Cancer

Question 1

What are the causes of cancers

Answer 1

Cancer can be said to be a disease of aberrant cell proliferation and differentiation
In the normal bronchial are very obviously differentiated layers
In the abnormal bronchial is lack differentiation, can’t distinguish layers
Would expect a similar frequency of tumours in all human population but not the case
Risk of developing certain cancers are different depending on where you live
The pattern of incidents is indicative of where in the world you live

Question 2

Nature vs Nurture

Answer 2

Environmental influences (nurture) can have a larger impact than your ethnic origin (nature) as to what types of cancer you are likely to get

Question 3

What do we mean by environmental influences?

Answer 3

Infection
Diet
Noxious agents

Question 4

Environmental influences - Infection - Peyton Roux - 1910

Answer 4

1. Took a chicken with sarcoma in breast muscles
2. Remove sarcoma and break up into small chunks of tissue
3. Grind up sarcoma with sand
4. Collect filtrate that has passed through fine-pore filter
5. Inject filtrate into young chicken
6. Observe sarcoma in injected chicken
7. Now know that this material contained a sarcoma virus
   Cancer arises because virus encodes a hyperactive form of a human tyrosine kinase gene
   Used think all cancers were caused by viruses but obviously we now know that is wrong

Question 5

Examples of cancers known to be caused by infections

Answer 5

Nasopharyngeal carcinoma - caused by Epstein-Barr virus
Cervical carcinoma - caused by human papillomavirus
Kaposi’s sarcoma - caused by human herpesvirus 8
Not just viral infections can also be caused by Helicobacter pylorii - included in increased risk of gastric carcinoma

Question 6

Environmental influeces - diet

Answer 6

Aspergillus oryzae referred to as Koji mould is fungus that is found to affect rice, peanuts etc. and can lead to hepatocellular carcinoma
You can see how food preferences and climates can influence the types of cancers we can get
Koji mould causes pathocellular cancers as it causes an aflatoxin, passes through liver and modified there, in cytostome p50 system tries to make insoluble things more soluble to be able to be excreted, in case aflatoxin it actually activates it into aflatoxin-2,3-epoxide which target G in DNA and caused mutations and damage in DNA.

Question 7

Environmental influences - noxious substences

Answer 7

Asbestos - naturally occurring silicate
The dust causes mesothelioma which is rare cancer that occurs in lungs
It is a fatal cancer
Occurs to people who have had significant exposure to asbestos dust

Question 8

Cancer causes and there environmental influence

Answer 8

Smoking (NA)
Diet, overweight and obesity (D)
Lack of exercise (D)
Viruses (I)
Alcohol (D)
UV and ionising radiation (NA)
Occupational carcinogens (NA)

Question 9

Genetic vs Environment

Answer 9

EF cannot explain all cancer incidences
People do have genetic predispositions to certain cancers

Question 10

Genetically predisposed cancers

Answer 10

Retinoblastoma
Li-Fraumeni Syndrome
Wilms Tumour
Gorlin’s Syndrome
Breast Cancer Syndrome
Familial adenomatous polyposis coli (FAP)

Question 11

Cancer is consequence of chromosomal changes

Answer 11

1959 - people noticed difference in genetics people who got Chronic Myeloid Leukaemia, they have different chromosome 22 arrangement
Chromosomal translocation underlies CML, known at did FISH and saw chromosome and protein coding areas in different place to expected and also created probe that worked out where the break point was (the damage)
Chromosomal translocation has such devastating effects as bring together ABL (9q34, a protein kinase and a positive regulator of cell growth) and BCR (22q11), these shouldn’t be together
When ABL fused to BCR cannot switch off, leads to constant proliferation which is first step towards carcinogenesis

Question 12

CML provides example another cancer paradigm - oncogene

Answer 12

Oncogene - gene with potential to cause cancer by transforming cellular behaviour
Normal version gene called proto oncogenes, as it is before it becomes cancerous
There genes affect cellular behaviour, effect morphology of cell

Question 13

How do oncogene come about

Answer 13

Chromosome rearrangement - nearby regulatory DNA sequence caused normal protein to be overproduced
Chromosome rearrangement - fusion to actively transcribed gene produces hyperactive fusion protein
Gene amplification - Normal protein greatly overproduced
Regulatory mutation - normal protein greatly overproduced
Deletion or point mutation in coding sequence - hyperactive protein made in normal amount

Question 14

The identification of the first human oncogene

Answer 14

RAS, it won’t dissociate or move v. quickly, it is a slow GTPase
Guano Nucleotide exchange protein has to go in to make change in ras from its GDP bound form (normally off) to its GTP bound form (normally on), undergoes conformational change
Exchange is to make it move from off to on again as obviously body need it on but not all the time
Mutation in Gleichen 12 and Glutamine 26 will cause ras to be permanently on, bad

