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M1 Cancer > Cancer Biology > Flashcards

Cancer Biology Flashcards

1
Q

What are the 10 hallmarks of cancer?

A

1) Growth signal autonomy
2) Insensitivity to growth inhibitory signals
3) Resisting apoptotic cell death
4) Unlimited replication potential
5) Angiogenesis
6) Invasion and metastasis
7) Avoiding immune destruction
8) Reprogramming energy metabolism
9) Genomic instability
10) Promoting inflammation

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2
Q

What are the types of mutation that can cause Cancer?

A

Types:
1) Activating -> Proto-oncogenes -> growth signal autonomy
2) Inactivating -> tumour supressor genes -> insensitivity to growth inhibitory signals
3) Genes regulating apoptosis
4) Genes regulating DNA repair
5) Genes conferring growth advantages (eg. angiogenesis, invasiveness)
6) Genes maintain genomic stability

These can be (I) somatic (ii) germline mutations

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3
Q

What are 5 Proto-oncogene activating mutations that lead to growth signal autonomy?

A

1) Growth factor mutation (eg. PDGF activation)

2) Growth factor receptor mutations (eg. HER2 amplification, EGFR L858R structural change)

3) Cell signalling molecule mutations (eg. RAS mutations, BRAF mutations, PI3K mutations)

4) Transcription factor mutations (eg. MYC upregulation)

5) Cell cycle component mutations (eg. cyclin/CDK mutations)

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4
Q

What is the #1 abnormality in proto-oncogenes in humans?

A

RAS mutations (stuck in ATP-bound active state)

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5
Q

How is HER2 screening done?

A

IHC. (protein exp.), FISH (gene amplification)

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6
Q

What is the form of therapy used in HER2+ breast cancers?

A

Targeted therapy: Trastuzumab (anti-HER2 mAb)

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7
Q

How do EGFR mutations cause cancer?

A

Mutations to the tyrosine kinase to be constitutively active (growth receptor signalling independent of ligand binding)

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8
Q

What therapy can be used in L858R+ EGFR lung adenocarcinoma?

A

EGFR TKIs (eg. Ertotinib, Gefitinib, Afatinib)

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9
Q

Which cell signalling pathway is affected in RAS, BRAF, and PI3K mutations?

A

MAPK pathway

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10
Q

What do mutations in MYC genes do?

A

MYC -> master transcription factor of cell growth (activates)
Upregulations of MYC genes cause growth signal autonomy leading to many cancers (eg. Burkitt’s lymphoma, Neuroblastoma)

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11
Q

What cancer is associated with a histological “Starry Sky” appearance?

A

Burkitt’s Lymphoma

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12
Q

What form of cyclin is commonly mutated in Mantle Cell Lymphoma?

A

CCND1 (Cyclin D)

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13
Q

What are the common activating cell cycle component mutations?

A

CCND1 (Cyclin D) amplification/translocations (Mantle cell lymphoma)
CDK4 amplification/point mutations (Glioblastoma)

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14
Q

What are the pre-requisites for Tumour Suppressor gene inactivating mutations to precipitate as cancer-causing?

A

Both alleles of TS proteins must be inactivate to have an effect @ the cellular level (TS proteins act in a autosomal recessive manner)

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15
Q

What are the 2 main targets for growth suppression evasion?

A

Retinoblastoma
Tp53

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16
Q

How do retinoblastoma regulate the cell cycle physiologically?

A

Prevents progression from G1 to S phase unless phosphorylated by cyclin D - CDK4/6 complex

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17
Q

How can the physiological control of the cell cycle by Retinoblastoma be compromised?

A

1) loss of f(x) mutations in both RB alleles
2) gain of f(x) mutations that upregulate cyclin D-CDK4/6 activity

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18
Q

What are 4 upstream activators p53?

A

1) DNA dmg
2) Aberrant growth signals
3) Oncogene activation
4) Cell stress (eg. Hypoxia, Nucleotide depletion)

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19
Q

What are 4 downstream effects of p53?

A

1) Inhibiting angiogenesis
2) Initiating apoptosis
3) DNA repair
4) Cell cycle arrest/senescence

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20
Q

What syndrome is associated with a biallelic loss of f(x) in Tp53?

A

Li-Fraumeni syndrome

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21
Q

How is apoptosis executed?

A

1) Intrinsic/extrinsic pathways
2) Activation of proteolytic cascade of caspases
3) Cell destruction

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22
Q

What is an example of an extrinsic pathway initiating apoptosis?

A

Fas-FasL interaction by CD8+ Tc cells

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23
Q

What are the 6 mechanisms to evade apoptosis?

A

1) p53 -> loss of f(x) of pro-apoptotic factors (eg. BAX)
2) Reduced egress of cytochrome from mitochondria
3) Loss of APAF1 (apoptotic peptidase activating factor 1)
4) Upregulation of IAP (inhibitors of apoptosis
5) Reduced CD95
6) Inactivation of (i) death-induced signalling complex, (ii) FAS-associated via death domain (FADD)

24
Q

What gene mutation and cancer is associated with resisting apoptotic cell death?

A

Follicular Lymphoma
BCL2 translocation -> over-activation of anti-apoptotic BCL2

25
Q

How do cancerous cell attain unlimited replicative potential?

