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B33CAN - Biology & Physiology > Intro/What makes a cancer? > Flashcards

Intro/What makes a cancer? Flashcards

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1
Q

What are cancers and how do they originate?

A
  • Diverse group of over 200 diseases
  • Uncontrolled growth of abnormal cells in the body (malignant cells)
  • Caused by genetic changes (mutations) in somatic cells (sperm/egg)
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2
Q

Is cancer inherited?

A

No; mutations in an individual’s somatic cells.

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3
Q

What is the common feature of cancer?

A

Uncontrolled abnormal cell growth/proliferation

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4
Q

Do cancers change, and if so, why?

A
  • Cancer adapts in response to selection pressures, changing in morphology + DNA behaviour
  • Cells which proliferate are selective, dominating.
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5
Q

Where do cancers most commonly originate?

A

Epithelial cells

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6
Q

What behaviours do a normal cell exhibit (conversely to cancers)?

A
  • Proliferate only when instructed
  • Apoptosis when required
  • Stay local (apart from immune system/blood)
  • Communicate + cooperate w/other cells, inc. immune system
  • Senesce after a number of divisions (cancer cells divide indefinitely)
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7
Q

After how many divisions does a normal cells senesce? What is this called?

A
  • 40-60 generations/divisions

- Hayflick limit

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8
Q

What are the 6 Hallmarks of Cancer?

A
  • Sustaining proliferative signalling
  • Evading growth suppressors
  • Activating invasion and metastases
  • Enabling replicative immortality
  • Inducing angiogenesis
  • Resisting cell death
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9
Q

Do cancers evolve?

A
  • Constantly; mutating all the time.

- Selection pressure for survival + reproduction

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10
Q

What makes a ‘successful’ cancer cell?

A
  • Cells that proliferate fastest, thus accumulating the most mutations to switch on proliferating machinery
  • Become dominant in a population
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11
Q

What is meant by cancer stem cells? How can this be applied to therapy?

A
  • Theory that not all cells in a cancer are equal
  • Small population of cancer stem cells (CSCs) give rise to other cancer cells (+ more CSCs)
  • Therapies need to kill CSCs to avoid remissions; tumour reoccurs even with treatment if not all CSCs killed.
  • CSCs can lead to metastases
  • Developed from mutated normal stem cells
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12
Q

How do cancers behave regarding the balance between proliferation and remaining stable?

A
  • The balance shifts towards proliferation and survival

- Thus there is an accumulation of abnormal cells

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13
Q

Why is there an accumulation of abnormal cells in cancer?

A
  • Increase in division (proliferation)

- Decrease in cell death (apoptosis)

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14
Q

What do genes do?

A
  • Control cell division:

Cell division, death, or neither.

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15
Q

What occurs with gene mutation?

A
  • Changing genetic information
  • Addition, removal or swapping of nucleotides
  • Harmful, beneficial or neutral.
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16
Q

What are the two main genes that regulate cancer and what are their functions?

A

Proto-oncogenes and tumour suppressor genes.

  • Proto-oncogenes; encode proteins that increase cell division (proliferation), decrease cell death (apoptosis).
  • Tumour suppressor genes; encode proteins that reduce cell division (proliferation), induce cell death (apoptosis).
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17
Q

What is the difference between proto-oncogenes and oncogenes?

A

Proto-oncogenes are ‘normal’; proliferation is vital for normal cell growth too, but oncogenes cause cancer (sans proto).

18
Q

What is the third class of genes that influence cancers?

A
  • DNA stability/repair genes
  • Often lumped in with the tumour suppressors, they encode proteins that maintain DNA stability by repairing DNA and protecting against accumulation of mutations.
19
Q

Describe the car analogy for the balance of cancer genes.

A
  • Tree; cancer
  • Car; cell/patient
  • Accelerator; proto-oncogene
  • Faulty accelerator; oncogene
  • Brakes; tumour suppressor (oncogene isn’t necessarily an issue provided the brakes work)
20
Q

What gene mutations result in a malignant tumour?

A
  • A mutated proto-oncogene (an oncogene); leading to abnormal division e.g. if mutated so oncogene is permanently switched on
  • A mutated tumour suppressor in that a mutation renders it inactive
21
Q

How is proliferation deregulated in cancer cells?

A
  • Increased pro-growth signals; e.g. extra ligands; constitutive activation of receptors; mutations in signalling pathways
  • Disabled checkpoints; cell cycle checkpoints normally prevent proliferation as response to numerous stresses.
22
Q

What are the two major tumour suppressor genes?

A
  • p53 (TP53, tumour protein 53)

- RB1 (retinoblastoma 1)

23
Q

What role does the gene p53 play and what is the gene’s significance?

A

“Guardian of the genome”

  • Blocks cell cycle in response to cellular damage
  • Induces apoptosis if DNA damage is irreparable
  • Thus leads to changes in gene expression to coordinate above
  • Most commonly mutated gene in cancers; 29, 898 mutations identified.
24
Q

What is p53 and what shape does it take?

A
  • Tumour suppressor gene
  • Transcription factor
  • Tetramer (4 identical molecules)
25
Q

What role does the gene RB1 play and what is its significance?

A
  • Blocks cell cycle by binding (and inhibiting) E2F transcription factor
  • Inhibits transcription of genes needed for cell cycle progression; RB1 needs to be inhibited for cell cycle to occur
  • Leads to changes in gene expression
  • First tumour suppressor to be identified
26
Q

How is the tumour suppressor gene RB1 inhibited?

A
  • Inhibited by phosphorylation (e.g. by cyclic D-CDK4)

- This allows cell cycle to continue

27
Q

What are the two major proto-oncogenes and their properties?

