenetics TSG or protonocogene?

A

TSG mutation
Recessive so could be combination (x2 genetic, X2 epigenetic or one of each)

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15
Q

What is the function of the BRCA1/2 genes?

A

BRCA1 (chromosmome 17) - functions in checkpoint activation and DNA repair
BRCA2 (chromosomes 13) - mediator of core mechanism of homologous recomination (Double stranded DNA repair)

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16
Q

How do the BRCA genes relate to cancer?

A

Associated with breast and prostate cancer
Mutations in BRCA1/2 - 60% of cancer cases caused by a known genetic mutation
Around 70% of people with either a BRCA1/2 mutation will develop breast cancer by age 70-8-yrs

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17
Q

Describe how genome maintenace genes may not be considered recessive mutations when relating to cancer in the classical sense.

A

Only one mutated copy - still causes a loss of function - some damage is repair and some is not
Can still lead to the same consequence as when both alleles mutated (cancer critical) but often takes longer.
More susceptible to secondary mutations in other genes. (two hit hypothesis)

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18
Q

What are the main celllular pathways affected in cancer to cause genomic instability?

A

Base and nucleotide excision repair
Mismatch repair
Double-stranded break repair
DNA replication
Chromosome segregation
Telomere maintenance

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19
Q

What is base and nucleotide excision repair?
How does it relate to cancer?

A

Function is to remove and reapir abnormal DNA bases/nucleotides
Germline mutations of these pathways predispose people to colonic polyposis or skin cancers

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20
Q

What is mismatch repair?
How does it relate to cancer?

A

Acts immediately after DNA replication to correct base mismatches, as well as insertions or deletions at repetitive sequences
Loss of function in MSH2 and MLH1 can result in hypermutation and microsatellite instability.

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21
Q

What is double strand break repair and how does it relate to cancer?

A
  1. Homologous recombination repair of double strands - sister molecule is used as a template - includes BRCA genes - important for repair to stalled or collapsed replication forks
  2. Non-homologous end joining - removes DSB in a error prone way - defects in this increase chromosomal instability with elevated chromosomal rearrangements and point mutations
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22
Q

How can DNA replication be affected in cancer?

A

Oncogene activation
loss of TSG
DNA polymerase inhibition
nucleoside imbalances,
replication fork blocking DNA lesions
clashes of replication forks with ongoing transcription

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23
Q

What are the impacts of DNA replication damage in cancer?

A

Replication stress trigger DNA DSB formation, recombination and chromosomal rearrangment
Replication fork stalling, reversal and collapse

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24
Q

What can cause problems in chromosomal segragation in cancerous cells?

A

Directly - defects in mitotic checkpoinr, sister chromatid cohesion, spindle geometry and spindle dynamics
Indirectly - structural chromosome rearrangements generated before mitosis via replicative stress, defective repair or telomere fusion

25
Q

What are the consequences of damaged to chromosome segragation that leads to cancer cells?

A

Poor chromosome spindle attachments and mis-segregation of chromatids during anaphase
Results in generating aneuploid daughter cells

26
Q

What is the implication of telomere maintenance malfunction in cancer cells?

A

Telomere erosion or uncapping results in catastrophic chromosomal instability
Reactivation of telomerase expression in cancer cells can alleviate this instability.

27
Q

What are some characteristic features of cancer genomes?

A

Whole genome replication
Chromosomal loss or gain
Chromothripsis - excess genomic rearrangement involving one or more chromosomes
Translocation
Tandem duplication
Loss of heterozygosity at fragile sites
Focal deletions
Focal amplifications
Hypermutation
Katagis - localised hypermutation
C.T transition (purine to purine and vise versa)
C. G transversion (purine to pyramidine)

28
Q

What are some common causes of DNA mutations that occurs in cancer cells?

A

Errors in stages of cell cycle - chromosomal segragation, metaphase defects etc
Mitotic defects - centriole amplification
Pre-mitotic defects: DNA replication stress, DNA damage repair defects, telomere dysfunction
UV radiation
Tobacco related DNA damage
Cytotoxic chemotherapy

29
Q

What cell types should you expect to find in the cancer microenvironment?

A

Cancerous Cell Duc cells
Myoepithelial cell
Immune cells - NK cells, T cells, B cells, macrophage, DC etc
Apoptopic cells
Fat cells
Endothelial cells, rbcs, pericytes
Fibroblasts

30
Q

Describe the structure of the ECM in the tumour microenvironment

A

Epithelial tissue supported by basal lamina then connective tissue called stroma that is ….
Mainly collagen - also laminin and fibronectin (secreted by fibroblasts and other cells)
Act as anchors for cells by interaction with integrins on cell surface
Proteoglycan make up rest of space - are able to bind to and sequester growth factors
Very dynamic and can be remodelled by cancerous cells or effects

31
Q

What is the role of the ECM in cellular migration?