A

Reactivation of telomerases

26
Q

Are telomerases present in normal adult somatic cells?

A

No

27
Q

How does angiogenesis benefit cancer?

A

1) provides nutrients for continued growth
2) promotes metastasis by granting access to vasculature

28
Q

What are 2 anti-angiogenic factors?

A

1) p53
2) thrombospondin 1 (TSP1)

29
Q

What are 5 pro-angiogenic factors?

A

1) Vascular endothelial GF
2)Fibroblast GF
3) Hepatocyte-derived GF
4) Epidermal GF
5) Platelet-derived GF

30
Q

What are 2 ways VEGF can be upregulated?

A

1) Oncogenes. (eg. RAS, MYC, MAPK mutations)
2) Hypoxia -> stabilise HIF1a (O2 sensitive transcription factor)

31
Q

Is there targeted therapy for cancers caused by VEGF mutations/upregulation?

A

Yes. Bevacizumab (anti-VEGF mAb)

32
Q

What are the 9 steps of the invasion metastasis cascade?

A

1) E-cadherin activation
2) Loosening of tumour cells
3) Cancer cells breach basement membrane
4) Epithelial-Mesenchymal Transition(cancer cells traverse interstitial connective tissue)
5) Secretion of proteolytic enzymes
6) Penetration of vascular basement membrane
7) Circulation as emboli/single cells
8) Extravasation @ distant sites
9) Angiogenesis

33
Q

How are tumour cells usually recognised by the immune system?

A

Tumour Ags presented by MHC 1 & recognised by CD8+ CTLs

34
Q

How do cancer cells evade immune detection/destruction?

A

1) loss of tumour-specific Ags
2) loss of histocompatibility Ags
3) secretion of T cell inhibitory cytokines (eg. TGF-beta)
4) exp. of inhibitory cell surface proteins (PD-L1)

35
Q

How can cancers avoiding immune detection be treated?

A

Immune checkpoint targeted therapy (eg. anti-PD1/PD-L1 mabs)

36
Q

What kind of energy metabolism reprogramming do cancer cells undergo?

A

Primarily utilise lactic acid fermentation even w sufficient O2 and functional mitochondria

37
Q

What is the “Warburg effect”?

A

Increased glucose uptake and fermentation of glucose to lactate in the presence of O2 and functional mitochondria by cancer cells

38
Q

Why do cancer cells reprogram their energy metabolism?

A

For the diversion of glycolytic intermediates to biosynthetic pathways to synthesis macromolecules and organelles needed for rapid cell growth
—> outcompete other cells w/o altered metabolism

39
Q

What are 2 ways genomic instability can occur?

A

1) Breakdown of surveillance mechanism (loss of p53)
2) Breakdown of DNA repair mechanisms (DNA MMR deficiency)

40
Q

What is the process of DNA repair by MMR proteins?

A

1) Mismatch recognitions
2) Strand choice
3) Excision
4) Resynthesis

41
Q

What are the pairs of MMR proteins?

A

1) MSH 2 and 6
2) MLH 1 and PMS 2

42
Q

How can MMR deficiencies lead to cancer?

A

Germline mutations in 1/4 MMR genes
- Hypermutation of MLH1 gene promoter —> monoallelic loss of MLH protein exp.

+ 2nd hit -> total loss of MMR f(x)

Leads to high levels of microsatellite instability —> ^rate of mutation -> ^genetic hits (eg. TS genes, proto-oncogenes) -> ^malignancy

43
Q

What cancer is associated with loss of MMR protein function?

A

Hereditary nonpolyposis cancer syndrome (HNPCC)

44
Q

What are the 3 clinically significant characteristics of dMMR+ tumours?

A

1) high tumour mutational load -> tumour neoAg
2) active anti-tumoural immune response + ^exp. of checkpoint proteins
3) Gd response to PD-1 based immune checkpoint inhibitory immunotherapy

45
Q

What can hypermethylation of MMR gene promoters do?

A

lead to MMR deficiency and microsatellite instability (MSH-I) phenotype

46
Q

What is the paradoxical hallmark of cancer that enhances tumourigenesis and progression?

A

Promoting Inflammation

47
Q

Why would inflammation be good for a tumour?

A

It can supply
1) Growth factors
2) Pro-angiogenic factors
3) ECM-modifying enzymes
4) Mutagenic ROS
to the tumour microenvironment

48
Q

What is p53?

A

It is a transcription factor

49
Q

What is MYC?

A

The master transcription factor of cell growth. Mutations associated with Burkitt’s Lymphoma

50
Q

Is BCL2 anti-apoptotic or pro-apopototic?

A

Anti-apoptotic

51
Q

What do telomerases do?

A

Maintain the length of telomeres to confer replicative immortality

52
Q

How does p53 inhibit angiogenesis?

A

By downregulating Thrombospondin 1 (TSP 1)

53
Q

What gene translocation is associated with Burkitt’s Lymphoma?

A

t(8,14)

54
Q

What gene translocation is associated with mantle cell lymphoma?

A

t(11,14)

55
Q

What gene translocation is associated with Follicular B cell Lymphoma

A

t(14, 18)

M1 Cancer (4 decks)

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