L16: Neoplasia 3

Question 1

Define carcinogenesis?

Answer 1

Initiator of cancer formation

Question 2

What are the different categories of carcingogens?

Answer 2

Intrinsic
- Hereditary 
- Age 
- Sex (particularly hormones)
Extrinsic
- Environment 
--> Chemicals 
--> Radiation 
--> Infection 
- Behaviour

Question 3

What are some of the behavioural carcinogens?

Answer 3

High BMI
Low fruit and vegetable intake
Lack of physical activity 
Tobacco use --> 25% of all deaths from cancer
Alcohol 
Sun exposure

Question 4

What does smoking increase the risk of?

Answer 4

Biggest preventable cause of cancer
Lung cancer 7/10 develop
Mouth 
Pharaynx
Nose and sinus
Larynx
Oesophagus 
Liver
Pancreas
Stomach 
Kidney 
Bowel 
Ovary 
Bladder
Cervix 
Some types of leukaemia

Question 5

What is one of the biggest indicators of the causes of cancers?

Answer 5

Look at migrating populations
Compare baseline risk in home country
Change in risk after settled in new geographic location
Approximately 85% cancer due to environmental risk factors
e.g. Japanese men lung cancer risk 75% risk in Japan move to Hawaii risk reduced to 15%–> environmental component

Question 6

What have chemicals shown us about carcinogenesis?

Answer 6

Chemical 2-naothylamine industrial chemical used to dye clothes
Causes malignant neoplasms
Showed
1- Delay between carcinogen exposure and malignant neoplasm onset
2- Risk of cancer depends on total carcinogen dosage
3- Sometimes organ specificity for particular carcinogens

Question 7

How do chemical carcinogens work?

Answer 7

Initiator needed to make the mutation–> sufficient dose needed
Followed by prolonged exposure to a promoter

Question 8

How do we work out what chemicals will go on to cause mutations and act as carcinogens?

Answer 8

Ames test
Tells you what chemical maybe an initiator and what maybe a promoter
Two tubes of Salmonella stain with rat liver extract–> add potential mutagen to one tube compare control plate and test plate
Grow the culture
See if the mutagen is an initiator and if it is carcinogenic
Carcinogens that are both initiators and promoters are called–> complete carcinogens

Question 9

What do initiators have to cause?

Answer 9

Non lethal genetic damage

Lethal genetic damage will cause the cell to die and be apoptosed

Question 10

What are the different types of chemical carcinogens?

Answer 10

Polycyclin aromatic hydrocarbons
Aromatic amines
N-nitroso compounds
Alkylating agents 
Natural products --> asbestos 
Some are pro-carcinogens--> converted to carcinogens by cytochrome p450 enzymes in liver

Question 11

What types of radiation are capable of causing DNA damage? How do they work?

Answer 11

Radiation–> any type of energy travelling through space
Ultraviolet (UV)–> does not penetrate deeper into skin
X-rays, Alpha particles and Beta particles–> ionising radiation, removes electrons from atoms

Damage:

• Directly–> Radioactive particles crash into DNA–> missence mutations and RNA breaks (single base changes or DS breaks)
• Indirectly via free radials–> crash into water–> produce OH radicals –> damage DNA

Question 12

What is the most important type of radiation?

Answer 12

UV radiation
Constant exposure
Increase risk of skin cancer

Question 13

What are the main exposures to ionising radiation?

Answer 13

Natural background radiation –> radon (from the earths crust–> damages DNA bases and causes SS and DS breaks)
Medical tests

Question 14

How can infections lead to cancers?

Answer 14

Some infections are carcinogenic
Can work against the genes that control cell growth
Or
Indirectly causing chronic tissue damage promoting regeneration which acts as a promoter or cause new mutations from DNA replication errors

Question 15

Give an example of an infection that is a known direct carcinogen?

Answer 15

Human Papilloma Virus (HPV)–> cervical cancer
Expresses E6 and E7 proteins that inhibit p53 and pRB protein function
E6–> p53–> Inhibits apoptosis
E7–> pRB–> Important cell checkpoint
Preventing virus infected cells from dying and being removed

Question 16

Give an example of an infection that is a known indirect carcinogen?

Answer 16

Heptatis B and C
Cause chronic liver cell injury–> regeneration (mutations more likely)
HIV –> reduced immunity–> allowing potentially carcinogenic infections to occur

Question 17

Give an example of an infection that is a known indirect carcinogen?

Answer 17

Heptatis B and C
Cause chronic liver cell injury–> regeneration
HIV –> reduced immunity–> allowing potentially carcinogenic infections to occur

Question 18

How was the inheritance of neoplasias discovered?

Answer 18

Surgeon- Hilario De Gouvea removed retinoblastom tumour from young boy
Boy survived grew up had a daughter–> same tumour, something inherited?
100 yrs later–> Knudson noticed two distinct types of Rb
- Early–> Both eyes
- Later–> One eye
Postulated the two hit hypothesis
–> Familial inheritence–> only require one sporadic hit
–> Sporadic occurrence–> requires two sporadic hits

Question 19

What is the two hit hypothesis?

