WK 6- HALLMARKS OF CANCER

Question 1

What are the 8 hallmarks of cancer

Answer 1

1. Sustaining proliferative signalling
2. Evading growth suppressors
3. Resisting cell death
4. Enabling replicative immortality
5. Inducing angiogenesis
6. Activation of invasion and metastasis
7. Deregulating cellular energetics
8. Avoiding immune destruction

Question 2

What are the two enabling characteristics of cancer cells

Answer 2

1. genome instability and mutation

2. tumour promoting inflammation

Question 3

How are growth factors involved in sustaining proliferative signalling

Answer 3

Growth factors are generally not mutated- just develop the ability to synthesis the stimulate the same growth factors that they can then respond to (gain of function)- by creating their stimulus, they create a cycle that leads to increased and unregulated release of growth factor

Question 4

How do growth factor receptors contribute to sustaining proliferative signalling

Answer 4

Oncogenes encode for numerous growth factor receptors-> results in mutated receptors that are constitutively active-> leads to constant cell growth and proliferation

Question 5

What is the most important growth factor receptor

Answer 5

Tyrosine kinase family- RTK (receptor tyrosine kinase)

Question 6

What is the function of receptor tyrosine kinase

Answer 6

RTK sit on cellular membrane and when a growth factor binds, it causes the cell to dimerize and phosphorylate-> causes activation-> when RTK is active it triggers downstream pathways, such as RAS to occur-> RAS leads to cell growth

Question 7

What gene encodes for HER2- how does HER2 become mutated- what cancer arises

Answer 7

ERBB2-> when ERRB2 undergoes amplification, it causes the HER2 (human epidermal growth factor receptor) to become over expressed and lead to constitutive activation-> leads to proliferation of cells and BREAST CANCER

Question 8

What gene encodes for EGFR- how does EGFR become mutated- what cancer arises

Answer 8

ERBB1 encodes for EGFR (epidermal growth factor receptor)-> when ERBB1 suffers a point mutation it causes overexpression of EGFR and constitutive activity-> leads to cellular proliferation and LUNG ADENOCARCINOMA

Question 9

What are the downstream components of the RAS pathway (KRAS/NRAS/HRAS)

Answer 9

When activated, RAS stimulates the RAF and PI3K pathways

Question 10

How is RAS activated

Answer 10

When RTK is activated, it causes a switch from GDP to GTP-> causing downstream activation

Question 11

What tumour suppressor gene inhibits PI3K

Answer 11

PTEN

Question 12

Are mutations to tumour suppressor genes a gain or loss of function

Answer 12

Loss of function

Question 13

Are mutations to oncogenes a gain or loss of function

Answer 13

Gain of function

Question 14

What does PI3K activate

Answer 14

Akt and mTOR-> these stimulate pro-growth metabolism and increased protein synthesis

Question 15

What does RAF activate

Answer 15

MAPK pathway that then stimulates transcription factors MYC and D-cyclins-> causes cell cycle progression, pro-growth metabolism and increased protein synthesis

Question 16

How does RAS become inactivated (stop downstream cell growth)- what mutations prevent this

Answer 16

GAP (GTPase activating protein) binds to RAS and degrades GTP- Mutations that result in decreased GAP activity/mutate GAP lead to constant activation of RAS- constant cell growth

Question 17

What is an example of a mutated non-receptor tyrosine kinases

Answer 17

ABL gene is translocated and fused with BCR gene-> results in a fusion product that is constitutively active and triggering cell growth via downstream pathways

Question 18

What is MYC

Answer 18

Transcriptional regulator of cell growth-> activates transcription of genes involved in cell growth (D-cyclins)-> if MYC is mutated (gain of function) it will lead to uncontrolled cell growth

Question 19

What are tumour suppressor genes (5 functions)

Answer 19

Genes that encode proteins that are;

1. receptors for growth factors that inhibit cell proliferation
2. are negative regulators of cell cycle entry/progression
3. are checkpoint control proteins (stop cycle is DNA is damaged/abnormal and will promote apoptosis)
4. are regulators of cell adhesion
5. are DNA repair enzymes

Question 20

What is the Rb gene- is it a tumour suppressor gene or oncogene?

