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Cancer > Christine > Flashcards

Christine Flashcards

1
Q

Cancer

A

The unregulated growth of abnormal (immature/blast-like) cells, often at inappropriate locations

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2
Q

Hallmarks of cancer

A 
Sustained proliferative signalling
Evasion of growth suppressors
Avoiding immune destruction
Replicative immortality
Tumour-promoting inflammation
Invasion and metastasis
Induction of angiogenesis
Genome instability (high frequency of mutations)
Resisting cell death
Deregulated cellular energetics (e.g. increased aerobic glycolysis)
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3
Q

How are tumours classified?

A

According to their tissue of origin

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4
Q

Carcinomas

A

Arise from epithelial cells (~90 % of cancers)

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5
Q

Adenocarcinomas

A

Arise from glandular tissue e.g. breast

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6
Q

Sarcomas

A

Arise from connective tissue/muscle

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7
Q

Leukaemias

A

Blood-derived sarcomas

i.e. a subset of sarcomas

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8
Q

Benign tumours

A

Cells resemble normal cells but with increased growth - i.e. the cells are abnormal but do not have enough mutations to be cancerous, and can still perform some normal functions
Tend to be localised
Often surrounded by a fibrous capsule
Usually require little treatment but can be surgically removed if required

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9
Q

Malignant tumours

A

Rapidly grow and divide
Tend to be less well-differentiated than normal cells
High nucleus to cytoplasm ratio with fewer specialised structures
Invade surrounding tissues, making them more difficult to treat (less definition between where tumour ends and normal tissue starts)
Can enter the circulation and grow at a distant site (metastasise)

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10
Q

Oncogene

A

A gene that has the potential to cause cancer

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11
Q

Mutations in Her2

A
  1. Point mutation of Val to Gun in the transmembrane region leads to dimerisation of the receptor in the absence of ligand, resulting in its constitutive activation
  2. Deletion mutation leading to loss of the extracellular ligand-binding domain causes constitutive activation of the receptor
  3. Over-expression of Her-2 (by up to 100 fold in many human breast cancers) causes cells to proliferate in the presence of very low concentrations of of EGF
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12
Q

Proposed mechanisms of action of Herceptin

A

Decreases activation of signalling pathways
Induces downregulation of the receptor
Increases PTEN activation
Induces cell cycle arrest
May increase apoptosis and reduce angiogenesis
May promote antibody-dependent cellular cytotoxicity (ADCC)

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13
Q

Molecular mechanisms of cancer

A

Cancer cells usually contain 3-7 mutations (Knudson hypothesis - multiple mutations are required for cancer development)
The malignant transformation of a single cell is sufficient to give rise to a tumour - cancer is a “clonal disease”
Any cell in a specific tissue is as likely to be transformed as any other cell of the same type
Benign tissues surrounding malignant tissue often contain all but one of the mutations

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14
Q

Gain of function mutations in oncogenes

A

Point mutation leading to constitutive activation
Gene amplification leading to an increase in the amount of protein produced
Chromosomal translocation

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15
Q

Retrovirus

A

Contains reverse transcriptase so can transcribe their RNA into DNA after entering a cell
This retroviral DNA can then be incorporated into the chromosomal DNA of the host cell and be expressed

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16
Q

Oncogenic retrovirus

A

A retrovirus capable of inducing malignancies in host cells

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17
Q

Structure of c-Src

A 
N-terminal SH3 domain (binds to proline-rich sequences)
SH2 domain (binds to phosphorylated Tyr residues)
Kinase domain (phosphorylates substrates)
C-terminal Tyr
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18
Q

Regulation of c-Src activity

A

Phosphorylation of the C-terminal Tyr creates an intramolecular binding site for the SH2 domain, resulting in auto-inhibition of the protein through masking of the kinase domain
The action of phosphatases leads to dephosphorylation of the C-terminal Tyr, leading to dissociation of the SH2 domain and activation of c-Src

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19
Q

Her2+ breast cancers

A

Her2+ cells are associated with a more aggressive tumour phenotype and reduced survival rate (more serious prognosis)
Cells grow faster so tumours are more likely to recur

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20
Q

Detection of Her2+ breast cancers

A

IHC

FISH (more sensitive)

