HC3 - Multi-step tumorigenesis Flashcards
senescence
- non-growing but viable state
- provoked by a variety of physiological stresses
crisis
- apoptotic death of cells
- provoked by erosion of telomeres
pre-malignant cells escape crisis
activate expression of hTERT
hTERT
telomerase enzyme that exends telomeres in hexanucleotide increments
immortal cells
- stabilize telomeres with telomerase or ALT mechanism
- prerequisite to the development of all human cancers
end-to-end chromosomal fusion
- repeated cycle of breakage-fusion-bridge (BFB) cycle
- aneuploidy
development cancers
over years/decades
curing all cancer
raises life expectancy with 3-5 years > due to late onset
risk of death
increases as 4-7th power of elapsed life
different tumor progressions cooexist
use of progression schemes for determination
surgical removal of early-stage lesions
reduces risk of disease
increasing neoplastic phenotypes
correlates with corresponding increase in the number of altered loci
genomic alterations
- proto-oncogenic activation an tumor suppressor gene inactivation
- accumulate with tumor progression
loss of heterozygosity (LOH)
can expose a faulty allele if it was masked/dominated
colon carcinomas
~80% inactive APC gene
multiple genetic routes
can lead to a similar outcome
tumor progression
a series of clonal expensions
survival of the fittest in tumors
cancer cells compete for limited resources
selection in tumors
favors cells endowed with ability to proliferate and survive in tisse
highly heterogenous tumors
- genomic instability > mutation rate increases
- Darwinian selection cannot keep up with genetic diversification
- specific subclones > may support each other
- more complexity > epigenetic plasticity
Peto’s paradox (Richard Peto)
- within one species > cancer risk and body size = positively correlated
- between species > no correlation between incidence and number of cells
larger organisms (Peto’s paradox)
- may have more developed tumor suppression mechanisms
- bigger and slower dividing cells
- lower energy turnover
truely normal primary cells
resistant to single hit transformation
difficulty with transformation of human fibroblasts
5-6 different circuits need to be disrupted simultaneously
non-mutagenic/toxic agents
promote tumorigenesis
tabacco smoke
source of genotoxic chemicals
alchohol
very toxic to epithelial cells of mouth and throat
mitogenic agents
promote cell proliferation
steroid hormones
estrogen and progesteron > stimulate proliferation of cells in reproductive tissues
more menstruation cycles
leads to higher risk in breast cancer, 1 year absence = 20% decrease in risk
chronic inflammation
promotes tumorigenesis
anti-inflammatory drugs
reduce cancer risk
non-steroid anti-inflammatory drug (NSAID)
asparin
common targets NSAIDs
- cyclooxygenase-2 > biosynthesis of prostagladin E2 (PGE2)
prostagladin E2 (PGE2)
pro-inflammatory molecule with tumor-promoting capabilities
carcinogenic
not equal to mutagenic
complete carcinogens
genotoxic and mitogenic, can initiate and promote tumorigenesis