A

Cells form a leading edge which firmly attaches to the ECM
Attachment is between integrins of cell and fibronectin of ECM
Can move forward by interacting with fibronectin
Collage fibres form cross links to form tracks to guide the direction of movement.
Cancer cells do this through an epithelial to mesenchymal transition (make more mobile)

32
Q

How does cancer progress from a single cell entity?

A

Starts in a dividing cells - division becomes deregulated due to..
1. Activity of protoconcogenes (proliferative signal)
2. Loss of TSG (lack growth inhibitory signals)
Mutations accumulate within cancerous cells and its lineage (often result of damage to DNA repair mechanisms)
THis changes cellular behaviour
Able to form interactions with surrounding environment and alter ECM to form the tumour microenvironment.

33
Q

What cells can cancer corrupt in the ECM?

A

Macrophages - Tumour Associated Macrophages
Fibroblasts - Cancer Associated Fibroblasts
Activated endothelial cells

34
Q

What are the conditions in the tumour microenvironment?

A

Hypoxia
Low pH
Low glucose levels

35
Q

How does cancer cells induced angiogensis?

A

Hypoxia in the tumour microenvironment
Triggers cancer cells to produced VEGF
Acts on VEGFR on endothelial cells
Effect through MAPK signalling
Triggers endothelial cell proliferation and angiogenesis

36
Q

How are tumour associated macrophages produced?

A

Cancer cells use chemoattractans CSF-1 and IL-1b to attract macrophages and transform into TAM

37
Q

What is the role of Tumour Associated Macrophages in the microenvironment?

A

Release growth factors
EGF - encourage cancer cell proliferation
VEGF - encourage endothelial cell proliferation - sustain angiogenesis
Secrete proteases - release sequestered growth factors from the ECM GAGs. - reinforces proliferation signalling

38
Q

How are cancer associated fibroblasts produced?

A

Considered activated normal fibroblasts
Cancer cell uses signalling such as Hedgehog and PDGF to activate fibroblasts

39
Q

What is the role of cancer associated fibroblasts in the tumour microenvironment?

A

Produce high levels of collagen and enzymes to remodel the ECM
Work together using lysyl oxidase to cross link collagen to form tracks for cancer cells to migrate on.
Produce signalling molecules - VEGF and FGF - to contribute to angiogenesis

40
Q

How are hypoxic conditions beneficial to the tumour microenvironment?

A

Cause cancer cells to activate hypoxia-inducible Factors (HIFs)
Transcription factors so alter gene expression in order to survive in hypoxic environment
Code for VEGFs (angiogenesis causing)

Exacerbates corruption of TME, promote tumour progression

Free oxygen radicals generated - increases genetic instability.

41
Q

What is the role of angiogensis for cancer cells?

A

Overcome hypoxic environment
Supply oxygen and nutrients, remove waste.
Newly formed endothelial cells secrete growth factors (PDGF and GM_CSF) to encourage growth of adjacent tumour cells

42
Q

How is the balance of angiogensis promoted in cancer cells?

A

By angiogensis promoters and inhibitors
In early tumours tends to be no or little angiogenesis so remain small or in-situ.
Later turn on angiogenic switch to terminate quiescence
Increased production of angiogenic factors: VEGF FGF
Decrease angiogenic inhibitors: angiostain, endostatin and orvasculostatin
Hypoxia triggers angiogenesis through HIF transcription factor

43
Q

Describe the process of angiogenesis in cancer cells?

A
  1. Hypoxia - induces HIF-1 expression which acts as a transcription factor for pro-angiogenic substances such as VEGF
  2. Hypoxia - upregulates protease to degrade basement membrane and detach pericytes
  3. Tip cell migration - specialised to migrate down angiogenic factor gradient (towards cancer cell)
  4. Tube formation - endothelial cells differentiate into highly proliferative stalk cells behind tip cell in order to make a new vessel
  5. VEGF stimulates DLL4 secretion which binds to NOtch-1 receptors and down regulates blood vessel size
  6. PDGF beta stimulates pericyte attachment and reduced proliferation and VEGF sensitivity. Results in a mature blood vessel supplying the tumour.
44
Q

What are the outcomes of a loss of p53 in tumour cells?

A

Remove cell cyle checkpoints - increase proliferation
Create environment favouring angiogenesis

45
Q

What are some of the genes p53 upregulates and their function?