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21
Q

Main classes of tumour suppressor genes

A
  1. Growth/development suppressors e.g. TGFb, patched1
  2. Cell cycle checkpoint proteins e.g. pRb, p53
  3. Cell cycle inhibitors e.g. CDKIs
  4. Inducers of apoptosis e.g. Bad, p53
  5. DNA repair enzymes (xeroderma pigmentosa)
  6. Developmental pathways e.g. patched (Hh pathway), Wnt pathway
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22
Q

Cellular responses to p53

A 
Cell cycle arrest (to allow DNA repair before the cell cycle continues)
DNA repair
Senescence
Apoptosis
Differentiation
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23
Q

p53 also acts as transcriptional regulator of…

A

p21 (CDKI, causes cell cycle arrest)
MDM2 (p53 inhibitor, autoregulation)
Bax (pro-apoptotic protein)

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24
Q

CDB3, PRIMA-1

A

Stabilise mutant p53 and restore its transcriptional function

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25
Q

Nutlin

A

Inhibits interaction between p53 and MDM2

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26
Q

Pifithrin

A

Suppresses the endogenous action of p53 in normal tissue in order to reduce the severe side effects associated with chemo/radiotherapy

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27
Q

Ras/MAPK pathway

A

Essential for cell growth

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28
Q

PI3K/PKB pathway

A

Essential for cell survival (anti-apoptotic)

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29
Q

Evidence for cancer stem cells

A

Cancer is a disease of proliferating cells, but most mature cells don’t proliferate
Tumours are often heterogeneous in terms of cellular differentiation, but cancers are clonal
Cancer is caused by the accumulation of mutations in a single cell, but most cells have a finite lifetime and don’t live long enough to acquire >3 mutations

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30
Q

Pluripotent cell

A

Can differentiate into many different cell types

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31
Q

Stem cells are…

A

…pluripotent and unspecialised

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32
Q

Where have small numbers of residual stem cells been identified in adult tissue?

A 
Blood (bone marrow)
Intestine
Skin
Muscle
Liver
Brain
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33
Q

Purpose of stem cells in the bone marrow

A

Required for normal cell turnover

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34
Q

Purpose of stem cells in the liver and muscle

A

Involved in healing

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35
Q

Teratoma

A

Tumour made up of several different types of tissue

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36
Q

Why do stem cells have more opportunity for mutations to accumulate?

A

They are long-lived and self-renew (proliferate)

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37
Q

How can the heterogeneity of the tumour mass be accounted for?

A

The asymmetric division of stem cells

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38
Q

Wnt signalling pathway

A

Proto-oncogene pathway
Leads to the regulation of gene transcription
Controls tissue regeneration in adult bone marrow, skin and intestine

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39
Q

LRP-5/6

A

Lipoprotein receptor-related protein

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40
Q

Protein components of the beta-catenin destruction complex

A

Axin
APC
CK1
GSK3

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41
Q

How does the beta-catenin destruction complex degrade beta-catenin?

A

By targeting it for ubiquitination after phosphorylation by GSK3

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42
Q

Reasons for over-expression of beta-catenin

A

Mutations in beta-catenin
Deficiencies in the beta-catenin destruction complex e.g. LOF APC
Over-expression of Wnt ligands

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43
Q

Telomeres

A

The ends of linear chromosomes

TTAGGG repeats

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44
Q

Function of telomeres

A

“Disposable buffers”

They are truncated during cell division - their presence protects the genes before them on the chromosome from being truncated instead

45
Q

Telomerase

A

Promotes telomere lengthening

46
Q

Expression profile of telomerase

A

Active in stem cells, germ cells, hair follicles and 90 % of cancer cells
Low/absent in somatic cells

47
Q

TTAGGG repeats in embryonic/stem cells

A

3-20 kb

Indefinite replication

48
Q

TTAGGG repeats in cancer cells

A 
Up to 55 kb
Persisten growth (but also chromosome instability - breakage/deletions)
49
Q

Why are cells with sufficient telomerase activity considered immortal?

A

They can divide past the Hayflick limit without entering senescence/apoptosis

50
Q

Why do cancer cells employ telomerases?

