CANCER TRAITS 2 Flashcards
What is angiogenesis?
Formation of new vessels from pre-existing blood vessels (sprouting)
Normal angiogenesis:
Embryonic development
Wound healing
Female reproductive cycle
How are blood vessels essential
Supply nutrients & O2
Remove metabolic waste & O2
Enable immune surveillance
What is abnormal angiogenesis?
Abnormal angiogenesis contributes to disease:
Insufficient vessel growth–> stroke, myocardial infarction, neurodegeneration
Excessive vessel growth–> cancer, inflammatory disorders
What is tumour hypoxia
upregulation of angiogenic inducers (e.g. VEGF)
*Hypoxia: not enough oxygen
What are angiogenic inhibitors
Anti-angiogenic factors
Endogenous angiogenesis inhibitors (e.g. thrombospondin-1) regulate angiogenesis during tissue remodelling & wound healing
Act as barriers to induction of angiogenesis in tumours
What are angiogenic inducers
Pro-angiogenic factors
Tumour cells produce angiogenic factors (e.g. VEGF)–> directional growth of endothelial cells
Matrix metalloproteinases (MMPs) help secrete some of these factors
What is angiogenic switch
During tumour development, “angiogenic switch” allows cells to induce & sustain angiogenesis from vascular quiescence
Counterbalancing positive & negative signals, encourages or blocks angiogenesis
What are the names of growth of the tumour
small tumour -> sprouting capillary -> growing tumour
What is tumour angiogenesis
a.Tumours can’t grow beyond 1-2mm^3, due to lack of O2 & nutrients–> cells become hypoxic
b.Hypoxia stabilises hypoxia inducible factors in tumour cells–> increased gene expression of angiogeneic inducers
c.New network of blood vessels grows in & around tumour
- Oxygen & nutrients delivery increases
- Tumour can grow
- Provides a route for cells to shed off & metastasise
How does tumour cells evade apoptosis
Loss of p53 tumour suppressors–> removes p53 damage control form apoptosis-inducing system
Increased expression of anti-apoptotic proteins (Bcl-2) or downregulate proapoptotic factors (Bax) or interfere with extrinsic death receptor pathway
What results in dysregulated apoptosis and cancer
- disrupted dance of bcl-2 family of proteins
- increased expression of IAP’s
- reduced expression of caspases
- defects/mutations in p53
- impaired receptor signalling pathway
How is apoptosis triggered
in response to physiologic stress during carcinogenesis or due to anticancer therapy
why does invasion and metastasis occur
Cancer cells escape primary tumour mass & colonise new areas in the body with more nutrients & space
Metastases are mixture of cancer & normal cells from host tissue
What is autophagy
mediates both tumour cell survival and death
- metabolites generated during autophagy support survival of stressed, nutrient-limited cancer cell enviroments
What are factors to consider in necrosis and cancer
Seems beneficial–> removes hyperproliferating cancer cells
Can be pro-inflammatory & tumour promoting
Releases pro-inflammatory signals in tissue microenvironment–> recruitment of inflammatory cells
These check for tissue damage & remove necrotic debris
But tumours gain an advantage by tolerating necrosis:
Allows recruitment of inflammatory cells
These bring growth-stimulating factors to surviving cells within tumours–> stimulate angiogenesis, cell proliferation & invasiveness
What is invasion + EMT
Initiation of metatasis requires invasion–> enabled by epithelial-mesenchymal transition (EMT)
What is the invasion and metastasis cascade
Local invasion of basement membrane & cell migration (2)
Intravasation of cancer cells into nearby blood & lymphatic vessels (3)
Transit & survival of cancer cells in circulation (4)
Escape of cancer cells from vessel lumina into parenchyma of distant tissues (extravasation) (6)
Formation of small cancer cells nodules at secondary site (micrometastases) (7)
Growth of micrometastases into macroscopic tumours (colonisation)
what is MET
Mesenchymal-epithelial transition (MET): reverse process of EMT, important for establishing metastasis
What is EMT
transdifferentiation program of epithelial to mesenchymal cells–> offers cell plasticity
what occurs in epithelial cells in EMT
Epithelial cells:
Lose polarity & cell-cell adhesion (loss of E-cadherin)
Gain migratory & invasive properties
Become mesenchymal stem cells (multipotent cells that can differentiate into various types)
How is replicative immortality enabled in normal cells
limited cell division = lead to stop of growth due to 2 barriers t proliferation: senescence & crisis
what is senescence
irreversible non-proliferative viable state
Cells that overcome this barrier enter crisis
What is crisis?
Crisis involves cell death & genomic instability
If cells emerge from crisis, they acquire unlimited replicative potential (immortalisation)
What are telomeres
protective end caps of chromosomes (thousands of TTAGGG repeats)
What do cancer cells do to telomerase
overexposes telomerase to overcome telomere shortening, senescence and cell death this is as telomeric DNA from chromosomes ends shorten during each cell cycle 50-100 bp
How is telomeres maintained in cancer cells
Upregulation telomerase expression
Activation of ALT
Telomeres maintained above critical length threshold allow unlimited cell multiplication
What can telomeres not do?
protect ends of chromosomes from end-to-end fusions
Results in genetic instability–> crisis–> cell death
Telomerase absent in non-immortal cells but overexpressed in immortalised cells (e.g. cancer cells)
why are up mechanisms of telomere up regulation surpressed
These mechanisms are suppressed in normal cells to avoid unlimited replication
What is ALT
alternative lengthening of telomeres; a telomerase-independent mechanism by which cancer cells avoid the degradation of telomeres
What is the invasion metastasis cascade involve?
invasion
intravasion
survival in circulation
extravasin
micrometastases
colonisation
What do tumours need
new vessels to survive, achieved by up regulation of angiogenesis usually in response to hypoxia
