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Stem cells, Ageing and Cancer > Cell cycle deregulation in cancer > Flashcards

Cell cycle deregulation in cancer Flashcards

1
Q

what are the 6 essential hallmarks required for cancer to become malignant?

A
  1. ability to grow autonomously (without growth signals/factors)
  2. disregard cytostatic signals
  3. ignore apoptotic signals
  4. stimulate angiogenesis
  5. invade and metastasise
  6. become immortal - can keep dividing
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2
Q

what controls cell proliferation?

A

growth factors

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3
Q

what are growth factors (GFs)?

A

GFs are relatively small proteins released by some cells, which travel through intercellular space and convey messages to other cells
- they are mitogens = ability to induce cell proliferation

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4
Q

what happens if normal cells are in the presence or absence of GFs?

A

presence: the cells divide

absence: the cells remain quiescent and do not divide

almost all normal cells require signals to grow and divide

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5
Q

what happens if cancer cells are in the presence or absence of GFs?

A

cancer cells proliferate no matter the presence of absence of GFs
- cancer cells do not need GFs to proliferate, they do this autonomously

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6
Q

what is growth vs quiescence?

A

the growth vs quiescence decision determines whether cells proliferate and divide or stay in a resting state
- The decision of growth v/s quiescence must be taken in consultation with neighbouring cells within the tissue

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7
Q

what determines the growth vs quiescence decision?

A

growth factors

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8
Q

what normal cells are an exception to growth signals being needed for proliferation?

A

embryonic stem cells: mouse ES cells grown in vitro appear able to drive their own proliferation through internally generated signals
- Only example of WT cells able to generate a benign tumour (teratoma) when injected in an adult organism = tumorigenic

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9
Q

why are external growth signals required for proliferation?

A
  • To maintain the precise structure of the tissue in which the cells are located
  • So that cell proliferation occurs across the tissue, not just individual cells, in order to maintain organ function
  • If not controlled – organ function compromised
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10
Q

what leads to the sustained proliferative signalling of cancer cells?

A
  • the cell cycle machinery is influenced by cancer-associated proteins (oncogenes and tumour suppressors) which disrupt normal control mechanisms
  • sustained proliferative signalling
  • cancer cells don’t need presence of GFs to grow
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11
Q

how do growth hormones work in normal cells?

A

growth hormone leads to signalling cascade, leading to proteins being translated to trigger growth

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12
Q

in what ways may cancer cells induce uncontrolled cancer proliferation?

A
  1. Cancer cells may produce growth factors by themselves  autocrine proliferative stimulation
  2. Cancer cells send signals to stimulate surrounding normal cells to produce growth factors – increase tumour size
  3. Cancer deregulation of growth factor receptor signalling  elevated level of receptors or ligand-independent firing
  4. Constitutive activation of signalling DOWNSTREAM of growth factor receptors
    - Increase activity of signalling cascade
  5. Disruption of negative feedback mechanisms that attenuate proliferative signalling
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13
Q

what causes uncontrolled cell proliferation?

A

the deregulation of the cell cycle

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14
Q

what are the 5 phases of the cell cycle?

A
  1. G0/quiescent - cells do not proliferate
  2. gap-1 (G1) - cells either decide to stay in G0 or progress to S-phase
  3. S-phase - DNA is replicated
  4. gap-2 (G2) - preparation for mitosis
  5. mitosis
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15
Q

what cells can be in G0/quiescence phase?

A

terminally differentiated cells are in a permanent quiescent state

other cells are transiently in a quiescent state and can re-enter the cell cycle

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16
Q

what is the longest phase of the cell cycle?

A

G1 - main point where cells decide to stay in G0 or continue onto cell cycle

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17
Q

what occurs during mitosis?

A

duplicated DNA is equally divided into 2 daughter cells, and cytokinesis splits their cytoplasms to form 2 individual daughter cells

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18
Q

what is the growth vs quiescence decision?

A
  • There is a discrete window to consult the extracellular environment: from the onset of G1 phase to an hour or 2 before the G1-to-S transition.
  • G1 decision-making machinery apparent in the responses of cultured cells to extracellular signals
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19
Q

when does the growth vs quiescence decision occur?