A

So they can maintain their telomeric DNA in order to continue dividing indefinitely (immortalisation)

51
Q

Hayflick limit

A

The number of times a normal human cell population will divide before cell division stops

52
Q

Hedgehog signalling pathway

A

Transmits signals to embryonic cells required for proper differentiation

53
Q

Metastasis

A

The ability of cancer cells to break away from their site of origin (the primary tumour) and travel to and recolonise at distant sites
Cancerous growths at sites far removed from where the primary tumours first arose

54
Q

What is the fundamental difference between benign and malignant tumours?

A

Metastasis

55
Q

What % of deaths from cancer are primary tumours responsible for?

A

10
Other 90 % from metastases
i.e. metastasis is the most life-threatening aspect of human cancer

56
Q

Mechanisms employed by tumour cells for carrying out metastasis

A

Downregulation of E-cadherin expression
Induce surrounding stromal cells to produce MMPs that digest the ECM
Change integrin expression
Epithelial-mesenchymal transition (EMT)

57
Q

Downregulation of E-cadherin expression

A

Mechanism of metastasis
E-cadherins are responsible for forming adherens junctions between epithelial cells
Loss of E-cadherin expression decreases the strength of adhesion, therefore increasing tumour cel motility and allowing tumour cells to physically detach from the primary tumour

58
Q

Induce surrounding stromal cells to produce MMPs that digest the ECM

A

Mechanism of metastasis
Tumour cells release CSF-1 (colony-stimulating factor-1) to recruit macrophages to the stroma
Macrophages secrete MMPs that catalyse the degradation of components of the ECM (e.g. collagen)
This creates space for tumour cells to move

59
Q

Changes in integrin expression

A

Mechanism of metastasis
Integrins are involved in anchoring cells to the ECM
Changes in their expression allow tumour cells to move through the ECM

60
Q

Intravasation

A

Degradation of the basal lamina allows cancer cells to move through the basement membrane into the blood or a lymphatic vessel

61
Q

Why does the lymph system favour metastatic tumour cells?

A

It is slower flowing than the blood, so there is less stress to harm them

62
Q

Extravasation

A

The process of tumour cells leaving their vessel and invading the surrounding tissue
Typically occurs in small capillaries because the tumour cells are large and become trapped

63
Q

EMT

A

Epithelial-mesenchymal transition
When epithelial cells assume the shape and transcriptional programme characteristic of mesenchymal cells
The process by which epithelial cells lose their polarity and cell-cell adhesion, gaining migratory and invasive properties to become mesenchymal stem cells

64
Q

Metastatic tropism

A

The preference/selection for where a tumour metastases, depending on its organ of origin

65
Q

Metastatic tropism in breast cancers

A

Tend to metastasise throughout the body e.g. bone, lungs, liver, brain

66
Q

Metastatic tropism in prostate tumours

A

Recolonise in the bone

67
Q

Metastatic tropism in colon carcinomas

A

Recolonise in the liver

68
Q

Theories of metastatic tropism

A

First-pass organ

Seed and soil hypothesis

69
Q

First-pass organ theory

A

Tumour cells recolonise in the first organ they encounter due to trapping in the capillary network
i.e. many breast tumours form metastases in the lungs

70
Q

Seed and soil hypothesis

A

Tumour cells recolonise in tissues with similar growth factors to their tissue of origin
or
in tissues that have been ‘prepared’ to receive tumour cells
There is evidence that tumour cells secrete cytokines to ‘prepare’ tissues for recolonisation, creating a “pre-metastatic niche”

71
Q

MMP inhibitors as a therapeutic approach to metastasis

A

GM6001
Broad spectrum, reversible MMP inhibitor
Broad spectrum contributed to disappointing clinical performance - dose-limiting muscular and skeletal pain
Anti-tumour and anti-angiogenic activity
Anionic hydroxamic acid motif forms a bidentate complex with the active site zinc
Used in combination with cetuximab (EGFR inhibitor) and celecoxib (COX2 inhibitor)

72
Q

EMT inhibitors as a therapeutic approach to metastasis

A

AB-16B5
Humanised monoclonal antibody for clusterin
Clusterin promotes tumour cell migration, invasion and metastasis through stimulation of the EMT pathway
Currently in phase I clinical trials for advanced solid tumours

73
Q

NM23

A 
Metastatic suppressor (gene, not drug)
Reactivation could be a therapeutic approach to metastasis
74
Q

Angiogenesis

A

The development/formation of new blood vessels from pre-existing vasculature through extension/remodelling of existing capillaries

75
Q

Vasculogenesis

A

De novo blood vessel formation i.e. no existing vasculature

opposite to angiogenesis

76
Q

Physiological angiogenesis

A

Occurs naturally during embryogenesis, wound healing, menstrual cycle

77
Q

Pathological angiogenesis

A

A hallmark of cancer

78
Q

Why is angiogenesis essential for tumour progression and metastasis?

