7. Tumour initiation and promotion

Question 1

what is tumour progression?

Answer 1

1. the process of normal cells evolving into cells with increasing neoplastic phenotypes
2. progression is driven by mutation and epigenetic events that effect genes controlling cell proliferation, survival and other traits associated with malignant cells

Question 2

what is the main evidence for cancer development being a multistage process?

Answer 2

1. age is the highest risk factor for cancer
2. suggests you need time to accumulate mutations
3. evidenced by the 20 year delay between the increase in smoking and the increase in lung cancer

Question 3

what are the 4 stages of multistage carcinogenesis?

Answer 3

1. initiation event
2. promotion
3. transformation
4. progression

Question 4

what is initiation?

Answer 4

1. a genetic change or mutation in a stem cell
2. this is irreversible

Question 5

what is promotion?

Answer 5

1. promoters are usually environmental factors
2. stimulates clonal proliferation/expansion of the initiated cell
3. this is reversible as promoters are not mutagenic

Question 6

what is transformation?

Answer 6

1. the transition into a malignant cell
2. point it becomes cancer

Question 7

what is progression?

Answer 7

1. metastasis
2. distribution through the body

Question 8

what is the Aimes test?

Answer 8

a test to determine if something is a mutagen

Question 9

what is the process of the Aimes test?

Answer 9

1. A test compound is added to a liver cell culture
2. metabolic activation to activate the carcinogen
3. added to a modified bacteria that needs a supplement to grow
4. eventually the chemical will hit the gene which means it can grow without supplement
5. lots of colonies = strong carcinogen
6. few colonies = weak carcinogen

Question 10

what is the mouse skin multistage carcinogenesis?

Answer 10

1. add a carcinogen/initiating agent to mouse skin
2. cause an initiation event
3. it can sit there as a mutated cell
4. add a TPA to cause inflammation
5. inflammation causes expansion of the mutated cell
6. becomes cancer

Question 11

what is a TPA?

Answer 11

1. a tumour promoting agent
2. not a mutagen but affects gene expression and causes inflammation
3. activates many signalling pathways

Question 12

what are indirect acting carcinogens?

Answer 12

they are metabolised into a carcinogen in the body
eg Benzo(a)Pyrene -> 7,8-diol-9,10-epoxide which binds guanine causing mutation in c-ras protooncogene

Question 13

how could genetic variation lead to differences in cancer risk response?

Answer 13

Possibly variation in our ability to activate and detoxify the pro-carcinogens into carcinogens and the speed at which we can do it

Question 14

how can we link carcinogens to specific cancers?

Answer 14

1. different carcinogens cause different mutations creating “fingerprints” for each carcinogen
2. this was used to prove passive smoking was causing cancer and making it illegal

Question 15

different c-ras mutations proved in mouse skin carcinogenesis

Answer 15

1. 7,8-diol-9,10-epoxide binds to guanine causing codon 12 mutations in tumours
2. Dimethylbenzanthracene binds to adenosine causing codon 61 mutations in the tumours

Question 16

scheme of initiation and promotion of epidermal carcinomas

Answer 16

1. normal cell exposed to a carcinogen resulting in an initiated cell
2. the initiated cell can sit harmless for ages
3. if exposed to repeated rounds of promoter treatment then it can lead to papilloma formation
4. if promoter exposure continues then advanced papilloma forms
5. advanced papillomas cannot regress but can be stable if promoter exposure stops
6. if it doesn’t stop then papilloma becomes carcinomas

Question 17

Genes and proteins involved in mouse skin carcinogenesis

Answer 17

1. classic oncogene RAS occurs in a cell and the proliferates
2. addition mutations accumulate including p53
3. p53 mutation leads to a rapid increase in mutation due to genome instability
4. so much instability that expansion can continue independent of promoters

Question 18

when does promotion need to happen?

