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L2 Stem Cells > Cell cycle deregulation in cancer > Flashcards

Cell cycle deregulation in cancer Flashcards

1
Q

What are the 6 hallmarks of cancer cells?

A
  • Autonomous growth
  • Ignore cytostatic signals
  • Ignore apoptotic signals
  • Stimulate angiogenesis
  • Invade and metastasise
  • Immortality
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2
Q

What is angiogenesis?

A

Formation of new blood vessels

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3
Q

What controls normal cell proliferation?

A

Growth factors (GFs)

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4
Q

What are mitogens? (2)

A
  • Growth factors
  • Induce proliferation
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5
Q

How do cancer cells proliferate more than normal? (5)

A
  • Produce growth factors by themselves
  • Signal to nearby cells to produce growth factors
  • Deregulation in growth factor receptor signalling
  • Constitutive activation of signalling downstream from growth factor receptors
  • Disruption of negative feedback that prevents proliferative signalling
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6
Q

How can deregulation of growth factor receptor signalling cause uncontrolled cancer cell proliferation? (2)

A
  • Elevated levels of receptors
  • Ligand-independent firing (constitutive activation)
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7
Q

What is G0? (2)

A
  • Quiescence
  • Can be permanent or transient
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8
Q

What are the stages of the cell cycle? (5)

A
  • G0
  • G1
  • S
  • G2
  • Mitosis
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9
Q

What is the restriction (R) point? (2)

A
  • A window in G1 up to a couple of hours before the transition into S phase where the cell decides whether to progress through the cell cycle or revert to G0 based on extracellular signals
  • Often deregulated in cancer cells
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10
Q

How can the cell cycle be studied? (3)

A
  • Flow cytometry
  • Immunofluorescence
  • FUCCI
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11
Q

What is flow cytometry?

A

Analysis of the cell cycle based on measuring the DNA content

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12
Q

How can immunofluorescence be used to study the cell cycle?

A

Stain for proteins that are specifically expressed in different phases of the cell cycle

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13
Q

What is BrdU? (3)

A
  • Bromo-2deoxyuridine
  • Replaces thymidine during DNA synthesis
  • Used to identify cells in S phase
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14
Q

Which marker is used to identify cells in S phase?

A

BrdU

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15
Q

Which marker is used to identify cells in G2/M?

A

Cyclin B1

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16
Q

Which marker is used to identify cells undergoing mitosis?

A

Histone H3

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17
Q

What is histone H3? (2)

A
  • Phosphorylated during chromosome condensation
  • Used to identify cells undergoing mitosis
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18
Q

What is the disadvantage of flow cytometry and immunofluorescence?

A

Can’t be used in vivo because cells need to be fixed

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19
Q

What is FUCCI?

A

Fluorescence Ubiquitin Cell Cycle Indicator

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20
Q

How does FUCCI work? (3)

A
  • Cdt1 is marked with red fluorescence and is expressed during G1 (low expression to start then increases)
  • Geminin is marked with green fluorescence and is expressed during S and G2
  • Allows you to observe the dynamics of the cell cycle in living cells
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21
Q

What is the FUCCI transgenic mouse? (2)

A
  • Mouse expressing the red G1 marker was crossed with a mouse expressing the green S/G2/M marker
  • Results in a mouse where every somatic cell expressed red or green
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22
Q

What does no/low red fluorescence indicate in the FUCCI system?

A

Cells in early G1

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23
Q

What does strong red fluorescence indicate in the FUCCI system?

A

Cells in late G1

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24
Q

What does yellow/orange fluorescence indicate in the FUCCI system?

A

Cells in G1/S transition (red and green fluorescence)

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25
Q

What does green fluorescence indicate in the FUCCI system?

A

Cells in S/G2/M

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26
Q

How does the cell cycle stage impact cell fate? (2)

A
  • Cells in early G1 differentiate into endoderm and mesoderm but not neuroectoderm
  • Cells in late G1 differentiate into neuroectoderm but not endoderm or mesoderm
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27
Q

What do cells in early G1 differentiate into?