Answer 20

Tumour suppressor gene- Retinoblastoma gene product

Question 21

What is the function of the Rb gene- how does mutation lead to cancer

Answer 21

Rb protein binds regulatory transcription factor E2F which is required for synthesis of DNA replication enzymes→ when bound to E2F, transcription/ replication is blocked.
-Growth factors (via Ras pathway) activate CDK4/6 which phosphorylates and inhibits Rb, removing block of E2F, and transition to S phase occurs→Disruption/deletion of the Rb gene therefore leads to uncontrolled cell proliferation

Question 22

What is TP53- what is it’s functions

Answer 22

Tumour suppressor gene-regulates cell cycle progression, DNA repair, cellular senescence and apoptosis

Question 23

What is Li-fraumeni syndrome

Answer 23

Occurs when a mutated copy of TP53 is inherited, predisposing to malignant tumours (only require 1 more hit/mutation)

Question 24

Why do mutations in BRCA1/2 lead to cancer

Answer 24

Oncogene->BRCA genes are involved in the repair of double-stranded DNA breaks by homologous recombination–> cells that express mutated BRCA genes develop chromosomal breaks and severe aneuploidy

Question 25

Does mutation in BRCA2 lead to ovarian or breast cancer

Answer 25

BRCA2 is high breast cancer- BRCA1 causes ovarian/prostate cancer

Question 26

What is APC

Answer 26

Tumour suppressor gene- Negatively regulates the Wnt/β-catenin pathway (acts an anti-proliferative) → WNT can induce cellular proliferation by binding to its receptor and sending signals to prevent the degradation of β-catenin (β-catenin is able to move to the nucleus and activate cell proliferation)→ APC encourages degradation of β-catenin→ if APC is mutated then cell proliferation results

Question 27

What is PTEN

Answer 27

Tumour suppressor gene- negative regulator of PI3K/AKT signalling

Question 28

What is the role of TGF-Beta in cell proliferation

Answer 28

Potent inhibitor of proliferation | -loss-of-function mutations in TGF-β receptors or downstream signal pathways are involved in numerous cancers

Question 29

What is the role of CDKN2A

Answer 29

Functions as a negative regulator of cell cycle entry / progression - encodes tumor suppressor proteins including p16/INK4a (CDK inhibitor) and ARF (stabilizes p53) - loss-of-function mutations in diverse familial and sporadic cancers

Question 30

What is the function of E-Cadherin / β-catenin

Answer 30

E cadherin is a cell surface protein that maintains intercellular adhesiveness and binds to β-catenin - when there is loss of cell-cell contact (eg epithelium injury), interaction between E-cadherin and β-catenin are disrupted→ this promotes translocation of β-catenin to nucleus, where it stimulates genes that promote proliferation (normal repair process) - if there is cell to cell E-cadherin connection (ie. No endothelial damage) it will inhibit proliferation (contact inhibition

Question 31

How does mutation to E-Cadherin / β-catenin axis cause cancer

Answer 31

Mutation of the E-cadherin/β-catenin axis results in loss of contact inhibition in many cancers causing increased proliferation→ contributes to the local invasion and metastatic ability

Question 32

How are cancer cells resistant to cell death/apoptosis (3 ways)

Answer 32

1. mutation of Bcl2→ leads to overexpression of Bcl2→ leads to inhibition of apopsotis (Bcl2 is an antiapoptotic protein) 2. p53 is ineffective (normally promotes apoptosis) 3. Reduced levels of Fas (CD95) can also render tumor cells less susceptible to apoptosis through extrinsic pathways involving Fas ligand (FasL)

Question 33

What allows cells to have replicative immortality

Answer 33

Telomerase: maintains temoleres at the ends of chromosomes and stops degradation/shortening upon each replication --> normal cells have such small levels of telomerase that they have no protection against telomere shortening- therefore do not have replicative immortality