A

toward the end of G1

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20
Q

what occurs during the growth vs quiescence decision?

A
  1. Serum and growth factors removed before the cells have completed 80-90% of G1 -> cell fail to proceed further and revert to G0 state
  2. Serum and growth factors removed in the final hr of G1 -> G1 completed, so proceed to S, G2 and M phase

Cells can only respond to the signals in their environment called a certain point - This is called the restriction point (R point)

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21
Q

what is the restriction point (R point)?

A
  • A weighty decision must be made towards the end of G1: here a cell must make up its mind whether it will go to S, remain in G1 or go to G0 (retreating from active cycle) -> made at a transition called R point
  • If a cell should decide at the R point to continue advancing through the cell cycle, it commits itself to proceed into S and complete a programmed series of event (s, G2 & M) that enable it to divide into 2 daughter cells, even if growth factors are not present any longer
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22
Q

what other factors can influence the growth vs quiescence decision?

A

anti-mitogenic factors such as TGFb are able to impose their growth inhibitory effects only during this period in early and mid-G1

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23
Q

how is the growth vs quiescence decision and R point changed in cancer?

A

In cancer, cell cycle is similar to normal cells (late G1-to-M phases), but the R-point decision-making machinery is changed/deregulated

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24
Q

what methods can be used to study the cell cycle?

A
  1. flow cytometry
  2. immunofluorescence
  3. FUCCI system
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25
Q

what is the process of flow cytometry in studying the cell cycle?

A
  • Cell cycle is analysed by measuring DNA content inside each individual cell
  • Cells are treated with a fluorescent dye that labels DNA quantitatively
  • As the DNA content doubles during the S phase, the intensity of fluorescence increases in proportion.
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26
Q

what does flow cytometry show about the DNA content at different phases of the cell cycle?

A
  • As the DNA content doubles during the S phase, the intensity of fluorescence increases in proportion.
  • Thus, cells in G0 and G1 phase (before S) have half the fluorescent signal as those in G2 or M phase
  • Quiescent cells have small peak for G2-M, but in dividing cells G2-M peak is much higher, as more DNA is present and they are undergoing proliferation
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27
Q

what are the limitations of flow cytometry?

A
  • can only run single cells - cannot analyse whole tissues
  • samples must be fixed, so can only be used in vitro, not in vivo
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28
Q

how can immunofluorescence be used to study the cell cycle?

A
  • The progression through the cell cycle can be measured by staining for proteins that are specifically expressed in different phases of the cell cycle
  • Can use combination of stains to determine where in the cell cycle the cells are
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29
Q

which protein stains correlate to which phase of the cell cycle in immunofluorescence?

A

BrdU = bromo-2-deoxyuridine  replaces thymidine during DNA synthesis -> short pulse identifies cells in S phase

Cyclin B1 = G2/M marker

Histone H3 = role in mitotic chromosome condensation, phosphorylated during mitosis

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30
Q

which cell cycle phases are positive for which protein stain in immunofluorescence?

A
  • Cells in G1 will be negative for all markers
  • Cells in S will be positive for BrdU and negative for rest
  • Cells in G2/M will be positive for cyclin B1 and negative for rest
  • Cells in mitosis will be positive for Histone H3 and negative for rest
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31
Q

what are the limitations of immunofluorescence?

A
  • not quantitative - qualitative image analysis
  • samples must be fixed, so can only be used in vitro, not in vivo
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32
Q

how can mitosis be studied using immunofluorscence?

A
  • Mitosis can be been monitored using immunofluorescence & epifluorescence microscopy
  • Although not quantitative, this method allows the visualisation of the different sub-phases of mitosis.
  • Useful when designing drugs which interfere with mitosis, microtubule poisons and anti-mitotic drugs are in clinical trials for a variety of cancer types
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33
Q

what does the FUCCI analysis of the cell cycle enable?

A

visualisation of the cell cycle in vivo

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34
Q

why is it difficult to analyse proliferation in living organisms?

A

Difficult to analyse proliferation in living organisms because traditional cell cycle markers rely on immunofluorescent detection -> tissue fixation

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35
Q

what does FUCCI stand for?

