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302 SBM: Cancer > Hallmarks of cancer > Flashcards

Hallmarks of cancer Flashcards

1
Q

What are the 6 cellular hallmarks of cancer?

A
  1. Autonomy from growth signals
  2. Evasion of growth inhibitory signals
  3. Evasion of apoptosis
  4. Unlimited replicative potential
  5. Angiogenesis
  6. Invasion and metastasis
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2
Q

What is the difference between a germ cell mutation and a somatic cell mutation?

A

Germ cell mutations are inheritable

Somatic cell mutations are not but account for most mutations. These can give rise to cancer

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3
Q

What is the evidence that suggests that cancer is a genetic disease?

A
  • Age incidence (accumulation of mutations as we age)
  • Carcinogens ar mutagens
  • DNA of tumours is abnormal
  • Mutations in specific genes generate cells bearing hallmarks of cancer
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4
Q

Viral infections are also associated with some cancers

For the following cancer types state the associated viral infection

  1. Cervical carcinoma
  2. Adult T cell lymphoma
  3. Burkitt’s lymphoma
  4. Hepatocellular carcinoma
A
  1. HPV 16& 18
  2. HTLV1 (Human T cell Leukaemia Virus)
  3. EBV
  4. Hepatitis B and C
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5
Q

What does ultraviolet light and chemical carcinogens have in common in the pathogenesis of cancer?

A
  1. Interact with components. of DNA to cause damage
  2. Damage may be to bases or sugar phosphate backbone
  3. Damage may be repaired, misrepaired or unrepaired
  4. Unrepaired or misrepaired damage that does not trigger cell death will be passes on to daughter cells
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6
Q

Outline how mutations cause cancer?

A
  1. mutations must affect expression of protein products of genes involved in pathways associated with the cancer phenotype
  2. usually growth, differentiation and cell death
  3. mutated genes and their products may become overactive= oncogene
    OR
    other carcinogenic mutations lead to a loss of function of the gene= tumour suppressor genes
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7
Q

What is an oncogene?
How do they arise?
How do they contribute to malignancy

A

often a mutated version of a normal human genes (proto-oncogenes). The overactive or overexpressed form of the protein masks the effects of the normal form

Mutation of just one allele is required for oncogenic effect

Increase activity of pro-malignant pathways e.g. cell growth, replication, angiogenesis, invasion, metastasis

AND

Inhibit activity of anti-malignancy pathways e.g. apoptosis, cell cycle regulation, growth inhibition

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8
Q

State 4 ways in which mutations may affect gene function such that it becomes an oncogene

A
  1. increase level of expression of the gene
  2. de-regulate expression of the gene
  3. alter the protein product so it is more active
  4. alter the protein product so it is not degraded
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9
Q

erbB1 encodes the EGFR receptor (a growth factor receptor)

Describe how an oncogenic in these gene can cause cancer

A

Oncogenic mutations generate EGFR that is activated even in the absence of EGF

Amplication of erbB increases membrane expression of EGFR

The end result is over-activity of RAS-MAPK pathway and overexpression of growth promoting genes

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10
Q

State 2 genes that act as oncogenes in breast cancer

What does the presence of these mutations means for the patient?

A

erbB2 is amplified in about 25% of breast cancer

HER2 is overexpressed in these cancers

  • These cancers tend to be more aggressive and less responsive to standard treatments
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11
Q

ras is mutated in up to 30% of human cancers. How does it lead to oncogenesis

A
  • There are many different mutations that can occur
  • Most result in loss of GTP-ase activity of RAS protein
  • RAS remains bound to GTP and is constitutively activated
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12
Q

What is a tumour suppressor gene?

A

A mutation in a gene that usually codes for a protein that suppresses pro-malignany processes. They usually have a role in apoptosis, cell cycle checkpoints, growth inhibition and DNA repair

Loss of normal function of key proteins in these pathways is carcinogenic

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13
Q

How do tumour suppressor genes arise? How are they expressed?

A
  • Arise when both alleles are affected
  • RECESSIVE
  • mutated tumour suppressor genes may be inherited but more commonly occur spontaneously
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14
Q

Give an example of a tumour suppressor gene

A

BRCA1
BRCA2
Retinoblastoma (Rb)

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15
Q

p53 is a tumour suppressor gene mutated in up to 50% of cancers

How does mutated p53 lead to oncogenesis?
(think about the functions p53 usually does)

A

p53 causes cell cycle arrest
-cells proceed to mitosis with damaged DNA

p53 is involved in apoptosis
- damaged p53 means the cell fails to undergo apoptosis when damaged

p53 inhibits angiogenesis
- tumour angiogenesis persists

p53 is involved in DNA repair
- incomplete DNA repair

In summary

  • increased mutation rate
  • reduced cell death
  • increased tumour growth
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16
Q

Mutant p53 can be inherited. Describe which syndrome this may be found in

A

Li- Fraumeni syndrome

  • grossly elevated cancer risk
  • sarcoma, breast cancer, leukaemia, brain tumours at an early age
  • germline mutation (e.g. p53)
17
Q

Describe familial adeonmatous polyposis coli (FAP)

  • genotype
  • inheritance
  • phenotype
A
  • inherited mutations in the APC gene
  • one mutant allele inherited + spontaneous mutations in other allele in colonic epithelial cells
  • develop multiple colonic polyps in early adulthood. These predispose to cancer
  • Patients have a very high risk of colon cancer
18
Q

Other than in the context of FAP, how else may APC gene mutations occur?

A

Mutated gene found in up to 90% of sporadic colorectal cancers

  • the cellular environment of colonic mucosa may predispose to spontaneous mutations in the gene

colon cancer is the result of a multistep carcinogenesis (a chain of genetic events lead to cancer)

19
Q

Consider the adenoma-carcinoma sequence.