Question 34

What is the stem cell theory of carcinogenesis

Answer 34

CSCs (cancer stem cells) divide infrequently, are capable of self-renewal, assymetric division and generation of a diversity of mature cell types→traditional chemotherapy targets rapidly dividing non-CSCs but may spare quiescent CSCs→may explain instances of cancer recurrence

Question 35

What are some examples of angiogenic factors and where are they released from

Answer 35

Include HIFI-alpha (Hypoxia-inducible factor 1-alpha) and Vascular Epithelial Growth Factor-> are released from tumour & stroma and inflammatory cells

Question 36

What is the process by which metastases occurs

Answer 36

a) cross into blood/ lymph vessels (intravasation) b) transported through the blood/lymph vessels to distant tissue sites c) escapes from circulation and cross into tissues (extravasation) d) adapt to the new local tissue environment and proliferate

Question 37

What must tumour cells do to invade surrounding tissue

Answer 37

a) detach from adjacent cells (loss of integrin, cadhedrins) b) degrade the ECM (produce proteases eg MMP (matrixmetallo protease) c) attach to and migrate through ECM (express adhesion molecules) d) migrate (increased locomotion-diapedesis)

Question 38

What are 3 factors that influence where a tumour cell emboli can lodge and begin to grow

Answer 38

- vascular and lymphatic drainage from the primary - interaction with specific receptors eg some tumour cells express CD44 adhesion molecules that bind to venules in lymph nodes - the microenvironment of the organ or site (eg tissue rich in protease inhibitors might be resistant to penetration by tumor cells)

Question 39

What is meant by deregulating cellular energetics- how does this help tumour growth

Answer 39

Tumour cells undergo a metabolic switch from oxidative phosphorylation to glycolysis (Warburg effect)→shunts more metabolites into intermediates (proteins, nucleotides, lipids) that can be used to support cellular synthetic pathways/enable growth

Question 40

How do cancer cells avoid immune destruction

Answer 40

Cancer cells express molecules that are foreign-> innate and adaptive immune system can recognize and eliminate cells displaying abnormal antigens

Question 41

What kind of 'abnormal' molecules do cancer cells possess that healthy cells don't

Answer 41

1. selective growth of antigen-negative variants (don’t express antigens that allows them to be recognised) 2. loss or reduced expression of histocompatibility antigens 3. increased expression of immunosuppressive factor (inhib signals or cytokines)

Question 42

How does the enabling characteristic- Genome instability and Mutation- lead to cancer formation

Answer 42

defective proteins (eg. DNA repair genes) allow mutations to occur in other genes that collectively result high amounts of damaged cells that are able to avoid cell death by apoptosis

Question 43

What does microsatellite instability mean

Answer 43

regions of repetitive DNA sequences prone to shortening or extension when mismatch repair enzymes are defective→ leads to cancer formation

Question 44

What causes the systemic signs of cancer (eg anemia, fatigue, cachexia (muscle wasting and weight loss)

Answer 44

chronic inflammation of cancer causing release of chemokines/cytokines

Question 45

How does chronic inflammation assist in tumour growth ( 6 ways)

Answer 45

1. release of growth factors / proteases that promote proliferation 2. inhibition of growth suppressors (eg adhesion molecules) 3. enhancing resistance to cell death 4. inducing angiogenesis 5. facilitating invasion and metastasis (eg by degrading ECM or by inducing tumor cell mobility) 6. Contributing to immune evasion (eg activating M2 macrophages

Question 46

What is FAP

Answer 46

Familial adenomatous polypopsis; - disorder associated with development of thousands of colonic polyps and early onset colon carcinoma - both copies of the APC gene must be lost (2 hits, can be somatic or inherited)→ loss of function of APC gene

Question 47

What is Lynch syndrome

Answer 47

Patients inherit on mutated copy of DNA repair genes involved in mismatch repair (e.g., MSH2 and MLH1) - second hit occurs in a colonic epithelial cell - gradual accumulation of errors in multiple genes including proto-oncogenes and tumor suppressor genes and mismatch repair mutations show microsatellite instability → leads to cancer formation