Cancer

Question 1

What is cancer?

Answer 1

disease resulting from a malignant growth or tumour caused by abnormal and uncontrolled cell division

• a disease of DNA damage resulting in aberrant (abnormal) signal transduction

is predominantly a disease of old age

Question 2

What is carcinogenesis? What are the steps?

Answer 2

formation of cancer
- involves a multi-hit mechanism of 4-8 mutations

initiation - changes are induced in cells
promotion - cell proliferation allows outgrowth of mutated cell
progression - cells that grow out acquire all the characteristics of malignant cancer cells = can spread

Question 3

What are the different causes of cancer?

Answer 3

chemicals - from diet, job, lifestyle-smoking, alcohol

radiation - UV, gamma rays, radioactivity

viruses - epstein-barr virus causes lymphoma, hepatits B and C cause liver cancer

genetic predisposition - inherited faulty genes (BRCA genes) and proteins (pRb) can make cancer more likely

immune suppression - viral cancers can occur because the immune system is suppressed/compromised = transplants

cofactors - do not cause cancer but act as promoters of the initiated cells, oestrogen for breast cancer and testosterone for prostate cancer

Question 4

What are tumours? How do they accumulate?

Answer 4

tumours are usually clonal
- derive from a single cancer cell

derive from changes in

• proto-oncogenes
• tumour suppressor genes
• metastasis suppressor genes

Question 5

How are protons-oncogenes and tumour suppressor genes identified?

Answer 5

oncogenic retroviruses and DNA tumour viruses

• viruses contribute to the emergence of cancer
• can study the genes in viruses and show which genes contribute to a cancer cells phenotype

DNA transfection = artificial introduction of nucleic acids into cells

• human tumour DNA is introduced into mouse cells
• genes can be analysed to see which one causes the conversion of normal cells into cancerous cells in humans
• identifies the ras genes

chromosome analysis
- identify what genes have been corrupted in the tumour cells

human genetic linkage studies

• track genetic disposition in families
• identify the common genes involved

Question 6

What are oncogenes?

Answer 6

oncogenes cause cancer

• proto-oncogenes regulate cell growth and are converted to oncogenes
• conversion occurs due to mutations affecting the structure and expression of protons-oncogenes

oncogenes

• act dominantly = only one mutated allele is enough to subvert the signal pathway
• promote cell division = generate constitutive (continuous) growth signals

Question 7

What are examples of protons-oncogenes that can be mutated?

Answer 7

EGFR - epidermal growth factor receptor
PDGFR - platelet derivative growth factor receptor
HER2 - growth factor receptor
RAS
ABL, SRC - tyrosine kinase
MYC, JUN, FOS - transcription
blc-2 - apoptosis blocker

Question 8

How does protons-oncogene mutation of the following generate a constitutive growth signal?
EGF/EGFR
PDGF/PDGFR
ras
src
myc/jun/fos

Answer 8

EGF and PDGF are mitogenic factors
- stimulate cell division

EGF and PDGF bind to their receptors
- bind to EGFR and PDGFR

Binding of mitogenic factors causes a conformational change in the RAS and SRC proteins
- RAS sends as signal to the nucleus which causes activation of the transcription factors

Activated transcription factors initiate cell proliferation/division

Question 9

What is the affect of
absent mitogenic factors?
mutated ras protein?
mutated transcription factors?

Answer 9

absent mitogenic factors
- normal cells do not undergo cell division

mutated ras protein

• constantly switched on = GTP is bound constantly
• sends constitutive signals to the nucleus resulting in the transcription factors being active constantly

mutated transcription factors
- results in cell division that is not reliant on the presence or absence of mitogenic proteins

Question 10

What are ras proteins?

Answer 10

made/coded for by the ras gene

• switched on by bound GTP
• switched off by hydrolysis of GTP to GDP

Question 11

What is apoptosis?

Answer 11

programmed cell death

Question 12

What are tumour suppressor genes?

Answer 12

genes which co-operate with photo-oncogenes to regulate cell growth

act recessively

• can still function with only one activated
• unrestrained cell growth requires both alleles to be inactivated

Question 13

What are some examples of tumour suppressor genes?

Answer 13

RB1 = retinoblastoma protein
- regulates entry into the cell cycle = G1-S entry

p53 = transcription factor

• acts at G1-S and G2-M
• senses DNA damage and puts the cell into cell cycle arrest to give it time to repair the damaged DNA
• unrepairable damage triggers apoptosis

BRCA 1 and BRCA 2
- are involved in DNA repair

Question 14

What is metastasis?

Answer 14

process in which cells from the primary tumour spread to other sites to form a secondary tumour

• spread can happen via the blood or the lymphatic system
• is a multistep process
• metastasis kills the patient

Question 15

What are the protein processes involved in metastasis?

Answer 15

metalloproteinases

• digests the extracellular matrix and the basement membrane = breakdown
• allows the tumour to migrate through the body

TIMPS
- tissue inhibitors of metalloproteinases

angiogenesis factors

• enable the growth/formation of capillaries
• allows blood supply to the secondary location

Question 16

How does metastasis occur?

Answer 16

primary neoplasm (tumour)

• requires nutrients as it has gotten larger
• stimulates for metalloproteinases (MMP) to be made which digest the basement membrane and extracellular matrix (made up of collagen and glycoprotein)

vascularisation
- induced formation of capillary system (blood vessels) to bring in nutrients

invasion of the capillary tubes

• capillary tubes can have leakage
• tumour cells can cross the capillary and enter the blood circulation = travel via blood or lymphatic system

arrest in organs
- tumour cells can arrest in a distant organ

extravasation into the surrounding tissue = leakage
- MMP stimulated so the tumour can leave the organ and adhere to the surrounding tissue

adherence to the vascular wall

• enters surrounding tissue
• growth and division to form the secondary tumour

Question 17

What do the metastasis models show?

Answer 17

shows that tumour need the correct environment in order to spread
- anatomical model = tumour spreads to first organ or tissue that it connected by lymphatic or blood vessels to the primary tumour

• soil and seed/organ preference model = found tissue with low blood supply undergoing metastasis and tissues with high blood supply not undergoing metastasis

Question 18

How can cells communicate during metastasis?

Answer 18

autocrine
- cancerous cells can stimulate their own growth

paracrine

• interactions between the host cell and cancerous cell
• used to facilitate its movement and invasion of the extracellular matrix and basement membrane into the capillary

Question 19

What are the hallmarks of cancer?

Answer 19

unlimited proliferation 
sufficiency in growth signals 
- constitutive signals 
inactive growth inhibitory signals
- inactive tumour suppressor genes  
evade apoptosis 
sustained angiogenesis
- formation of blood vessels
invasion and spread

Question 20

How can cancer be treated?

Answer 20

surgery 
radiotherapy
chemotherapy 
hormone therapy
block oncogenic activity 
stimulate tumour suppressors 
immune system 
block metastasis
- by blocking angiogenesis