Answer 18

1. after the initiation event within a certain amount of time
2. need initiation to have clonal expansion due to promoters
3. spread out promoter events can not result in cancer and cause regression
4. having repeated initiated events without promotion can lead to cancer if a mutation like p53 occurs

Question 19

what can accumulation of mutations in growth control genes lead to?

Answer 19

natural selection of the fitter varients

Question 20

how does heterogeneity occur in cancers?

Answer 20

1. as the cancers progresses the genome becomes increasingly unstable
2. the rate of mutation can be quicker than the rate of expansion
3. less fit populations can be outgrown
4. means a tumour can be made up of genetically distinct sectors
5. making the tumours hard to treat

Question 21

what is very common?

Answer 21

having initiated cells

Question 22

how long can it take for an adulthood cancer to develop?

Answer 22

20-35 years

Question 23

up until what stage are tumours treatable with surgery?

Answer 23

pre-cancerous

Question 24

what is the best way to reduce colon cancer morbidity and mortality?

Answer 24

to prevent it

Question 25

what happens if you inherit a cancer-causing mutation?

Answer 25

1. the mutation is an initiation event
2. the chance of developing cancer is much greater and occurs much earlier in life

Question 26

Intestinal stem cells and colorectal cancer

Answer 26

1. 1 cell thick to absorb water and nutrients
2. the stem cells are at the bottom of the crypt to protect them and prevent exposure to mutagens
3. stem cells divide and differentiate to replace cells being sloughed off
4. it doesn’t matter if non stem cells are mutated as the cells will be shed and apoptosed
5. If the stem cells get a mutation then all the daughter cells will carry the mutation and give rise to cancer

Question 27

Normal ß-catenin signalling

Answer 27

1. ß-catenin forms part of the destruction complex in the cell with APC and axin
2. acts as a scaffold to recruit kinases that phosphorylate the complex
3. this keep ß-catenin levels low in the cell
4. there are also repressors that keep it low

Question 28

ß-catenin signalling and Wnt ligand

Answer 28

1. Wnt ligand recruits the destruction complex to the receptor and ß-catenin is stabilised
2. this promotes cyclin D
3. drives proliferation by switching on transcription

Question 29

ß-catenin in colon cancer

Answer 29

1. APC or axin mutation with APC being the most common
2. the destruction complex cannot form
3. ß-catenin is never switched off or repressed
4. cell proliferation is constantly driven
5. leads to persistent growth and lesions that can become cancerous

Question 30

Are 2 oncogenic mutations enough to make a cancer?

Answer 30

no
Start with K-Ras mutation and APC mutation but more are needed to lead to cancer

Question 31

Colorectal carcinogenesis process

Answer 31

1. Germ-line or somatic mutation of tumour suppressor genes
2. methylation abnormalities and inactivation of normal alleles
3. protooncogene mutations and homozygous loss of additional TSGs, over expression of COX2
4. additional mutations and gross chromosomal alterations

Question 32

what is familial adenomatous polyposis?

Answer 32

1. an inherited APC mutation carried in every colon cell
2. lots more initiation events
3. the same rate of progression as sporadic mutation
4. mutant APC also leads to a higher chance of losing the wild type copy and developing adenoma

Question 34

why is it clinically important to know how tumours form?

Answer 34

1. we can prevent cancer by identifying benign tumours and removing them
2. we can identify which benign tumours are just that and which could become malignant
3. know what to look for in screening

Question 35

what are the 2 key genes types to idenify in multistage carcinogenesis?

Answer 35

1. which genes are involved in turning normal cells into benign cells
2. which genes are involved in turning benign tumours into metastatic tumours

Question 36

why is knowing what genes are involved in multistage carcinogenesis important?

Answer 36

1. can we target them to prevent cancer development
2. can we target metastatic genes to prevent the spread of cancer or treat cancer

Question 37

why is understanding metastasis important?

Answer 37

because most solid tumour patients do not die from the primary cancer but from the metastatic cancer