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PATH30001 - Mechanisms of Disease > Lecture 32 - Cancer Signalling > Flashcards

Lecture 32 - Cancer Signalling Flashcards

1
Q

Describe the trends in Australia in cancer

A
  • Increased incidence
  • Decreased mortality
  • Increased rates of 5-year relative survival
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2
Q

Which signalling pathways are invariably altered in cancer?

A
  • Cell survival
  • Cell growth
  • Cell differentiation
  • Metastatic potential (?)
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3
Q

What is meant by signalling?

A

Biological communication at the submolecular / molecular level

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4
Q

Describe the Hanahan and Weinberg paper

A

Hallmarks of Cancer:

2000:
 • Evasion of apoptosis
 • Sustained angiogenesis
 • Immortal: limitless potential for replication
 • Metastasis and tissue invasion
 • Insensitivity to antigrowth signals
 • Self-sufficiency in growth signals
2011:
 • Avoidance of immune destruction
 • Tumour promoting inflammation
 • Genome instability
 • Deregulation of cellular energetics
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5
Q

Describe the major molecular events involved in cancer evolution

A
  1. Triggers / build up of events:

a. Environmental agents that damage DNA
• Chemicals
• Radiation
• Viruses

b. Inherited mutations in genes affecting:
• DNA repair
• Cell growth
• Apoptosis

  1. DNA damage
  2. Mutations in somatic cells

4.
• Impaired apoptosis
• Activation of oncogenes
• Inactivation of tumour suppressor genes

  1. Altered gene products
    Abnormal structural and regulatory proteins
  2. Malignant tumour
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6
Q

What is dysplasia?

A

Change in cell or tissue phenotype

Abnormality of development

Epithelial anomaly of growth and differentiation

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7
Q

Which classes of normal regulatory genes are the principal targets of genetic damage in carcinogenesis?

Characterise their involvement in carcinogenesis

A
  • DNA repair genes
  • Proto-oncogenes
  • Tumour suppressor genes
  • Genes that regulate apoptosis

In almost all cases of carcinogenesis, all classes are involved, and the pathways they are involved in interact

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8
Q

List the types of mutations that occur in cancer

A
  1. Errors in DNA replication that are not repaired
    • e.g. BRCA1 & BRCA2
    • Accumulation of errors in “hotspots” (TSFs, oncogenes)
  2. Point mutations
    • Activation of oncogenes
    • Inactivation of TSGs
  3. Amplification of oncogenes
    • CNV
  4. Chromosomal rearrangements
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9
Q

Mutation in which class of genes may often be an early event that allows rapid accumulation of secondary mutations?

A

Mutations in DNA repair genes

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10
Q

What is meant by mutation?

A

Change in a DNA sequence away from normal

This implies there is a normal allele that is prevalent in the population and the mutation changes this to a rare and abnormal variant

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11
Q

Describe how chromosomal translocations can lead to carcinogenesis

A
  1. Translocation between Chromosomes 9 and 22
  2. Fusion of the ABL and BCR loci

ABL: oncogene (tyrosine kinase)
BCR: Breakpoint cluster region

  1. BCR-ABL fusion protein
    Constitutively active tyrosine kinase
  2. Chronic myeloid leukaemia
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12
Q

What can immunohistochemistry tell us about cancer?

A

Fluorescently tagged mAbs that allow detection of markers of proliferation

Examples:
• PCNA: proliferating cell nuclear antigen
• Ki-67: recognises specific antigen in Hodgkin lymphoma

In tumour tissue there are very high levels of these markers of proliferation in comparison to normal tissue

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13
Q

Describe the rate neoplastic growth

A

Theoretically:
• 90 days to do from one cell to 10^9 (1g)
• After one more month, the tumour would weigh 1kg
• This would require all cells to remain in cell cycle and no cell loss

Realistically:
• Takes longer, because not all cell divide and some die

Lag phase:
 • Slow growth
 • Cells sensitive to the micro-environment
 • Immune regulated killing of cells
 • Poor blood supply

Growth phase:
• Exponential
• Angiogenesis: tumour has a rich blood supply delivering nutrients that allow it to rapidly increase in size

Plateau:
• Necrosis, because tumour is too big
• Growth slows

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14
Q

Describe the normal steps in proliferation

Which aspects of this could lead to carcinogenesis, to a greater and lesser extent?

