1: L11

Question 1

What are the 6 hallmarks of cancer

Answer 1

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

Question 2

Name the 2 enabling characteristics

Answer 2

1. Genome instability

2. Inflammation

Question 3

Name the 2 emerging characteristics

Answer 3

1. Cellular energetics/metabolism

2. Avoiding the immune system

Question 4

Hallmark 1: Evading apoptosis- what 2 pathways needs to be mutated

Answer 4

a. Apoptotic ‘sensors’ (detect need to apoptose)

b. Apoptotic ‘effectors’ (carry out the apop) i.e. caspases

Question 5

Hallmark 1: Evading apoptosis- what does the redundancy in effectors mean

Answer 5

• Redundancy in effectors means that tumors with one mutated effector may be killed by drugs that increase another effector

Question 6

Hallmark 2: Self-sufficiency in growth signals - name two growth factor made by cancer cells

Answer 6

Platelet derived growth factor made by glioblastoma or tumor growth factor alpha by sarcoma

Question 7

Hallmark 2: Self-sufficiency in growth signals- what pathway is mutated in 25% of cancers

Answer 7

Ras-MAPK

Question 8

Hallmark 3: Insensitivity to anti-growth signals- two pathways used

Answer 8

Myc-Max

Example: pRB/E2F

Question 9

Hallmark 3: Insensitivity to anti-growth signals- describe myc-Max

Answer 9

• 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

Question 10

Hallmark 3: Insensitivity to anti-growth signals-describe pRB/E2F

Answer 10

• 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

Question 11

Hallmark 4: Sustained angiogenesis describe conditions needed + wha occurs without blood supply

Answer 11

• All cells in a tissue need to be ~100μm from a blood vessel
o Without blood: hypoxia and nutrient starvation

Question 12

Hallmark 4: Sustained angiogenesis 5 ways tumour cells trigger new vessels

Answer 12

recruitment of endothelial progentirot cells 
intussusceptive angiogenesis 
lymphangiogenesis
vasculogenic mimicry 
vessel cooption

Question 13

Hallmark 5: Limitless replicative potential why need this

Answer 13

• Cells in culture will enter senescence after a limited number of doublings (telomere shorten after every divide // can only get so small)

Question 14

Hallmark 5: Limitless replicative potential 2 ways of telomere maintenance

Answer 14

a. 80-90% of cancers upregulate telomerase

b. 10-20% use the ALT mechanism that uses a recombination based process for alternative telomere lengthening

Question 15

Hallmark 6: Tissue invasion and metastasis what does it require

Answer 15

• 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)

Question 16

Hallmark 6: Tissue invasion and metastasis how does it affect adherins + focal adhesions

Answer 16

1. Adherens Junctions (cell-cell adhesion): E-cadherin (key to cell-cell bridging molecule) is lost in most invasive epithelial cancers
2. 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

Question 17

Enabling characteristics = Genome instability describe

Answer 17

• 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

Question 18

Enabling characteristics= Inflammation describe

Answer 18

• 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

Question 19

Emerging hallmarks = Cellular energetics/metabolism describe

Answer 19

• Warburg effect: even with oxygen, most cancer cells produce energy by high rate of glycolysis (not mitochondrial oxidative phosphorylation) – glucose addiction!!

Question 20

Emerging hallmarks = Avoiding the immune system describe

Answer 20

• 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

Question 21

Describe Multi-hit Model of Carcinogenesis

Answer 21

• Each hallmark contributes to cancer: you need all 6, need accumulation of all in each cell
o 2 enablers help the tumor get them

Question 22

• Why some cancer drugs fail

Answer 22

targeting one hallmark might activate others

• Eg. Targeting angiogenesis can trigger metastasis as cells search for new energy supply

Question 23

Limitiations of hallmarks model

Answer 23

1. 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.
2. 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.