Models of carcinogenesis

Question 1

Describe the pathogenesis of cancer

Answer 1

• multi-step process that involves the accumulation of mutations over times
• occurs when cells defense mechanism of DNA repair has been evaded

Question 2

What are the 3 assumptions made in regards to carcinogenesis

Answer 2

• malignant transformation of a single cells is sufficient to give rise to a tumour
• any cell in a tissue is as likely to be transformed as any other of the same type
• once a malignant cell is generated the mean time tumour detection is generally constant

Question 3

What are the 5 models of carcinogenesis?

Answer 3

1. mutational
2. genome instability
3. non-genotoxic
4. darwinian
5. tissue organisation

Question 4

Model 1 - chemical carcinogens

Answer 4

• cancer is a multi-step process, initiation, promotion and progression
• presence of multiple mutations supports the feature that cancer arises through the accumulation of irreversible DNA damage

Question 5

Specific chemicals which induce cancer

Answer 5

chimney smoke = scrotal carcinoma
benzene = acute leukemias
radium = osteosarcoma
arsenic = skin carcinoma

Question 6

What are the 4 classes of carcinogens?

Answer 6

1. chemical - polycyclic aromatic hydrocarbons, aromatic amines, alkylating agents
2. physical = radiation (ionising, UV) asbestos
3. heritable = predisposition
4. viral - hep B, epstein barr

Question 7

What are the 4 major groups in chemical carcinogens?

Answer 7

• aromatic hydrocarbons
• aromatic amines
• nitrosamines
• alkylating agents
  they exert their effects by adding functional groups to DNA bases called DNA adducts

Question 8

What is the Ames test?

Answer 8

a test to determine the mutagenic activity of chemicals by observing whether they cause mutations in sample bacteria

Question 9

How do physical carcinogens act?

Answer 9

• impart energy into biological material
• radiation is the primary physical agent
• ionising (x-ray)
• UV

Question 10

How do heritable carcinogens act?

Answer 10

• 5% of all cancers
• inherited germ-line mutation has an increased risk of developing certain tumour but are rarely involved in causing cancer immediately
• usually due to mutation of a single gene
• affected gene is often involved in controlling the cell cycle or the repair of DNA damage

Question 11

What are some syndromes caused by DNA repair defects

Answer 11

• ataxia telangiectasia
• blooms syndrome
• fanconis anaemia
• li-fraumeni syndrome

Question 12

What are some syndromes caused by chromosomal abnormalities

Answer 12

• downs syndrome

- klinefelters syndrome

Question 13

Describe ataxia telangiectasia

Answer 13

• neuromotor dysfunction, dilation of blood vessels
• mutation in ATM gene, codes for serine/threonine kinase that is recruited and activated by dsDNA breaks leading to cell cycle arrest, DNA repair ad apoptosis - cell cycle arrest
  cancer predisposition - lymphoma, leukaemia

Question 14

Describe blooms syndrome

Answer 14

• short stature, rarely exceed 5ft, skin rash that develops after exposure to sun
• mutation in BLM gene that provides instructions for coding member of the RecQ helicase family that helps maintain the structure and integrity of DNA
• cancer predisposition - skin cancer, basal cell carcinoma

Question 15

Describe lynch syndrome

Answer 15

• doesn’t cause any symptoms
• first sign is that person has bowel or womb cancer
• mutations in DNA mismatch repair genes, MLH1, MSH2, MSH6, PMS2
  cancer predisposition - colorectal cancer

Question 16

What are the properties required of tumourigenic viruses?

Answer 16

• stable association with cells : chromosomal integration
• must not kill cells : non-permissive host, suppression of viral lytic cycle, viral release by budding
• must evade immune surveillance of infected cells : immune suppression, viral antigens not expressed at cell surface

Question 17

Viruses associated with human cancer

Answer 17

DNA viruses - EBV, papiloma virus, hep b, burkitts lymphoma

RNA retroviruses - HTLV-1

Question 18

Describe model 2 - genome instability

Answer 18

• two hit hypothesis - multiple hits are required to cause cancer
• if first mutated allele was inherited the second mutation would lead to cancer
  at least two events are required, and first event must survive in tissue long enough to sustain a second event

Question 19

Describe model 3 - non- genotoxic

Answer 19

• tumour promoters - 1,4 dichlorobenzene
• endocrine modifiers
• receptor ediators
• immunosuppressants - cyclosporine

Question 20

Describe model 4 - darwinian

Answer 20

carcinogenesis by mutation and selection model of clonal expansion

• role of the environment in selecting cells that have some acquired advantage
• sequential accumulation of mutations due to exposure to carcinogens
• tumour cells will be selected for ability to grow and invade
• selection will include resistance to therapy
• some mutations may be deleterious for tumour

Question 21

What are the two forms of model 5 - tissue organisation?

Answer 21

• somatic mutation theory (SMT)

- tissue organisation field theory (TOFT)

Question 22

Describe SMT

Answer 22

• somatic mutation theory (SMT) - cancer is derived from a single somatic cells that has successively accumulated multiple DNA mutations
• those mutations damage the genes which control cell proliferation and cell cycle
• lesions are a result of DNA-level events
• single catastrophic event triggering carcinogenesis

Question 23

Describe TOFT

Answer 23

• tissue organisation field theory (TOFT)
• carcinogenesis is primarily a problem of tissue organisation
• carcinogenic agents destroy the normal tissue architecture thus disrupting cell-to-cell signalling and compromising genomic integrity
• the DNA mutations are random and the effect, not the cause, of the tissue-level events
• carcinogenesis as general deterioration of the tissue microenvironment due to extracellular causes