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suggest different intrinsic and extrinsic risk factors for carcinogenesis - which group is more important?

- old age
- gender (hormones)
- genetics

Extrinsic (85%):
- lifestyle (30%): high BMI, low fruit/veg, smoking, alcohol
- environment: chemicals, radiation, infection


describe the 3 steps of carginogenesis

i. initiation: INITIATOR causes mutation

ii. promotion: chronic exposure to PROMOTERS causes cell proliferation and expansion of a monoclonal pop. of mutant cells

iii. progression: step-wise ACCUMULATION of mutations to become malignant neoplasm


describe 3 different types of initiator - how do they cause mutation?

1. chemicals (long delay between exposure and onset, risk depends on dosage, some organ specificity)

2. radiation, e.g. UV rays or ionising radiation (inc. X-rays). Mutagenic via:
- direct DNA damage (to DNA bases or single- and double-strand breaks)
- indirect damage by generating free radicals

3. infection:
- direct carcinogens (e.g. HPV and cervical cancer)
- indirect carcinogens via chronic tissue injury and resulting regeneration... DNA replication errors (e.g. HepB/C and liver cancer, H. pylori and gastric carcinoma)


name a chemical that can cause bladder cancer



how does HPV cause cancer

HPV expresses E6 and E7 proteins that inhibit p53 and pRB... cervical carcinoma


what are pro-carcinogens and complete carcinogens

Pro-carcinogens = chemicals that are only converted to carcinogens by CYP450s in liver

Complete carcinogens = both initiators and promoters (e.g. cigarette smoke)


which 3 types of genes must be affected by mutation for cancer to occur - what is their function and how many alleles must be affected

1. tumour suppressor genes
- act like break on tumour growth
- both alleles must be inactivated (2 hits)

2. proto-oncogenes
- enhance neoplastic growth
- 1 allele must be activated

3. care-taker genes
- type of TS gene that maintains genetic stability
- e.g. DNA repair genes


describe an example of a tumour suppressor gene

pRB: restrains cell proliferation by inhibiting passage through restriction point


describe an example of a proto-oncogene

RAS: small G protein that relays signals into cell, eventually pushing cell past cell cycle restriction point... activation of cyclin D... activation of CDK... entry into cell cycle


what is genetic instability

accelerated mutation rate caused by germline mutations affecting DNA repair (seen in some inherited cancers)

can involve:
- nucleotide, microsatellite or chromosomal instability
- abnormal chromo. segregation during mitosis


suggest why inherited malignancies are more likely to occur than spontaneous malignancies


- Inherited - 1st hit: germline mutation (affects all cells); 2nd hit = somatic mutation
- Spontaneous - both hits = somatic mutation in same cell (less likely)


what is the adenoma-carcinoma seqeuence

Accumulation of mutations, typically over decades, causing a colonic adenoma to become a colonic carcinoma:

i. normal epithelium...
ii. early adenoma/dysplastic crypt...
iii. intermediate adenoma...
iv. TGF-beta response inactivation... late adenoma...
vi. loss of p53 function... carcinoma...
vi. metastasis


name the 6 hallmarks of a fully evolved malignant neoplasm

what is the enabling characteristic?

1. self-sufficiency in growth signals
2. resistance to growth-stop signals
3. cell immortalisation (no division limit), e.g. telomerase gene activation
4. sustained angiogenesis ability, e.g. VEGF expression
5. apoptosis resistance
6. ability to invade and metastasise

enabling characteristic = genetic instability


which cellular changes must occur for a cancerous cell to be become invasive

Epithelial-to-mesenchymal transition

1. altered adhesion: reduced E-cadherin expression (decreased cell-cell adhesion), changed integrin expression (decreased cell-stromal protein adhesion)

2. altered stromal proteolysis: increased protease expression, esp. MMPs (basement membrane and stroma degradation)

3. altered motility: changed actin expression via Rho G proteins (cytoskeleton changes)


describe the 3 stages of metastasis

i. growth and invasion at primary site
ii. enter transport system and lodge at secondary site
iii. growth at secondary site to form new tumour - colonisation


how can cancer cells disseminate across the body - which method is used by carcinomas and sarcomas

- blood
- lymph
- transcoelomic

carcinomas: first lymph then blood
sarcomas: straight to blood


name the cancers that most frequently spread to bone

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- prostate
- breast
- lung
- renal
- thyroid


which 2 factors determine location of colonisation

1. regional drainage of blood (next capillary bed: often lungs, liver, bone or brain), lymph (draining lymph nodes) or coelomic fluid (other areas in coelomic space, adjacent organs)

2. seed and soil phenomenon: requires adequate "cancer niche" - provides growth factors and proteases


what is tumour dormancy

when metastatic cells fail to grow, instead forming micrometastases which can reactivate later