A

Fluorescence Ubiquitin Cell Cycle Indicator

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36
Q

what are the 2 components of the replication control system of eukaryotes? how are these expressed in FUCCI?

A
  1. Licencing factor Ctd1 (hCTD1) -> peaks in G1 before the onset of DNA replication, and declines abruptly after the initiation of S phase = RED
    - If cells are red they are in G1
  2. CTD1 inhibitor Geminin (hGem) -> expressed at high levels during S and G2 phase, low levels during mitosis and G1 = GREEN
    - If cells are green they are in S and G2
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37
Q

what is dual FUCCI?

A

in zebrafish, both reporters expressed from a single transgene – no need to cross zebrafish

38
Q

how is FUCCI used in a transgenic mouse?

A
  • Mouse expressing hCdt1 crossed with mouse with hGem marker, to produce hCdt1-hGem mouse
  • Every somatic cell nucleus exhibited either red or green fluorescence.
  • E13 FUCCI transgenic embryo were fixed and coronal sections of the brain were prepared.
  • Red and green fluorescence was examined in every section using confocal laser scanning microscopy
  • Red and green expressing cells were identified in the developing cerebral cortex.
  • Bright red cells -> post-mitotic neurons (hCdt1 accumulation after cell cycle exit)
39
Q

what does FUCCI analysis allow?

A

This technology allows for in vivo analysis of spatial and temporal patterns of cell-cycle dynamics, owing to the brightness of the fluorescence and the high contrast between the red and green colour

40
Q

what fluorescence do the different cell stages express in FUCCI analysis?

A

Early G1 = no/low red fluorescence

Late G1 = strong red fluorescence

G1/S = red and green fluorescence (yellow)

S/G2/M = green fluorescence

41
Q

how is the cell cycle linked to stem cell differentiation?

A

The cell cycle state of stem cells determines cell fate propensity
- the phase that the cells are in is important for cell lineage decisions

42
Q

how can the cell cycle and stem cell fate be analysed?

A

Generated FUCCI human embryonic stem cells and used FACS sorting isolate cells at different stages of the cell cycle -> induction of differentiation
- Stimulated the cells with different factors to form one of the 3 germ layers – stem cells will take a certain fate depending on which stage of cell cycle they are in

43
Q

what cell fate is induced when the stem cells are triggered to differentiate in early G1?

A

Early G1 stimulation differentiated to endoderm or mesoderm, cannot differentiate to neuroectoderm

44
Q

what cell fate is induced when the stem cells are triggered to differentiate in late G1?

A

Late G1 stimulation differentiated to neuroectoderm, not endoderm or mesoderm

45
Q

what cell fate is induced when the stem cells are triggered to differentiate in S/G2/M?

A

Cells in S, G2, M did not differentiate into the germ layers

46
Q

what is metastasis?

A

Metastasis = formation of secondary tumours in secondary sites
- Multi-step process, starting with the invasion of cancer cells into surrounding tissues
- Cancer cells in primary tumour acquire ability to invade into surrounding tissues and blood vessels
- ~90% of cancer death are due to metastasis

47
Q

does the cell cycle phase determine invasive ability of a cancer cell?

A

yes :D

48
Q

how can the impact of the cell cycle on cancer metastasis be analysed?

A

Invasive breast cancer cell line expressing the FUCCI reporters:
- Cells grown as 3D organoids embedded in extracellular matrix
- Can monitor if the cancer cells can leave the organoid and migrate into the ECM
- red cells in G1
- green cells in G2

49
Q

which cell cycle phase is linked to cancer invasive ability?

A
  • Cancer cells that can undergo metastasis first are in G1 phase and G2 phase cells behind
  • Red cells always at the front
  • The most invasive cells are the cells G1
50
Q

why are the cells that are in G1 more invasive?

A

Cancer cells in G1 express protein which degrades the ECM, allowing the rest of the cells to then migrate through

51
Q

why is it difficult to both inhibit the proliferation and metastasis of cancer?

A

To stop proliferation of cancer, cells in G1 phase must be blocked
- However, while this will prevent tumour growth, it will enable the cancer cells to become metastatic and spread around the body

52
Q

how is progression through the cell cycle controlled?