A

MYC (Myelocytomatosis, viral-origin):

  • Transcription factor
  • Promotes cell growth, switches off apoptosis (down regulates)
  • Leads to changes in gene expression

RAS (family HRAS, KRAS, NRAS)

  • G protein; single small unit GTPase, binds GDP (inactive) or GTP (active); NOT a GPCR
  • Activated by growth factors (e.g. EGF, on EGFR, an RTK)
  • Activates downstream signalling pathways (proliferative)
28
Q

What is meant by the ‘Central Axis’ of cancer signalling?

A

The main signalling pathways channel where it all converges, on four tumour suppressors (ARF > p53, INK4 > RB1) and two proto-oncogenes (RAS and MYC), together with E2F transcription factors regulated by RB1.

MDM2 is an oncoprotein (an ubiquitin ligase) that inhibits p53-mediated transcription; this ubiquitylation of p53 marks it for degradation = removal of a critical tumour suppressor. However ARF lies above MDM2 in the axis and can bind to it, even when bound to p53, to inhibit its actions.

As p53 has ARF as its big bro, RB1 has INK4. INK4 inhibits Cyclin D-CDK4; the kinase that phosphorylates RB1, thus prevents E2Fs activity as a transcription factor, stopping the cell cycle.

29
Q

How would oncogenic changes in the central axis be stopped in a healthy cell?

A

If MYC or RAS were upregulated or the loss of RB1 hence activation of E2F, ARF should be up-regulated itself to cause cell senescence/cycle arrest/apoptosis with p53 downstream.

30
Q

What processes occur with oncogene activation?

A

Proliferative:

  • metabolism
  • angiogenesis
  • protein synthesis
31
Q

What processes occur with tumour suppressor activation?

A

Arrest:

  • Senescence
  • Cell cycle arrest
32
Q

What is the difference between necrosis and apoptosis (the ways a cell can ‘die’)?

A

Necrosis; spillage of cell contents caused by injury/infection, resulting in inflammation and an immune response.

Apoptosis; programmed, ordered cell death; does not stimulate an immune response.
e.g. diminishing interdigital tissue as a foetus

33
Q

Can apoptosis/cell death be a good thing?

A
  • Proliferation is normally balanced by apoptosis; a healthy tissue doesn’t change in size.
  • Occurs in tumours particularly during early stages, limiting growth rates.
  • Protection against cancers
34
Q

What is meant by intrinsic/extrinsic pathways in regards to apoptosis?

A

Intrinsic: apoptosis activated by mitochondrion
Extrinsic: apoptosis activated by death receptor (e.g. ligand on lymphocyte)

35
Q

Briefly describe the intrinsic apoptosis pathway, with regards to what is released, the complex formed and the resulting action.

A
  • Mitochondrion receives apoptotic stimulus
  • Cytochrome C (previously stored in intermembrane space) is released
  • The protein Apaf1 (Apoptotic protease activating factor 1) is activated by cytochrome C, with hydrolysis of bound dATP to dADP
  • Assembly of apoptosome (multi-protein complex) triggered by dADP, in exchange for dATP/ATP
  • Procaspase-9 is recruited by the CARD (Caspase Activation and Recruitment Domain) and activated
  • Caspase-9 then cleaves and thus activates executioner procaspases
  • Caspase cascade is initiated, leading to apoptosis by caspases (type of cysteine protease)
36
Q

Describe the extrinsic apoptosis pathway.

A
  • (Killer) Lymphocyte expresses Fas ligand
  • Binds to Fas death receptor (AKA apoptosis antigen 1, APO-1)
  • FADD adaptor protein and procaspase-8 or 10 assemble into DISC (death inducing signalling-complex)
  • This results in the cleavage of and subsequent activation of caspase-8/10, activating executioner capsases that result in apoptosis.
37
Q

How are cancer cells resistant to apoptosis?

A
  • Upregulation of survival signals (anti-apoptotic) e.g. Bcl2 (B-cell lymphoma 2; allowing cell to survive despite apoptotic signals)
  • Downregulation of pro-apoptotic signals e.g. Bax, Apaf1, p53
38
Q

How is necrosis detrimental to the patient?

A

Much greater impact on neighbouring cells:

  • Pro-inflammatory signals released (inflammation is risk factor)
  • Immune cells recruited, promoting angiogenesis
  • Growth factors (e.g. IL-1a) released, promoting proliferation
39
Q

What does the Warburg effect entail?

A
  • Cancer cells often exhibit Warburg effect even when well oxygenated e.g. leukaemia
  • It is when aerobic glycolysis is favoured, favouring lactate production (with some CO2), though inefficient re. moles of ATP per glucose (3 vs. 36 in oxidative phosphorylation; abnormal metabolism)
40
Q

What do cancer cells exhibit the Warburg effect?

A
  • To maximise availability of raw materials for proliferation (growth potential)
  • The precursors of fatty acids, amino acids and nucleotides are the limiting factors for proliferation
  • Thus glucose is a major source of carbon; wasted as CO2 in oxidative phosphorylation, but savoured in aerobic glycolysis (as lactate product).
  • Thought to be side effect of MYC oncogene; upregulates glycolysis.
41
Q

How can the Warburg effect be exploited for anticancer therapy/disease monitoring?

A
  • Lactic acid (lactate = conjugate base) is produced from pyruvate
  • Thus a lower pH is seen in tumours; development of formulations that dump drug in acidic conditions (pH-responsive polymers)
  • Use of glucose by tumour cells can also be exploited for PET (positron emission tomography); labelled glucose preferentially taken up by tumour cells.

B33CAN - Biology & Physiology (7 decks)

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