Answer 19

Familial cancers–> First ‘hit’ inherited in germ line cells–> affects all cells in the body–> only requires one sporadic ‘hit’ to become cancer

Sporadic cancers–> No germline mutations so requires both ‘hits’ to be sporadic–> somatic mutations and to occur in the same cell

Question 20

What is the role of tumour suppressor genes? How is this altered in cancer?

Answer 20

Normal function–> stop cell proliferation
Loss of function
Both alleles must be damaged for transformation to occur–> Two mutations (hits) necessary
Abnormalities lead to failure to inhibit growth

Question 21

What is the role of proto-oncogenes? How is this altered in cancer?

Answer 21

Involved in signalling pathways to drive proliferation
Mutations–> excessive activation in one or more functions
Gain of function mutations
Mutation–> oncogenes
Encode oncoproteins–> promote cell growth in the absence of normal growth promoting signals
Oncogenes are dominant over proto-oncogenes

Question 22

Which was the first human oncogene to be discovered? What does it do?

Answer 22

RAS gene (proto-oncogene mutated to oncogene) 
mutated in 1/3 of all malignant neoplasms 
Normally-->Encodes a small G protein--> relays signals into cells-> pushes it past cycle restriction point 
Mutant RAS--> encodes a protein that is always active--> constant signal to push cell through the cycle restriction point

Question 23

How do mutations in RAS cause cancer? How does a mutation in Rb cause cancer?

Answer 23

Normally RAS require activation by GF–> then activate cyclin D–> CDK–> phospharylate Rb allowing cell to progress through cell cycle
Mutation in RAS means it constantly activate–> RB constantly phosphorylate–> cell cycle progression

Normally RB restrains proliferation
–> inhibits passage through restriction point
Mutation in RB allows unrestrained passage through the checkpoint

Question 24

What can cause cells to pass through the checkpoint unchecked?

Answer 24

RAS mutation–> protein always active–> continuously pushed through checkpoint
RB mutation–> inactivated–> unrestrained passage trough checkpoint
Opposing roles of proto-oncogenes and tumour suppressor genes

Question 25

What can proto-oncogenes encode?

Answer 25

Growth factors--> PGDF
Growth factor receptors--> HER2
Plasma membrane signal transducers--> RAS
Intracellular kinases--> BRAF
Transcription factors--> MYC 
Cell cycle regulators--> Cyclin D1
Apoptosis regulators--> BCL2

Question 26

What other mutation can lead to the formation of cancer?

Answer 26

Mutation in DNA repair genes

Normally–> prevent accumulation of DNA damage

Question 27

What are the different mechanisms of DNA repair?

Answer 27

Nucleotide excision
Mismatch repair
Double stranded breaks

Question 28

What is xeroderma pigmentosa?

Answer 28

Autosomal recessive disease
Mutation in one of 7 genes that affect DNA nucleotide excision repair
Patients sensitive to UV damage
Develop skin cancer at young age

Question 29

What is Hereditary Non-Polyposis Colon cancer (HNPCC) syndrome?

Answer 29

Autosomal dominant
Associated with colon cancer and germline mutations
Affects DNA mismatch repair genes

Question 30

What happens in familial breast carcinomas?

Answer 30

Associated with BRAC1 and BRAC2 genes
Important in DS DNA break repair
Can also be found in sporodic malignant neoplasms

Question 31

What can happen during mitosis that can cause cancer?

Answer 31

Chromosomal aggregation can be abnormal
Alteration account for accelerate mutation rate–> genetic instability
Genes that maintain stability–> caretaker genes–> class of tumour suppressor genes

Question 32

How many mutations are required to make a malignant neoplasm?

Answer 32

Unknown–> varies by tumour type and individual
Thought to be 10 or less
However colorectal cancer-> adenoma-carcinoma sequence
Normal–> early adenoma–> intermediate adenoma–> Late adenoma–> carcinoma–> metastasis
Mutations accumulate –> multiple mutations= progression

Question 33

What are the 6 hallmarks of cancer?

Answer 33

1) Self sufficiency in growth signals
2) Resistance to growth stop signals
3) Cell immortilisations (no limitation on number of replications)
4) Sustained ability to induce new blood vessels (angiogenesis)
5) Resistance to apoptosis
6) Ability to invade and produce metastases

Question 34

What is the enabling feature?

Answer 34

Genetic instability

Question 35

What is the model of cancer pathogenesis?

Answer 35

1. Somatic cells exposed to environmental carcinogens (chemicals, radiation, infection)
2. Either initiators or promoters
3. 5% of cancers inherited mutations are present- Germline
4. Mutations affect proto-oncogenes or tumour supressor genes
5. These mutations alter proteins produced
6. Progression–> cells acquire further activate oncogenes or inactivated tumour suppressor genes –> including ones that cause genetic instability
7. Over many years results in set if mutations that produce all of the ‘hallmarks of caner’