A

by cyclin/CDK complexes

53
Q

what are CDKs?

A

cyclin-dependent kinases: kinases deployed by the cell cycle machinery to help the cells progress from one phase to the next

54
Q

what regulates CDKs?

A

accessory proteins called cyclins
- in the absence of cyclins, CDKs are inactive
- if cyclins are present, CDKs are active and can phosphorylate downstream effectors

55
Q

what are cyclin/CDK complexes responsible for?

A
  • CDKs/cyclin complexes are responsible for sending out the signals to the proteins that carry out the work to move the cells through the cell cycle (via phosphorylation)
  • Activity of CDK must only be present under specific phases of cell – ensure correct direction of progression
56
Q

what mechanisms are used to regulate CDK activity?

A
  1. abundance of cyclin subunits
    - cyclins activate the catalytic activity of CDKs by 400,000 fold e.g. cyclin A/CDK2
  2. Cyclin/CDK association - cyclins help substrate recognition of the complex in the cell
    - CDK targets can only bind to CDK if cyclin is present
  3. activating/inhibiting phosphorylation events
    - if one side of of CDK is phosphorylated, it is active
    - if ATP-binding site of CDK is phosphorylated, it is inactive
  4. CKI proteins inhibit CDK: INK4 family and CIP/KIP family
    - when CKI proteins are removed, the ATP binding site is no longer phosphorylated, so CDK can activate
57
Q

how are CDK/cyclin complexes inhibited?

A

when the cyclin is phosphorylated and ubiquitinated

58
Q

what do cyclins ensure the coordination of?

A
  • The synthesis of individual cyclins coordinates the sequential completion of DNA replication and cell division
  • Collapse of cyclin levels as the cell progresses through the cell cycle occurs via degradation (ubiquitination-dependent)
  • Cyclin proteins are removed from cells via degradation to inhibit the complex
  • therefore, the cell cycle can only progress in one direction
59
Q

how do the cyclin/CDK levels vary during the cell cycle?

A
  • Cyclin D/cdk4/6: high levels in G1
  • Cyclin E/CDK2: low levels throughout most of G1, rapid increase after the R point
  • Cyclin A/CDK2: levels increase in concert with the entrance in S phase
  • Cyclin B/CDC2: levels increase in anticipation of mitosis
60
Q

what are CKIs and what are the 2 families of them?

A

CKIs are CDK-inhibitors

2 families:
- INK4
- CIP and KIP

61
Q

What is the role of CKIs?

A

they bind to CDK/cyclin complex and inactivate them to inhibit cell cycle progression

62
Q

which part of the cell cycle is deregulated in cancer?

A

the restriction point

63
Q

which cyclin/CDK complexes are deregulated in cancer?

A
  • Cyclin D with CDK4/6
  • Cyclin E with CDK2
64
Q

what are cyclin Ds?

A
  • D-type cyclins convey messages from the extracellular environment to the cell cycle clock in the nucleus
  • Levels of D do not vary dramatically as the cell advances through the cell cycle
  • Several pathways downstream of GF receptors stimulate accumulation of D.
  • D half-life ~30min
  • Because the levels of D fluctuate together with the levels of extracellular mitogens, D constantly inform the cell cycle clock of current conditions in the environment around the cell
65
Q

how are cyclin Ds regulated?

A
  • D-type cyclins are controlled by extracellular signals: growth factors + integrin-mediated ECM attachment
  • Different growth factors and cytokines converge to promote expression of cyclin D1
  • Integrins also stimulate expression of cyclin D1 to promote cell cycle progression
  • Removal of GFs -> rapid collapse of cyclin D1 levels
66
Q

which cyclin D is the most studied?

A
  • Cyclin D1 is crucial in growth, and is deregulated in cancer
67
Q

how is cyclin D deregulated in cancer?

A
  • Cancer-associated mutations in cyclin D1 results in constitutive nuclear localisation & impaired degradation of cyclin D1
  • Cyclin D1 has been found to be overexpressed in breast, lung cancer, melanoma & oral squamous cell carcinomas
  • Oncogenic activation (e.g. Ras) leads to increased cyclin D1 expression
  • Cyclin D1 KO mice do not form mammary tumours upon oncogene expression - for oncogenes to drive tumour formation, cyclin D1 must be present
68
Q

what does overexpression of cyclin D promote?