A
  1. GF
  2. GF receptor
  3. Intracellular kinase
  4. Transcription; translation
  5. Cell enters cell cycle
  6. Proliferation
Carcinogenesis:
Commonly:
 • Mutant receptor - always "on"
 • Mutant intracellular kinase
 • Mutant transcription factor

Not so common:
• Mutant cyclins and CDKs
• Over-expression of GFs

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15
Q

What is the name of the product of oncogenes?

A

Oncoproteins

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16
Q

Compare proto-oncogenes and oncogenes

A

Proto-oncogenes:
• Normall cellular genes
• Products almost always promote proliferation and suppress differentiation

Oncogenes:
• Mutant versions of proto-oncogenes
• Function autonomously without requirement for normal growth-promoting signals

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17
Q

Which transduction pathway is normally activated with GF signalling?

A
  • MAPK

* PI3 kinase

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18
Q

What type of receptor are GF receptors?

A

Tyrosine kinase receptors

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19
Q

Mutations in how many alleles is required for carcinogenesis in oncogenes and TSGs?

Compare the outcome of mutation in oncogenes and tumour suppressor genes

A

Oncogene mutation:
• Only 1 allele mutated
• Accelerated growth

Tumour suppressor gene mutation:
• Both alleles lost
• Continuous growth

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20
Q

Give examples of oncogenes and TSGs

A

Oncogenes:
• Her2-neu
• Ras
• Myc

TSGs:
 • p53
 • Rb
 • APC
 • PTEN
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21
Q

What do TSGs usually encode?

A

Proteins that inhibit cellular proliferation by regulating the cell cycle directly:
• Rb
• p53
• PTEN (inhibition of oncogenic pathways)

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22
Q

Describe LOH

A

Loss of heterozygosity
Part of Knudson’s “two hit” hypothesis

  1. One allele for the given TSG is already mutated (heterozygosity)
  2. Loss of normal function of the other allele
  3. LOH

(Both alleles of TSGs must be lost for tumour development)

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23
Q

Describe Knudson’s “Two Hit” hypothesis

A

Loss in one allele of a TSG is not enough to generate a tumour

LOH needed to form the tumour

Initial ‘hit’: i.e. loss of TSG may be:
• Inherited: earlier onset
• Sporadic

24
Q

Describe the different ways that functional TSGs can be lost

A

– Deletion –

    • miRNA –
      1. TSG transcribed into mRNA and leaves nucleus
      2. Abundant miRNA in cytosol, binds to target TSG mRNA
      3. TSG mRNA not transcribed
      4. Reduced tumour suppressor protein
    • Epigenetic changes –
      1. Focal CpG hypermethylation of promoter or start of transcription site of TSG
      2. TSG not expressed
25
Q

What are miRNAs?

A
  • Non-coding
  • Single stranded RNA
  • approx. 22 nucleotides

Function:
• Negative regulators of genes
• Through binding mRNA and preventing translation

26
Q

What is the mechanism through which cell division is controlled?

Describe its importance in cancer

A

Cell cycle

“Cancer is a disease of the cell cycle”
Since:
• Cancer is uncontrolled division
• Division controlled by cell cycle

27
Q

Which important functions does the cell cycle perform?

A
  • Regulation of the growth and mitotic phases

* Ensures faithful replication and segregation of genetic material

28
Q

What is the effect of oncogenes and TSGs on the cell cycle in cancer?

A

Cell cycle checkpoints are perturbed

Checkpoints:
• Checking the integrity of the DNA at various points in the cell cycle

Both TSGs and Oncogenes are involved in the checkpoints

TSGs:
• Normally stall the cell cycle
• e.g. p53

Oncogenes:
• Cause acceleration / bypass through the checkpoints

29
Q

Describe the role of p53 in carcinogenesis

A

p53:
• TF
• Regulates expression of cell cycle factors

Function
1. Cellular stress

  1. Up-regulation of p53
  2. Transcription of tumour suppressing genes
4. Cellular outcomes
 • Apoptosis
 • Cell-cycle arrest
 • DNA repair
 • Differentiation
 • Senescence

In cancer:
• Involved almost invariably
• Loss of p53 → cells no longer able to conduct normal regulatory functions (DNA repair, apoptosis etc)

