Hallmarks of cancer

Question 1

What are the 6 cellular hallmarks of cancer?

Answer 1

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

Question 2

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

Answer 2

Germ cell mutations are inheritable

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

Question 3

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

Answer 3

• 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

Question 4

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

Answer 4

1. HPV 16& 18
2. HTLV1 (Human T cell Leukaemia Virus)
3. EBV
4. Hepatitis B and C

Question 5

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

Answer 5

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

Question 6

Outline how mutations cause cancer?

Answer 6

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

Question 7

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

Answer 7

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

Question 8

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

Answer 8

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

Question 9

erbB1 encodes the EGFR receptor (a growth factor receptor)

Describe how an oncogenic in these gene can cause cancer

Answer 9

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

Question 10

State 2 genes that act as oncogenes in breast cancer

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

Answer 10

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

Question 11

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

Answer 11

• 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

Question 12

What is a tumour suppressor gene?

Answer 12

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

Question 13

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

Answer 13

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

Question 14

Give an example of a tumour suppressor gene

Answer 14

BRCA1
BRCA2
Retinoblastoma (Rb)

Question 15

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)

Answer 15

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

Question 16

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

Answer 16

Li- Fraumeni syndrome

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

Question 17

Describe familial adeonmatous polyposis coli (FAP)

• genotype
• inheritance
• phenotype

Answer 17

• 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

Question 18

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

Answer 18

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)

Question 19

Consider the adenoma-carcinoma sequence.

Outline the gene mutations that contribute to the multistep carcinogenesis

Answer 19

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

Question 20

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?

Answer 20

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

Question 21

Describe the role of growth signals in normal cell growth

Answer 21

• 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

Question 22

Describe the role of inhibitory growth signals in normal cell growth

How is response to these disregulated in carcinogenesis?

Answer 22

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

Question 23

What is apoptosis?

What is its function in the normal cell cycle?

Answer 23

Programmed cell death/ cell death that benefits tissue/organism

Pathway for controlling cell number and for eliminating damaged cells

Question 24

Outline the steps involved in apoptosis

Answer 24

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

Question 25

Compare the differences between apoptosis and necrosis in the following parameters 1. Patterns of death 2. Cell size 3. Plasma membrane 4. Mitochondria

Answer 25

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

Question 26

Compare the differences between apoptosis and necrosis in the following parameters 1. Organelle shape 2. Nuclei 3. DNA degradation 4. Cell degradation

Answer 26

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

Question 27

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?

Answer 27

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

Question 28

Describe the role of a mutated p53 gene in apoptosis

Answer 28

- 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

Question 29

Describe the role of telomeres in normal cell proliferation

Answer 29

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)

Question 30

Describe the role of telomerase in carcinogenesis

Answer 30

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

Question 31

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

Answer 31

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

Question 32

What is major stimulant of angiogenesis? When is upregulated?

Answer 32

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)

Question 33

What causes symptoms and eventually death in cancer?

Answer 33

Local invasion and metastasis

Question 34

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

Answer 34

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

Question 35

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

Answer 35

``` 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