A
  • cell proliferation
  • increased anchorage-independent growth (doesn’t need attachment to basement membrane to grow)
  • reduced chemotherapy sensitivity
  • elevated survival in presence of cisplatin (chemotherapy drug)
  • still requires serum to form a tumour
69
Q

what does downregulation of cyclin D promote? what does this show?

A
  • reduction of tumour growth and reduced proliferation
  • induction of apoptosis, due to G1 arrest in absence of cyclin D

shows that cyclin D is essential for the growth of cancer cells
- for tumour formation to occur, cyclin D must be present

70
Q

does inhibition of cyclin D by shRNA lentiviruses cause regression?

A

Targeting cyclin D1 could be good to limit tumour growth when you already have a tumour (not regression, tumour is just growing less)

71
Q

what is a Kaplan Meir survival curve?

A

non-parametric statistical method used to estimate survival function correlating to the level of a protein
- Each downward step in the lines represents an event (e.g. death) experienced by a patient in the corresponding group

72
Q

what does overexpression of cyclin D correlate with?

A

lower overall survival in gastric cancer patients:
- High level of D1 leads to lower survival of patient (low cyclin D1 leads to higher survival)
- Cyclin D1 is overexpressed in poorly differentiated gastric tumour -> poor prognosis
- Cyclin D1 overexpression is associated with increased invasion and metastasis
- Cyclin D1 can have a prognostic role in gastric cancers

73
Q

what is the role of cyclin E in the cell cycle?

A

After the R point, E-type cyclins (E1 and E2) associate with CDK2  phosphorylation of substrates required for entry in S phase

74
Q

how is cyclin E deregulated in cancer?

A
  • Cyclin E gene amplification was observed in 15 different tumour types, leading to cyclin E overexpression
  • E1 is overexpressed in 40% of ovarian high-grade serum carcinomas (HGSCs), as a result of gene amplification in half of the cases  cell cycle progression & resistance to therapy
75
Q

how does High Grade Serum Ovarian Carcinoma progress?

A
  • High Grade Serum Ovarian Carcinoma (HSOC) originates in the fallopian tube epithelium (FTE)
  • P53 mutations occur in the early stages of tumorigenesis, leading to cellular metastasis
  • Primary tumour is formed in the ovary, and can then form secondary tumours in peritoneum
  • STIC = non-invasive tumour, characterised by high proliferating ability
76
Q

what does overexpression of cyclin E promote?

A
  • Cyclin E1 overexpression in vitro strongly promotes cell growth of primary tumour cells
  • Cyclin E1 overexpression promotes clonogenic growth and loss of contact inhibition
  • Cyclin E1 has an oncogenic role in ovarian carcinoma
  • Cells overexpress mutant p53 as well
  • CCNE1 (cyclin E gene) overexpression drives phosphorylation of CDK2 = CDK activation
77
Q

what does cyclin E overexpression correlate with?

A

Patients with Cyclin E1 overexpression correlates with poor ovarian cancer survival (HGSOC)
- Cyclin E1 amplifications are associated with increased mRNA expression
- Protein overexpression are associate with poor survival of ovarian cancer patients
- Cyclin E overexpression occurs in early cancer lesions -> specifically involved in HGSOC development

78
Q

what is produced when cyclin E is cleaved?

A

Cleavage of cyclin E results in the expression of low molecular weight cyclin E -? stable protein, higher affinity for CDK2

79
Q

what does cyclin E cleavage correlate with in breast cancer?

A

Cyclin E cleavage correlates with poor prognosis in breast cancer
- Cleaved form of cyclin E1 was only observed in cancer leading to cell cycle deregulation & resistance to therapy
- Cleaved cyclin E may be a good protein to target cancer
- Cohort of 515 UK breast cancer patients: patients positive for low molecular weight cyclin E showed worse prognosis in all breast cancer subtypes analysed

80
Q

what kind of extracellular signals promote cell proliferation?

A

growth factors/mitogens

81
Q

what kind of extracellular signals inhibit cell proliferation and cell cycle progression?