Outline the gene mutations that contribute to the multistep carcinogenesis

A 
1. Normal colonic epithelium
(APC mutation)
2. small benign adenoma 
(polyp)
(K-ras DCC mutation)
3. large benign adenoma
(p53 mutation)
4. carcinoma
(Aneuploidy)
5. Metastases
20
Q

In the multistep carcinogenesis of colon cancer (and probably others to), spontaneous mutations in oncogenes and tumour suppresser genes are rare

Why is carcinogenesis more likely to occur in somatic cells that bare these mutations?

A

Cells bearing oncogenic mutations have proliferative and survival advantage

They generate mutated “clones”

And these mutant clones are more likely to develop further mutations, some of which will be pro-malignant

21
Q

Describe the role of growth signals in normal cell growth

A
  • Normal cells grow in response to extracellular growth factors
  • These bind to epidermal growth factor receptors on the cell membrane
  • Which triggers an intracellular signalling pathway (tyrosine kinase
  • Leading to activation of nuclear transcription factors, switching on expression of genes responsible for growth
22
Q

Describe the role of inhibitory growth signals in normal cell growth

How is response to these disregulated in carcinogenesis?

A

Normal cells do not actively divide all the time, despite possessing growth factor receptors

Growth inhibitory factors operate to prevent/restrict the rate of cell growth
- they inhibit pro-growth pathways at many levels

In cancer cells, pro-growth signals overcome growth inhibitory signals

23
Q

What is apoptosis?

What is its function in the normal cell cycle?

A

Programmed cell death/ cell death that benefits tissue/organism

Pathway for controlling cell number and for eliminating damaged cells

24
Q

Outline the steps involved in apoptosis

A

Initiated extrinsically (e.g. response to TNF) or intrinsically (in response to oxidative stress or DNA damage)

  1. Cytoplasmic shrinkage
  2. Nuclear breakdown (this involves degradation of chromatin)
  3. Cleavage of structural proteins (proteolysis by caspases)
  4. Membrane blebbing, apoptotic bodies
25
Q

Compare the differences between apoptosis and necrosis in the following parameters

  1. Patterns of death
  2. Cell size
  3. Plasma membrane
  4. Mitochondria
A

APOPTOSIS

  1. Single cells affected
  2. Shrinkage and fragmentation
  3. Plasma membrane is preserved, blebbed (bulges), phosphatidylserine on surface
  4. Increased mitochondrial membrane permeability –> contents released into cytoplasm, structure relatively preserved

NECROSIS

  1. groups of neighbouring cells
  2. swelling
  3. smoothing; early lysis
  4. swelling, disordered necrosis
26
Q

Compare the differences between apoptosis and necrosis in the following parameters

  1. Organelle shape
  2. Nuclei
  3. DNA degradation
  4. Cell degradation
A

APOPTOSIS

  1. Contracted “apoptotic bodies”
  2. Chromatin clumped and fragmented
  3. DNA is fragmented and appears in the cytoplasm
  4. Phagocytosis, no inflammation

NECROSIS

  1. Swelling, disruption
  2. Membrane disruption
  3. Diffuse and random degradation
  4. Inflammation, macrophage invasion
27
Q

Pro-apoptotic and anti-apoptotic proteins are involved in the regulation of apoptosis

Give an example of it

What happens in cells who can evade apoptosis?

A

Bcl-2: anti-apoptotic
Bax: pro-apoptotic
p53: pro-apoptotic

Cells deficient in pro-apoptotic signals are at risk of carcinogenesis. Upregulation of anti-apoptotic proteins also increase risk

28
Q

Describe the role of a mutated p53 gene in apoptosis

A
  • mutant p53 renders the cell less likely to undergo apoptosis (as its central in triggering apoptosis)
  • these p53 mutant cells are more likely to develop further mutations
  • they are also more resistant to cancer treatment
29
Q

Describe the role of telomeres in normal cell proliferation

A

Telomeres are repetitive DNA sequences at the end of chromosomes

They shorten with each round of DNA replication

Below a certain length –> apoptosis or cellular senescence (loss of ability to grow)

30
Q

Describe the role of telomerase in carcinogenesis

A

Telomere length is usually maintained by telomerase. In normal tissues it is typically inactive. In tumour cells it its upregulated.

Proteins that activate telomerase contribute to malignant transformation

31
Q

Why is it important to the survival of growing tumours that they undergo angiogenesis?

A

Cell growth is dependent on proximity to blood vessels

Uncontrolled cell growth in tumours means they get so big the distance between the cells and the vessels increases

The most distant cells become hypoxic –> senescence or necrosis

32
Q

What is major stimulant of angiogenesis?

When is upregulated?

A

Vascular endothelial growth factor (VEGF): which stimulates angiogenesis in response to hypoxia in normal tissues and tumours

In tumours it is upregulated
(in addition to the downregulation of inhibitors of angiogenesis)

33
Q

What causes symptoms and eventually death in cancer?

A

Local invasion and metastasis

34
Q

What is the role of the extracellular matrix and signals from adjacent cells in normal and cancerous cell survival?

A

Normal cells remain within their tissue of origin (mostly) and are demarcated by basement membranes. Here they are dependent on intreractions with the ECM and adjacent cells to survive

Cancer cells have abnormal interactions with neighbouring cells and ECM

  • they can survive without ECM signals
  • they can break free from inter- and extra-cellular connections via abnormal expression of integrins
35
Q

Which molecules are involved in the invasive capacity cancer cells have?

A 
Matrix metalloproteases (MMPs) 
- mediate invasion

TIMPS
- inhibit invasive capacity

These molecules are imbalanced in tumour cells

They enter and exit blood vessels via a similar mechanism

302 SBM: Cancer (3 decks)

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