A

Endoderm/mesoderm

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28
Q

What do cells in late G1 differentiate into?

A

Neuroectoderm

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29
Q

How does the cell cycle stage impact metastasis? (2)

A
  • Cells in G1 are the most invasive as they express a protease which degrades ECM
  • G1 cells migrate first and other cells follow
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30
Q

Why might a drug that blocks the cell cycle be dangerous?

A

Cells in G1 may be more invasive so blocking cells in G1 would stop tumour growth but would promote metastasis

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31
Q

What are CDKs? (3)

A
  • Cyclin-dependent kinases
  • Kinases which drive the progression of the cell cycle
  • Require cyclin binding to be active
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32
Q

What are cyclins?

A

Accessory proteins which form complexes with CDKs to drive the progression of the cell cycle

33
Q

How do cyclin/CDK complexes control the cell cycle? (2)

A
  • Cyclin binds to CDK to form a complex which activates the CDK
  • CDK can then phosphorylate downstream targets which make the cell cycle progress
34
Q

How is CDK activity regulated? (4)

A
  • Cyclins activate the catalytic activity of the CDK
  • Cyclin binding increases substrate recognition of the cyclin/CDK complex
  • Phosphorylation of the ATP-binding domain of the CDK causes inactivation
  • Binding of CKIs cause inactivation
35
Q

How is the cyclin/CDK complex removed when it is no longer needed? (2)

A
  • Cyclin is phosphorylated and ubiquitinated
  • Causes degradation of cyclin
36
Q

Which cyclin/CDK complex is expressed in G1?

A

Cyclin D + CDK 4/6

37
Q

Which cyclin/CDK complex is expressed in late G1?

A

Cyclin E + CDK2

38
Q

When is the R point?

A

Late G1

39
Q

What is the R point? (2)

A
  • The point where the cell decides to progress through the cell cycle or revert to G0
  • The cell no longer requires growth factors to enter into the cell cycle
40
Q

Which cyclin/CDK complex is expressed in S phase?

A

Cyclin A + CDK2

41
Q

Which cyclin/CDK complex is expressed in S/G2 phase?

A

Cyclin A + CDC2

42
Q

Which cyclin/CDK complex is expressed in M phase?

A

Cyclin B + CDC2

43
Q

Why can the cell cycle only progress in one direction?

A

Cyclins are ubiquitinated and degraded as the cell progresses through the cycle so the cycle can’t go backwards

44
Q

What is a CKI?

A

CDK inhibitor

45
Q

What are the 2 families of CKIs?

A
  • INK4
  • CIP and KIP
46
Q

Which cyclin/CDK complexes are present around the R point? (2)

A
  • Before: cyclin D + CDK 4/6
  • After: cyclin E + CDK 2
47
Q

What is the role of cyclin D1? (2)

A
  • Controlled by extracellular signals: growth factors and integrin-mediated ECM anchorage
  • Checks if the environment is good for proliferation
48
Q

How do mutations affect cyclin D1 in cancer? (3)

A
  • Constitutive nuclear localisation
  • Impaired degradation
  • Activation of oncogenes causes overexpression of cyclin D1
49
Q

How do oncogenes drive tumour formation?

A

Cause overexpression of cyclin D1

50
Q

What does overexpression of cyclin D1 cause in cancer cells? (3)

A
  • Increased cell proliferation
  • Increased anchorage-independent growth
  • Chemotherapy resistance
51
Q

What is shRNA? (2)

A
  • An RNA sequence which binds to a target mRNA and causes degradation
  • Causes reduced expression of the target protein
52
Q

What happens to cancer cells when you reduce cyclin D1 expression? (3)

A
  • Tumour grows slower
  • Induction of apoptosis
  • Not tumour regression
53
Q

What is overexpression of cyclin D1 associated with in gastric cancer? (3)

A
  • Poor prognosis
  • Lower overall survival
  • Increased invasion and metastasis
54
Q

Which cyclins are associated with cancer? (2)

A
  • D1
  • E1
55
Q

What is cyclin E + CDK2 complex required for?