A

Tumour growth is angiogenesis-dependent
Without the formation of new blood vessels, tumours can only grow to a max diameter of 2 mm
Growing tumours stimulate angiogenesis to ensure their own blood supply

79
Q

How is angiogenesis normally regulated?

A

Through the production of several pro- and anti-angiogenic factors
Pro = VEGF, bFGF, PDGF
Anti = endostatin, angiostatin, thrombospondin
Angiogenesis is normally suppressed through an excess of inhibitory anti-angiogenic factors - the difference between physiological and pathological angiogenesis lies in the tightly regulated balance of pro- and anti-angiogenic factors

80
Q

The ‘angiogenic switch’

A

Occurs when the finely tuned balance between pro- an anti-angiogenic factors is tipped in favour of angiogenesis
This occurs in hypoxic cells

81
Q

The angiogenic pathway

A
  1. Hypoxic/low pH conditions induce the activation of HIF-1 (hypoxia-inducible factor-1). HIF-1 is a tumour cell transcription factor that induces transcription of the VEGF gene. It is stabilised by hypoxia - in normal, well-oxygenated tissue, HIF-1 concentration is kept low by its continual degradation
  2. Tumour cells release VEGF
  3. VEGF diffuses into the nearby tissues and binds to VEGFRs on nearby blood vessel endothelial cells
  4. This activates the endothelial cells to produce enzymes e.g. MMPs that catalyse the degradation of the basal lamina and ECM proteins. This creates a physical space into which the endothelial cells can migrate
  5. The degradation of the basal lamina/ECM allows the endothelial cells to proliferate/migrate out of their original vessel walls and sprout towards to tumour cell (i.e. towards the source of the pro-angiogenic factor)
  6. Activation of VEGFR also increases intern expression on the endothelial cell surface, that aid migration by ‘pulling’ the sporting new blood vessel forwards
  7. The endothelial cells reorganise to form tubules with a central lumen, stabilised by smooth muscle cells and pericytes. PDGF and Ang1 are involved in this maturation of new blood vessels
  8. The new blood vessels interconnect to form a branched network (anastomosis)
82
Q

Normal blood vessels

A

Straight
Branch into successively smaller capillaries to create a widespread network for oxygen and nutrient delivery to the tissue

83
Q

Tumour vasculature

A

Tends to comprise a tangle of randomly interconnected vessels that branch erratically, vary in diameter and are generally oversize
Vessels are often weak and ‘leaky’ - there are large pores in the vessel walls that can lead to escape of fluid into the interstitium, leading to painful swelling in/around tumour tissues
The abnormal vessels often have irregular blood flow that can prevent treatment from reaching and attacking tumour cells
Dysfunctional vessels also produce hypoxic/low pH conditions that can prevent the function of immune cells

84
Q

Current anti-angiogenic approaches

A

Antisense RNA therapy against bFGF and PDGF
Soluble receptors/monoclonal antibodies e.g. Avastin
Enzyme inhibitors e.g. sunitinib, sorafenib
Activation of tumour suppressors e.g. p53 - up-regulates anti-angiogenic factors and down-regulates pro-angiogenic factors

85
Q

Avastin

A

Anti-VEGF monoclonal antibody
Binds to biologically active forms of VEGF and prevents its interaction with VEGFR
Only effective in some cancer types (e.g. metastatic colon, renal, ovarian) - other tumours use different pro-angiogenic factors so Avastin would be ineffective
Most effective when given in combination with cytotoxic drugs, because Avastin is cytostatic - it doesn’t kill the tumour cell, just decreases its growth

86
Q

Sunitinib, sorafenib

A

Inhibit VEGFR (but not specific)

87
Q

Why are the majority of current anti-angiogenic therapies ineffective against established tumours?