A

Thrombospondin - angiogenesis inhibitor
Brain specific angiogensis inhibitor
MMP2 - angiogensis inhibitor
EphA2 - induced apoptosis and inhibits angiogensis

46
Q

What are some of the genes p53 downregulates and their function?

A

MMP1 - promote angiogenesis
Cox-2 - promote angiogensis
VEGFA - pro angiogensis and permeability
HIF-1 - promote angiogenesis via activation of VEGF

47
Q

What are the consequences of DNA damage when p53 is functional?

A

Transcription dependent and independent effects on targets
- BAX gene expression - apoptosis
- cause senescence in cell
- repair in cell

48
Q

What are the consequences of DNA damage when p53 is mutated (non-functional)?

A

p53 dependent genes are not activated
No cell cycle arrest, no DNA repair and no senescence
leads to a mutant cells eventually develops into a malignant tumour through accumulation of mutations

49
Q

What factors influence the genetics of a cancer?

A
  1. Genetic disease (risk increase with age)
  2. Evolution of cancer to suit TME
  3. Heterogenicity (clonal evolution, epigenetics and interaction with ME)
50
Q

What is the idea of clonal evolution in cancer cells?

A

Originates from single founder cell which acquires mutations
Proliferates into many daughter cells
Different lienages of daughter cells will have some similar and some different environmental conditions - hence different selective pressures
May acquire different mutations in order to best suit their environment. Some sub-clones will expand as well adapted and others will undergo apoptosis
Over time leads to different cancer cell population with different genetic fingerprints (could think of each population of living in a different ecosystem or niche)

51
Q

What is the role of cancer stem cells?

A

Make up a small minority of the total cell population of tumour
Responsible for tumour growth
Can divide into more stem cells (less likely ) or tumour cells (more likely)
Results in a rapidly growing cancerous cell population and a more slowly growing stem cell population (over times leads to faster rate of growth)

52
Q

What is meant by intertumour heterogeneity?

A

Genetic and phenotypic variation between tumours of different tissues and cells types, or between different people

53
Q

What is meant by intratumour heterogenicity?

A

Variation within a tumour, many subclonal diversity - result of genetic or epigenetic changes
Subclones may intermingle or be geographically separate
if separated may be by blood vessels or microenvironment changes
Can be influences by cancer treatment acting as a selective pressure

54
Q

What ffactors can influence tissue ecosystem that may cause the evolution of somatic cells to form a cancerous environment?

A

Exposure/lifestyle
Constitutive genetics
Local regulators - oxygen, nutrients availability, space, cell-cell and cell-stomal interaction
Architectural constrains - physical compartments, basement membranes, restricted niches.
Systemic regulators - Hormones, growth factors, immune/inflammatory responses

55
Q

What are the two different ways to think of the mutations present in cancer cells?

A

Critical or drivers of cancer
Facilitators or passengers - modest effect on cancerous phenotype of cell

56
Q

What properties do cancer acquire over time?

A

Territorial expansion
proliferative self renwel
Migratoin and invasion
Evade therapy

57
Q

How do we adapt treatment to more complex or advanced cancers?

A

Show greater genetic diversity
Follow whack a mole strategy
Cycle of remission and relapse by using one treatment to target one sub population - then another sub population arises
Requires new treatments such as molecularly targeted therapies - target driver mutations and patient biomarker specific

58
Q

What is an example of synthetic lethality in breast cancer treatment?

A

BRCA1 - double stranded DNA repair by NHEJ and HR
PARP - single stranded DNA repair
Breat cancers normally have mutated BRCA1 (non functional) so rely on PARP gene to function.
Normal cells have BRCA1 and PARP functioning so are not reliant on just one pathway
Treatment that inhibits PARP will be lethal to cancers cells as DNA damage will not be able to be repaired, however in normal cells can use BRCA1 to repair DNA so remain unaffected.

59
Q

What are the new potential treatments being considered for advanced cancer?

A

Molecular targets based on patient biomeraks and driver mutations
Cancer immunity - CAR T Cells and immune checkpoint inhibitors, neoantigens
Target of altered metabolism - BRCA1 and PARP

60
Q

Describe how arginine dependency can be targeted in cancer treatment?

A

Arginine is important in the urea cycle
Some cancers lack ASS1 (that synthesised arginine inside the cell) - these are reliant on external sources of arginine
Cancer treatment ADI (Argiine degrading enzyme) degrades arginine in the ECF - no supply for cancer cells, however self cells with functioning ASS1 are not effected as can make own supply of arginine
Cancer cells - inhibited protein synthesis, decreased NO, increases apoptosis and autophagy and eukaryotic stress leading to cancer cell death.

Unit 10 (37 decks)

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