1: L11 Flashcards
What are the 6 hallmarks of cancer
Hallmark 1: Evading apoptosis
Hallmark 2: Self-sufficiency in growth signals
Hallmark 3: Insensitivity to anti-growth signals
Hallmark 4: Sustained angiogenesis
Hallmark 5: Limitless replicative potential
Hallmark 6: Tissue invasion and metastasis
Name the 2 enabling characteristics
- Genome instability
2. Inflammation
Name the 2 emerging characteristics
- Cellular energetics/metabolism
2. Avoiding the immune system
Hallmark 1: Evading apoptosis- what 2 pathways needs to be mutated
a. Apoptotic ‘sensors’ (detect need to apoptose)
b. Apoptotic ‘effectors’ (carry out the apop) i.e. caspases
Hallmark 1: Evading apoptosis- what does the redundancy in effectors mean
• Redundancy in effectors means that tumors with one mutated effector may be killed by drugs that increase another effector
Hallmark 2: Self-sufficiency in growth signals - name two growth factor made by cancer cells
Platelet derived growth factor made by glioblastoma or tumor growth factor alpha by sarcoma
Hallmark 2: Self-sufficiency in growth signals- what pathway is mutated in 25% of cancers
Ras-MAPK
Hallmark 3: Insensitivity to anti-growth signals- two pathways used
Myc-Max
Example: pRB/E2F
Hallmark 3: Insensitivity to anti-growth signals- describe myc-Max
- Myc, onco gene in many cancers
- Embryonic development= Myc-Max transcription factor keeps cells pluripotent (=actively divide)
- Maturity= cells stop Myc and make Mad-Max and this triggers differentiation (opposite to pluripotency)
- Cancers reactivate Myc, making more Myc-Max again
Hallmark 3: Insensitivity to anti-growth signals-describe pRB/E2F
• pRB/E2F pathway= key to directing G1 > S
• Normally: e2f inhibited by pRB in G1
1. CDK4 incr. during G1 + the pRB is phosphoralted and // no longer binds to e2f
2. // e2f is released= an active transciption factor
3. Triggers expression of genes required for moving into s phase
• TGFbeta (antigrowth factor) blocks this phosphorylation and therefore prevents freeing up E2F
o // cancer needs to mutate to prevent this pathway to activate
Hallmark 4: Sustained angiogenesis describe conditions needed + wha occurs without blood supply
• All cells in a tissue need to be ~100μm from a blood vessel
o Without blood: hypoxia and nutrient starvation
Hallmark 4: Sustained angiogenesis 5 ways tumour cells trigger new vessels
recruitment of endothelial progentirot cells intussusceptive angiogenesis lymphangiogenesis vasculogenic mimicry vessel cooption
Hallmark 5: Limitless replicative potential why need this
• Cells in culture will enter senescence after a limited number of doublings (telomere shorten after every divide // can only get so small)
Hallmark 5: Limitless replicative potential 2 ways of telomere maintenance
a. 80-90% of cancers upregulate telomerase
b. 10-20% use the ALT mechanism that uses a recombination based process for alternative telomere lengthening
Hallmark 6: Tissue invasion and metastasis what does it require
• Requires changes to the physical coupling of tumor cells to the stroma and activation of extracellular proteases (in order to invade epothelial = need to eat away at lamina)
Hallmark 6: Tissue invasion and metastasis how does it affect adherins + focal adhesions
- Adherens Junctions (cell-cell adhesion): E-cadherin (key to cell-cell bridging molecule) is lost in most invasive epithelial cancers
- Focal Adhesions (base-lamina adhesion): Tumors change the integrins produced to favour contact w/ disorganised matrices left behind by tumors, rather than the ordered ‘normal’ matrix of epithelial basal lamina
Enabling characteristics = Genome instability describe
- Usually mutations are corrected with high efficiency (“caretakers of the genome”)
- Cancer cells need to increase sensitivity to mutagenic agents and decrease efficiency of DNA repair
Enabling characteristics= Inflammation describe
- Tumors infiltrated by immune cells carrying out inflammation (tumor needs to trigger inflamation)
- Innate immune cells supply growth factors, survival factors, proangiogenic factors, ECM modifying enzymes, and release ROS that help mutate nearby cells
Emerging hallmarks = Cellular energetics/metabolism describe
• Warburg effect: even with oxygen, most cancer cells produce energy by high rate of glycolysis (not mitochondrial oxidative phosphorylation) – glucose addiction!!
Emerging hallmarks = Avoiding the immune system describe
- Immune system constantly surveys the body and eliminates transformed cells.
- Paradox: highly immunocompromised people do not necessarily have a higher burden of non-virally triggered cancer
Describe Multi-hit Model of Carcinogenesis
• Each hallmark contributes to cancer: you need all 6, need accumulation of all in each cell
o 2 enablers help the tumor get them
• Why some cancer drugs fail
targeting one hallmark might activate others
• Eg. Targeting angiogenesis can trigger metastasis as cells search for new energy supply
Limitiations of hallmarks model
- The wheel suggests each hallmark is considered equal, but some cancer subtypes rely more heavily on one or the other hallmark
- Eg. Breast and pancreatic cancers have vastly different survival rates. Our available arsenal of drugs work on targets that breast cancer rely on more. We know more about breast cancer weak spots than pancreatic. - The first five hallmarks are common to both benign and metastatic tumors, with the 6th hallmark directly relating to invasion. Yet metastasis is the real problem in cancer. We need to be targeting and understanding this process distinct from the benign ones.
