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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
What does green fluorescence indicate in the FUCCI system?
Cells in S/G2/M
26
How does the cell cycle stage impact cell fate? (2)
- Cells in early G1 differentiate into endoderm and mesoderm but not neuroectoderm - Cells in late G1 differentiate into neuroectoderm but not endoderm or mesoderm
27
What do cells in early G1 differentiate into?
Endoderm/mesoderm
28
What do cells in late G1 differentiate into?
Neuroectoderm
29
How does the cell cycle stage impact metastasis? (2)
- Cells in G1 are the most invasive as they express a protease which degrades ECM - G1 cells migrate first and other cells follow
30
Why might a drug that blocks the cell cycle be dangerous?
Cells in G1 may be more invasive so blocking cells in G1 would stop tumour growth but would promote metastasis
31
What are CDKs? (3)
- Cyclin-dependent kinases - Kinases which drive the progression of the cell cycle - Require cyclin binding to be active
32
What are cyclins?
Accessory proteins which form complexes with CDKs to drive the progression of the cell cycle
33
How do cyclin/CDK complexes control the cell cycle? (2)
- 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
How is CDK activity regulated? (4)
- 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
How is the cyclin/CDK complex removed when it is no longer needed? (2)
- Cyclin is phosphorylated and ubiquitinated - Causes degradation of cyclin
36
Which cyclin/CDK complex is expressed in G1?
Cyclin D + CDK 4/6
37
Which cyclin/CDK complex is expressed in late G1?
Cyclin E + CDK2
38
When is the R point?
Late G1
39
What is the R point? (2)
- 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
Which cyclin/CDK complex is expressed in S phase?
Cyclin A + CDK2
41
Which cyclin/CDK complex is expressed in S/G2 phase?
Cyclin A + CDC2
42
Which cyclin/CDK complex is expressed in M phase?
Cyclin B + CDC2
43
Why can the cell cycle only progress in one direction?
Cyclins are ubiquitinated and degraded as the cell progresses through the cycle so the cycle can't go backwards
44
What is a CKI?
CDK inhibitor
45
What are the 2 families of CKIs?
- INK4 - CIP and KIP
46
Which cyclin/CDK complexes are present around the R point? (2)
- Before: cyclin D + CDK 4/6 - After: cyclin E + CDK 2
47
What is the role of cyclin D1? (2)
- Controlled by extracellular signals: growth factors and integrin-mediated ECM anchorage - Checks if the environment is good for proliferation
48
How do mutations affect cyclin D1 in cancer? (3)
- Constitutive nuclear localisation - Impaired degradation - Activation of oncogenes causes overexpression of cyclin D1
49
How do oncogenes drive tumour formation?
Cause overexpression of cyclin D1
50
What does overexpression of cyclin D1 cause in cancer cells? (3)
- Increased cell proliferation - Increased anchorage-independent growth - Chemotherapy resistance
51
What is shRNA? (2)
- An RNA sequence which binds to a target mRNA and causes degradation - Causes reduced expression of the target protein
52
What happens to cancer cells when you reduce cyclin D1 expression? (3)
- Tumour grows slower - Induction of apoptosis - Not tumour regression
53
What is overexpression of cyclin D1 associated with in gastric cancer? (3)
- Poor prognosis - Lower overall survival - Increased invasion and metastasis
54
Which cyclins are associated with cancer? (2)
- D1 - E1
55
What is cyclin E + CDK2 complex required for?
Transition from G1 to S phase
56
How does High Grade Serum Ovarian Carcinoma (HGSOC) originate and progress? (4)
- 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
What does overexpression of cyclin E1 cause in ovarian cancer cells? (3)
- Promotes rapid cell growth - Promotes clonogenic growth - Promotes loss of contact inhibition
58
What is overexpression of cyclin E1 associated with in HGSOC? (2)
- Poor patient survival - Overexpression occurs in early lesions so cyclin E1 is involved in early HGSOC development
59
How is cyclin E involved in breast cancer? (3)
- 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
What is the cleaved form of cyclin E associated with in breast cancer?
Patient's positive for cleaved cyclin E had a worse prognosis in multiple breast cancer subtypes
61
What is the role of TGFβ signalling in normal cells?
Prevents progression through the cell cycle
62
What is the role of TGFβ signalling in cancer cells? (2)
- Early stages: blocks proliferation like in normal cells - Later stages: promotes invasion and metastasis
63
What is TGFβ?
Transforming Growth Factor β
64
How does TGFβ signalling work? (5)
- 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
What are R-SMADs? (2)
- Receptor-regulated SMADs - SMAD2/3
66
How does TGFβ signalling inhibit cell proliferation? (4)
- 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
How do mitogens influence TGFβ signalling in normal cells? (4)
- 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
What is the effect of Akt/PKB signalling on the cell cycle?
Drives the progression of the cell cycle by reducing nuclear localisation of CKIs
69
What is associated with nuclear localisation of p27-Kip1 in cancer patients?
Better prognosis
70
True or false: G0 can be reversible or irreversible
True
71
True or false: TGFβ promotes cell cycle progression
False
72
True or false: stem cells in early G1 differentiate into endoderm/mesoderm
True
73
True or false: cyclin D expression is downregulated in cancer
False
74
True or false: cells in G2 have increased invasiveness
False
75
True or false: TGFβ promotes invasion and metastasis
True
76
True or false: cytosolic p27 localisation correlates with poor prognosis
True
77
True or false: immunofluorescence can be used to study mitosis
True
78
How do TGFβ and mitogen signalling differ?
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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