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TIN > WK 6- HALLMARKS OF CANCER > Flashcards

WK 6- HALLMARKS OF CANCER Flashcards

1
Q

What are the 8 hallmarks of cancer

A
  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
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2
Q

What are the two enabling characteristics of cancer cells

A
  1. genome instability and mutation

2. tumour promoting inflammation

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3
Q

How are growth factors involved in sustaining proliferative signalling

A

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

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4
Q

How do growth factor receptors contribute to sustaining proliferative signalling

A

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

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5
Q

What is the most important growth factor receptor

A

Tyrosine kinase family- RTK (receptor tyrosine kinase)

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6
Q

What is the function of receptor tyrosine kinase

A

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

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7
Q

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

A

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

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8
Q

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

A

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

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9
Q

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

A

When activated, RAS stimulates the RAF and PI3K pathways

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10
Q

How is RAS activated

A

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

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11
Q

What tumour suppressor gene inhibits PI3K

A

PTEN

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12
Q

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

A

Loss of function

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13
Q

Are mutations to oncogenes a gain or loss of function

A

Gain of function

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14
Q

What does PI3K activate

A

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

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15
Q

What does RAF activate

A

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

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16
Q

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

A

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

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17
Q

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

A

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

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18
Q

What is MYC

A

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

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19
Q

What are tumour suppressor genes (5 functions)

A

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
20
Q

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

A

Tumour suppressor gene- Retinoblastoma gene product

21
Q

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

A

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

22
Q

What is TP53- what is it’s functions

A

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

23
Q

What is Li-fraumeni syndrome

A

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

24
Q

Why do mutations in BRCA1/2 lead to cancer

A

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

25
Q

Does mutation in BRCA2 lead to ovarian or breast cancer

A

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

26
Q

What is APC

A

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

27
Q

What is PTEN

A

Tumour suppressor gene- negative regulator of PI3K/AKT signalling

28
Q

What is the role of TGF-Beta in cell proliferation

A

Potent inhibitor of proliferation

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

29
Q

What is the role of CDKN2A

A

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
30
Q

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

A

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
31
Q

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

A

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

32
Q

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

A
  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)
33
Q

What allows cells to have replicative immortality

A

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

34
Q

What is the stem cell theory of carcinogenesis

A

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

35
Q

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

A

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

36
Q

What is the process by which metastases occurs

A

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

37
Q

What must tumour cells do to invade surrounding tissue

A

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)

38
Q

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

A
  • 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)
39
Q

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

A

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

40
Q

How do cancer cells avoid immune destruction

A

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

41
Q

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

A
  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)
42
Q

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

A

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

43
Q

What does microsatellite instability mean

A

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

44
Q

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

A

chronic inflammation of cancer causing release of chemokines/cytokines

45
Q

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

A
  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
46
Q

What is FAP

A

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
47
Q

What is Lynch syndrome

A

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

TIN (14 decks)

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