A

Transition from G1 to S phase

56
Q

How does High Grade Serum Ovarian Carcinoma (HGSOC) originate and progress? (4)

A
  • Cancer originates in the fallopian tube epithelium (FTE)
  • Mutations in p53 occur in early lesions
  • Cancer cells migrate, reach the ovary and form the primary tumour
  • Cells detach and metastasise
57
Q

What does overexpression of cyclin E1 cause in ovarian cancer cells? (3)

A
  • Promotes rapid cell growth
  • Promotes clonogenic growth
  • Promotes loss of contact inhibition
58
Q

What is overexpression of cyclin E1 associated with in HGSOC? (2)

A
  • Poor patient survival
  • Overexpression occurs in early lesions so cyclin E1 is involved in early HGSOC development
59
Q

How is cyclin E involved in breast cancer? (3)

A
  • Cyclin E is cleaved into a low molecular weight cyclin E which is more stable and has a higher affinity for CDK2
  • Causes cell cycle deregulation and chemotherapy resistance
  • Cleaved form is only seen in cancer
60
Q

What is the cleaved form of cyclin E associated with in breast cancer?

A

Patient’s positive for cleaved cyclin E had a worse prognosis in multiple breast cancer subtypes

61
Q

What is the role of TGFβ signalling in normal cells?

A

Prevents progression through the cell cycle

62
Q

What is the role of TGFβ signalling in cancer cells? (2)

A
  • Early stages: blocks proliferation like in normal cells
  • Later stages: promotes invasion and metastasis
63
Q

What is TGFβ?

A

Transforming Growth Factor β

64
Q

How does TGFβ signalling work? (5)

A
  • TGFβ binds to a type II receptor which recruits and phosphorylates a type I receptor
  • Type I receptor phosphorylates SMAD2/3 (R-SMADs)
  • SMAD2/3 bind SMAD4 and form a complex
  • R-SMAD/SMAD4 complexes accumulate in the nucleus and act as transcription factors
  • Acts on tumour suppressor genes and tumour promoting genes
65
Q

What are R-SMADs? (2)

A
  • Receptor-regulated SMADs
  • SMAD2/3
66
Q

How does TGFβ signalling inhibit cell proliferation? (4)

A
  • SMAD complex promotes transcription of p15-INK4B which is a CKI
  • Causes inhibition of cyclin D-CDK4/6 complexes so cells can’t reach R point
  • Also weakly activates p21-Cip1 (CKI) which inhibits all other CDK complexes
  • p27 strongly activated in response to DNA damage in order to stop the cell cycle until damage is repaired
67
Q

How do mitogens influence TGFβ signalling in normal cells? (4)

A
  • Mitogens bind and activate P13K which activates the Akt/PKB pathway
  • Akt phosphorylates p21-Cip1 which causes translocation into the cytoplasm
  • Akt phosphorylates p27-Kip1 in the cytosol and prevents nuclear translocation
  • Gets rid of CKIs and drives cell cycle progression
68
Q

What is the effect of Akt/PKB signalling on the cell cycle?

A

Drives the progression of the cell cycle by reducing nuclear localisation of CKIs

69
Q

What is associated with nuclear localisation of p27-Kip1 in cancer patients?

A

Better prognosis

70
Q

True or false: G0 can be reversible or irreversible

A

True

71
Q

True or false: TGFβ promotes cell cycle progression

A

False

72
Q

True or false: stem cells in early G1 differentiate into endoderm/mesoderm

A

True

73
Q

True or false: cyclin D expression is downregulated in cancer

A

False

74
Q

True or false: cells in G2 have increased invasiveness

A

False

75
Q

True or false: TGFβ promotes invasion and metastasis

A

True

76
Q

True or false: cytosolic p27 localisation correlates with poor prognosis

A

True

77
Q

True or false: immunofluorescence can be used to study mitosis

A

True

78
Q

How do TGFβ and mitogen signalling differ?

A

TGFβ inhibits cell cycle progression by inducing CKIs but mitogens promote cell cycle progression by inhibiting CKIs

L2 Stem Cells (12 decks)

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