cancer pathogenesis Flashcards
why is a benign tumour not cancer
not invasive
metastasis
When spread via blood or lymph
tobacco smoke contains
§ Volatile organics □ Aldehydes, acrolein, formaldehyde § Polycyclic aromatic hydrocarbons (PAH), benzopyrene § Tobacco specific nitrosamines § Heavy metals □ Chromium, lead
8 new capabilities required
- Self sufficient in growth signals
- Insensitive to antigrowth signals
- Evade apoptosis
- Can proliferate indefinitely - immortalised
- Can promote blood vessel growth- angiogenesis
- Can spread away from primary tumour - invasion and metastasis
- Cellular energy deregulation
- Immune system evasion
Two enabling factors
- Genome instability
2. Inflammation
- Oncogene activation
- Cells produce their own growth signals
Autocrine GF production
inhibitory signals
- Tumour suppressor genes - TSGs
- Familial cancers
§ Due to inheritance of a mutated allele on a TSG
§ Retinoblastoma
tumour suppressor gene
Most extracellular anti-proliferative signals use the
RB pathway
§ RB pathway disrupted in most human cancers
§ Hypophosphorylated Rb
□ Sequesters E2F
□ Blocks G1 to S phase progression
E2F
TF for progression of G1 to S phase
Rb pathway
§ Growth factors
□ Activate cyclin/CDK complexes - phosphorylate Rb which released E2F
□ Cell cycle progresses G1 to S phase
- Apoptosis
- Regulated process
- Cell structures degraded, nucleus fragmented, cell corpse engulfed
3 means of resistance to apoptosis
hormone receptor expression - increase survival signal
antiopoptotic protein levels increase
P53 mutations
- most common
Cell immortalisation
§ Re-expression of telomerase is used to immortalise cells
□ Used in experimental cell lines
telomeres
- Mitotic counting device with multiple TTAGGG repeats
Tumour microenvironment
- Oxygen and nutrients - vascular network
- Invasion and spread
- Avoiding immune detection
- Cancers co opt cells in the microenvironment
Angiogenesis
- Cells need nutrients and oxygen and to remove waste
- <100 micrometres from the blood stream
shift of signalling proteins in angiogenesis
increase VEGF and decrease thrombospondin 1
- Metastatic cascade
- Carcinoma in situ must move and degrade basement membrane
- Must enter blood vessel and survive in blood stream
- Stick to blood vessel wall
- Extravasate
- Survive and proliferate in new environment
- Li-fraumeni syndrome
§ TP53 - controls entry to apoptosis
- Neurofibromatosis
§ NF1 - RasGAP
§ Inactivates Ras
- Von Hippel-Lindau disease
§ VHL
§ Controls HIF-1 levels
- Familial adenomatous polyposis
§ Controls B catenin signalling
2 genome maintenance related familial cancers
Lynch syndrome
breast and ovarian cancers
- BRCA1 and 2