Question 15

Importance of ras in growth factor-induced growth

Answer 15

Growth factor causes dimerization of receptor (normally tylacine kinases) and bring about phosphorylation of themselves, this then become complementary from the binding of Grb2, this end acts as exchange factor to turn on RAS in cell
Therefore if growth factor not present then RAS will eventually turn itself off
If RAS left on permanently there is will lead to unwanted cell growth, gene expression and cell morphology and movement, you lose a point in chain growth factors, making it unneeded and is why RAS so important in growth tumours

Question 16

Cell fusion experiments - Rawel and Johnson

Answer 16

Concept dominant oncogene alone cannot explain cancer cell behaviour
Did cell fusion experiments where combined a normal cell with a cancer cell
Was debate around whether you would get a tumour or not when making these hybrid cells, but you don’t so make hypothesis that normal gene dominant and that they express tumour suppressor genes and during oncogenesis the function of these genes are lost
Might tumour suppressor genes exist:
- Yes - loss growth suppressor gene more likely then gain-of-function oncogene mutation
- No - loss of both alleles of putative growth suppressor genes unlikely

Question 17

Retinoblastoma and tumour suppression

Answer 17

Retinoblastoma tumour provides insight into tumour suppression
Arises sporadically as well as familiarly
Sporadic or unilateral retinoblastoma usually only affects one eye
Familial or bi-lateral almost always affects both eyes
Understood people with inherited version also prone to getting other types of cancers
People with familial retinoblastoma already inherited one mutant cope gene, therefore only required one hit to get cancer as only need one more mutation
If have sporadic retinoblastoma would require two hits get cancer, because takes two genetic events to occur takes longer to show

Question 18

Why is Knudsen’s one/two-hit hypothesis important

Answer 18

Provides evidence:
- For tumour suppressor gene hypothesis
- That cancer required loss of both wild-type alleles
- For basis inherited predisposition to cancer

Question 19

Identification tumour suppressor genes in familial cancer

Answer 19

Cytogenetic analysis provides evidence for Chr13 deletion in inherited retinoblastoma, so mutant allele and loss of tumour suppressor
They then found the genes that caused other inherited diseases and subsequent functional analysis identifies that all as tumour suppressor functions
- Retinoblastoma ~ Rb
- Li-Fraumeni Syndrome ~ P53
- Wilms Tumour ~ WT-1
- Gorlin’s Syndrome ~ Ptc
- Breast Cancer Syndrome ~ BRCA-1
- Familial adenomatous polyposis coli (FAP) ~ APC

Question 20

Comparison between oncogenes and tumour suppressor genes

Answer 20

Oncogenes
- Activating
- Gain of function
- Dominant
- Needs one allele mutated to get the effect
- Effect on the function of the protein product - enhanced
Tumour suppressor genes
- Inactivating
- Loss of function
- Recessive
- Need two alleles mutated to exert effect
- Effect on function of protein produced - reduced

Question 21

Cancer and age

Answer 21

More than one mutation is required for tumorigenesis
Cancer incidence increases with age also because we are now living longer
We can sequence the genome now which allows us to see the mutations that are common to certain cancers
Successive rounds of random inherited change and natural selection underpins tumour progression
From one lineage there can be an expansion of cells that no longer care about their neighbours (called cell expansion) and this leads to dangerous cell proliferation

Question 22

Cancer cells are genetically unstable

Answer 22

Genetic instability contributes to tumorigenic evolution
In cancerous cells often multiple translocations within chromosomes in cell
Genetic instability can be caused by defects in:
- DNA repair pathways
- Correction mechanisms for DNA replication errors
- Correction mechanisms for DNA segregation errors

Question 23

Cellular stressors and cancer

Answer 23

Cellular stressors such as DNA damage induce apoptosis in normal cells, but increased cell division and decreased apoptosis contributes to tumorigenesis
Normal cells respond to cellular stress through one critical signalling pathway, P53
P53 made at around same rate it is destroyed, only when one of stressors increases does it stabilise p53 and then this leads to first stopping of cell cycle
The senescence and then if there’s to much damage that can’t be fixed, p53 will causes apoptosis but if it gets fixed then p53 levels settle again
P53 is mutated in almost all types of cancers
Mutations in p53 and associated pathways disrupt intrinsic apoptosis
P53 is one example of a cell cycle checkpoint gene
Checkpoint loss contributes to genetic instability
Cell cycle checkpoints are often disrupted in cancer
Rb, mutated in retinoblastoma, becomes mutated in many other cancers
Rb operates at the restriction point