30
Q

Describe evasion of apoptosis in carcinogenesis

A

Apoptosis must be avoided for tumourigenesis

Mechanisms:
• Reduced CD95 (aka FAS)

  • Inactivation of death-induced signalling complex (aka pro-caspase 8) by FLICE
  • Upregulation of BCL-2
  • Reduced levels of BAX
  • Loss of APAF-1
  • Up-regulation of inhibitors of apoptosis
31
Q

Describe how the FAS-FASL pathway can be interrupted leading to tumour generation

A
  1. Reduced FAS expression on cell
  2. FLICE protein
    • Inactivates the death-induced signalling complex (aka pro-caspase 8)
32
Q

Describe the role of BCL-2 in tumour generation

A

BCL-2 is an anti-apoptotic

In cancer it can be up-regulated

33
Q

Describe the role of BAX in tumour generation

A

BAX is a pro-apoptotic

Loss of p53 → decreased BAX

34
Q

What is the role of APAF-1 in cancer?

A

APAF-1 is a pro-apoptotic

APAF-1 activates caspase 9 → apoptosis

Loss of APAF-1 → tumour growth

35
Q

Describe how tumour cells can become immortal

A

Telomeres endow limitless replicative potential (→ cancer)

Normal role of telomeres:

  • Telomerase adds more nucleotides to the telomeres so that they don’t become too short and thus lose integrity
  • Normally low telomerase activity in cells
  • Shortened telomeres eventually activate cell cycle checkpoints → senescence

In cancer:
• Shortened telomeres due to many cell replications

  • Reactivation of telomerase
  • Cells become immortal (avoid senescence)
36
Q

Describe generation of metastasis and the importance in carcinogenesis

A

Metastasis is important for tumour growth

Mechanism:
1. Detachment of tumour cells from one another
• Down-regulation of adherence molecules
• E-cadherin
• Beta-catenin
• Integrins

  1. Degradation of ECM
    • Metalloproteinases expressed at high levels
  2. Attachment to novel ECM components
  3. Migration in the blood
37
Q

Describe the importance of angiogenesis in carcinogenesis

A

Angiogenesis is important for the support of tumour growth.
They are very rapidly growing, and thus require a rich blood supply

Mechanism:
• VEGFs and VEGFRs upregulated
• Increased recruitment of vascular stem cells
• Angiogenesis

This is a popular therapeutic target
“Anti-angiogenics”

38
Q

Describe tumour cell heterogeneity

What is this due to?

A

Tumours are very heterogeneous

Even in one tumour, the genomes of cells in one region can be very different to the genomes of cells in another region

Tumour cells have the ability to mutate rapidly

Due to:
• Genomic instability
• Through loss of p53
• Loss of DNA repair proteins

This is probably why tumours rapidly become resistant to drugs

39
Q

What can tumour initiating cells do?

A

Allow human tumour growth when transplanted into immunodeficient mice

40
Q

Describe cancer stem cells

A

Have a high intrinsic resistance to conventional therapies

Make up only a small part of the bulk of the tumour

41
Q

Describe how cancer stem cells could be targeted, and how they are conventionally targeted

A

Cell mass containing cancer stem cells and tumour cells

Conventional therapy:
• Targets bulk of the tumour cells and not cancer stem cells
• Tumour relapse from cancer stem cell

Cancer stem cell specific therapy:
• Targets cancer stem cell and not cells that form the bulk of the tumour
• Tumour regression

42
Q

Describe how the various aspects of Hanahan & Weinberg’s model of cancer can be therapeutically targeted

A
  1. Self-sufficient growth factor signalling
    • EGFR inhibitors
  2. Evasion of growth suppressors
    • CDK inhibitors
  3. Avoidance of immune destruction
    • Immune activating anti-CTLA4 mAb
  4. Immortality
    • Telomerase inhibitors
  5. Angiogenesis
    • Inhibitors of VEGF signalling
  6. Metastasis
    • Inhibitors of HGF/c-Met
  7. Genome instability and mutation
    • PARP inhibitors
  8. Deregulation of cellular energetics
    • Aerobic glycolysis inhibitors
  9. Resistance of apoptosis
    • Pro-apoptotic BH3 mimetics
  10. Tumour promoting inflammation
    • Selective anti-inflammatory drugs
43
Q

