ANHB3323 Lecture Notes - Lecture 9: Basal Lamina, Reverse Transcriptase, P53
3 Jun 2018
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LECTURE NINE: Hallmarks of Cancer
6 Hallmarks of Cancer:
• Evading apoptosis
• Self sufficiency in growth signals
• Insensitivity to anti-growth signals
• Tissue invasion and metastasis
• Limitless replicative potential
• Sustained angiogenesis
Evading Apoptosis:
• Apoptotic sensors
o Cell surface receptors that bind survival or death factors
o Intracellular sensors that monitor DNA damage
o Signals converge on mitochondria → releases cytochrome C
• Apoptotic effectors → caspases → enzymes break down cell organelles
• Redundancy in effectors → tumors with one mutated effector may be
killed by drugs that increase another effector
Self Sufficiency in Growth Signals:
• Normal cells require external growth signals to move from a quiescent
state to proliferative state
• Include → diffusible growth factors, extracellular matrix components,
cell-cell adhesion molecules
• Tumor cells generate their own growth signals → e.g. platelet derived
growth factor
• Tumors overexpress the receptors in permanently activated forms
• Tumors mutate the downstream signaling molecules to be activated →
e.g. Ras-MAPK pathway mutated in 25% of all cancers
Insensitivity to Anti-Growth Signals:
• Normal cells can be pushed into a quiescent of differentiated state
• G1 → cells monitor environment to make decisions about division
• Anti-differentiation
o Embryonic development → high expression of Myc-Max
transcription factor → keeps cells pluripotent
o Maturity → cells make Mad-Max → triggers differentiation
o Cancers reactivate Myc → making more Myc-Max again
• pRB/E2F pathway → directs G1 to S transition → phosphorylation of pRB
releases E2F which activates transcription
• TGF-beta → stops G1 to S transition by blocking phosphorylation of pRB
Sustained Angiogenesis:
• All cells in a tissue need to be ~100um from a blood vessel
• Without blood → hypoxia and nutrient starvation
• Angiogenesis is an early to midstage step required for formation of
macroscopic tumors
• Process driven by a concentration gradient of growth factors
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