A

Transforming growth factor-beta (TGF-beta) inhibits cell proliferation and cell cycle progression in normal cells

82
Q

how is TGFb signalling implicated in cancer?

A

Early stages of tumour formation: TGFb arrests the growth of many cell types and blocks cell progression

Later stages of tumour progression: TGF-beta contributes to tumour invasiveness

83
Q

what is TGF beta signalling pathway involved in?

A

TGFb signalling pathway is involved in many cellular processes (cell growth, cell differention, apoptosis & cellular homeostasis)

84
Q

what i the process of TGFb signalling?

A
  1. TGFb superfamily ligands bind to a type II receptor, which recruits and phosphorylates a type I receptor.
  2. The type I receptor then phosphorylates receptor-regulated SMAD2/3 (R-SMADs) which can now bind SMAD4 (common SMAD or coSMAD).
  3. R-SMAD/SMAD4 complexes translocate and accumulate in the nucleus where they act as transcription factors
  4. Smad phosphorylation unmasks a nuclear localisation signal -> nuclear translocation of the SMAD complex
  5. Interaction of Smad with transcriptional co-activators and repressors
  6. SMAD7 = inhibitory SMAD, interacts with TGFbR1 to inhibit SMAD binding & promoted TGFbR ubiquitination & degradation
85
Q

how does TGFb control cell cycle progression?

A

TGFb strongly increases the levels of p15-INK4B (CKI), leading inhibition of cyclin D-CDK4/6 complexes, so cells can’t reach the R point

Activation of TGFb signalling causes weak induction of p21-Cip1 (CKI).
-Stronger induction of P21-CIP upon DNA damage, causing cell cycle to be halted until the genome is repaired
- This ensures a cell does not progress into S-phase & copy damaged DNA

86
Q

how do mitogenic factors promote cell cycle progression?

A

Mitogenic factors mute the action of CKI to favour cell cycle advance:
- Akt phosphorylates p21-Cip1 in the nucleus, leading to translocation of P21 out of nucleus and into the cytoplasm
- Akt phosphorylates p27-Kip1 in the cytosol and prevents P21 nuclear translocation
- therefore, cyclin/CDK complexes are no longer inhibited by CKIs in the nucleus, so can remain active and promote cell cycle progression

87
Q

how do mitogens and TGFb compare in controlling cell cycle progression?

A

Mitogens act in an opposite fashion to TGFb
- mitogens inhibit CKIs and promote cyclin/CDK complexes to promote cell cycle progression
- TGFb activate CKIs to inhibit cyclin/CDK complexes, thus inhibiting cell cycle progression

88
Q

what is an example of a mitogenic factor?

A

PI3K pathway, activated directly or indirectly by growth factor receptors  Akt = kinase activated downstream of PI3K

89
Q

what is promoted when constitutively active Akt is expressed in cells?

A
  • CKI p21 is excluded from nucleus and localised in the cytoplasm, meaning cyclin/CDK complexes in the nucleus can remain active and promote cell progression
90
Q

what is promoted when Akt is downregulated?

A

When dominant negative Akt is expressed, p21 can localise in the nucleus and inhibit CDK-cyclin complex, thus inhibiting cell cycle progression

91
Q

how does Akt correlate with breast cancer?

A

Akt activation induces cytoplasmic p27-Kip1, so cyclin/CDK complex in nucleus is no longer inhibited
- These effects on intracellular localisation appear to have clinical consequences.
- Low grade (less advanced) human mammary carcinomas: low levels of active Akt, so p27 in the nucleus -> able to exert anti-proliferative functions
- High-grade tumours: stronger Akt activation, so cytoplasmic p27
- Patients bearing primary tumours with nuclear p27 (green) have a relatively good prospect of long-term, disease-free survival over a period of 6 years after the diagnosis
- Patients with nuclear + cytosol localisation suffer significant relapses, many leading to death.

92
Q

does correlation with clinical outcome prove causation?

A

correlation with clinical outcome does not prove causation: i.e. that p27 mis-localisation causes clinical progression
- BUT important as prognostic marker

Stem cells, Ageing and Cancer (8 decks)

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