Discuss biochemical ‘circuits’ and their role in cancer and the therapeutics thereof

A

Complex interaction between various signalling pathways that modulate the outcomes

Can be divided into very specific functions

Examples:
 • Proliferation circuits
 • Viability circuits
 • Cytostasis and differentiation circuits
 • Motility circuits

Implication for therapeutics:
• This is important to consider when targeting cancers with therapeutics

  • Targeting a single factor in cancer works for a few months, but is incapable of continual inhibition
  • The tumour will evolve resistance to this particular drug
  • Drugs must target multiple signalling centres within a tumour
44
Q

What proportion of cancers have an inherited component?

A

Only 15%

Thus, most cancers are stochastic (environmentally related)

45
Q

What are the functions of the BCRA1 and BRCA2 genes?

How does this lead to tumour growth?

A

They are DNA repair genes

If there are mutations in these genes, DNA can not be repaired and there will be an accumulation of errors
(often in proto-oncogenes and TSGs)

Can lead to Breast, Ovarian and Pancreatic cancer

46
Q

What are some important DNA repair genes whose mutations are involved in cancer?

Describe their function

A
  • BCRA1
  • BCRA2
  • MSH2
  • MLH1

In the process of DNA replication, there will inevitably be mistakes and damage to the DNA

There are specific genes that encode proteins that repair DNA when this happens

Mutations in these genes can lead to an accumulation of other mutations (e.g. in proto-oncogenes, TSGs etc)

47
Q

What damage can occur to DNA during replication?

A
  • Single stranded breaks
  • Double stranded breaks
  • Bulky adducts
  • Mismatches
  • Insertions
  • Deletions
  • Methylation
48
Q

Describe mutations causing neuroblastoma

A

Massive amplification of a region on the chromosome that encodes n-myc (an oncogene)

N-myc regions also break off and form “Double minutes”: look like tiny chromosomes

“Double minutes” also able to form the n-myc proteins and drive the malignancy

49
Q

What is the role of differentiation in cancer?

A

Suppression of differentiation

Cells remain in an immature state

Immature cells continuously grow and divide

Thus, suppression of differentiation drives tumourigenesis

50
Q

What is the role of PTEN?

What about in cancer?

A
  • PTEN is a TSG: blocks oncogenic pathways
  • Normally blocks the PI3 kinase transduction pathway

Mutations:
• No longer able to inhibit PI3 kinase pathway
• Cell proliferation and growth

51
Q

What sort of mutation in the PI3 kinase pathway would lead to tumourigenesis?

A

Mutation so that the pathway is constitutively active

52
Q

Describe the interaction of PI3 kinase and PTEN in cancer

A

Pik3ca: oncogenic form of PI3 kinase gene
PTEN: suppressor of PI3K

Ovaries with various mutations:

  1. WT: normal sized ovaries
  2. Pik3ca mutation: not much difference
  3. PTEN KO: not much difference
  4. Pik3ca;PtenKO: massive tumours

Brain; lateral ventricles (normally contain many stem cells)
• WT: no tumours
• Mutant (Pik3ca;PTEN KO): massive tumours growing into lateral ventricles

Implication:
• Need oncogenic mutations as well as loss of Tumour suppression

53
Q

What is special about Retinoblastoma?

A

Cancer of the retina

Only cancer that is dependent on only one gene (Rb)

54
Q

Describe the cell cycle

A 
G1: growth
G1/S checkpoint: checking DNA
S: DNA replication
G2: growth phase
G2/M checkpoint: checking of DNA integrity after replication
M: cell division
55
Q

Describe the various mechanisms of apoptosis

A

A. Extrinsic

  1. FasL-Fas interaction
  2. FADD activation
  3. Activation of caspases
  4. Cell death

B. Intrinsic:

  1. Environmental stress (radiation, chemicals)
  2. DNA damage
  3. p53 response
  4. BAX
  5. Mitochondria loss of cytochrome c
  6. Activation of caspases
  7. Apoptosis
56
Q

What is the role of E-cadherin in cancer?

A

Holds cells together

Loss of E-cadherin allows cells to metastasise

57
Q

Which hallmark of cancer has been the target of a large proportion of therapeutics?

A

Angiogenesis

PATH30001 - Mechanisms of Disease (34 decks)

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