A

Established tumours already have a fully formed network of blood vessels
Current anti-angiogenic treatments are only really useful for preventing blood vessel growth in the first place

88
Q

Disadvantage of anti-angiogenic therapies

A

Long-term administration could impair natural wound-healing/menstruation
With Avastin, inhibition of VEGF could lead to an increase/surge in the levels of other growth factors in order to compensate, leading to tumour resistance

89
Q

Novel anti-angiogenic therapies

A

Aim to target newly formed blood vessels due to potential molecular differences between established and neovasculature

90
Q

ANET

A

Anti-neovascular therapy
Aims to disrupt neovessels, rather than inhibit their formation
Based on the fact that angiogenic endothelial cells are growing cells that would be damaged by cytotoxic agents (just like tumour cells), if the agents are effectively delivered to the cells (vascular targeting) e.g. direct cytotoxic drugs e.g. doxorubicin to endothelial cells
The eradication of endothelial cells would cause a complete cut-off of essential supplies to the tumour cells, leading to indirect but strong cytotoxicity (inhibition of angiogenesis just causes cytostasis)
i.e. the tumour would be eradicated completely

91
Q

Vascular gene therapy

A

Correct/alleviate disease through delivery of genes
Requires identification of the appropriate gene and specific delivery to the required area
May be possible with E-selectin, which has endothelial cell-specific expression
Link the promoter region of the E-selectin gene with the gene for dnVEGFR and target to rapidly proliferating cells using retroviruses

92
Q

Destruction of tumour vasculature (vasculature targeting)

A

e.g. Combretastatin
Binds to the beta-subunit of tubulin, preventing tubulin polymerisation and microtubule formation
This leads to a ‘ballooning’ of the vasculature endothelial cells, resulting in necrosis of the tumour core

93
Q

Nanoparticle techology

A

NGR peptide motif on the surface of the nanoparticle targets it to tumour endothelial cells (binds to CD13)
Nanoparticles contain bortezomib (= proteasome inhibitor)
In some cancers, the proteins that normally kill cancer cells are broken down too quickly by the proteasome

94
Q

Normalising tumour vessels

A

Would allow cancer therapies to penetrate the tumour mass and function more effectively

95
Q

c-Src

A

Non-receptor Tyr kinase

Activation leads to promotion of cell survival/proliferation

96
Q

HPV

A

Human Papilloma Virus

DNA onocovirus

97
Q

HPV proteins

A

Can interact with cellular proteins
E5 protein causes prolonged activation of PDGFR
E6 protein inactivates p53 through targeting for ubiquitination
E7 protein competes with pRb for E2F binding

98
Q

Deficient EGFR signalling

A

Associated with Alzheimer’s

99
Q

C-fos

A

Transcription factor
Forms a heterodimer with c-jun, resulting in the formation of AP-1 complex that binds to DNA leading to the production of cyclin D

100
Q

Ras as an anti-cancer target

A

Ras has a fatty acid modification that tethers it to the cell membrane
Inhibitors of this modification were developed but it was found that cancer cells just tethered Ras to the membrane using a different modification

101
Q

Inheriting one mutated copy of BRCA1

A

BRCA1 = TSG

60 % probability of developing breast cancer c.f. 2 % probability with 2 wild type alleles

102
Q

G1 to S phase transition

A
  1. Growth factors induce cyclin D expression
  2. Cyclin D assembles with CDK4/6 to form catalytically active kinase complex
  3. pRb in unphosphorylated form is bound to E2F (TF), preventing E2F-mediated transcription of genes required for DNA synthesis. Phosphorylation of pRb by cyclin D-CDK4/6 complex causes its dissociation from E2F allowing transcription of enzymes involved in DNA replication, irreversibly committing cells to S phase
  4. Phosphorylation is initiated by cyclin D-CDK4/6 and is completed by other CDKs e.g. cyclic E-CDK2
    Active E2F stimulates its own synthesis as well as that of cyclin E and CDK2 (positive feedback loop)
103
Q

LOF pRb

A

Removes E2F inhibition therefore E2F is constitutively active and continuously drives the transcription of genes required for S phase transition

104
Q

p53

A

Most critical molecule in cancer
Main detector of DNA damage
Maintains integrity of DNA

105
Q

How is p53 an exception to the ‘recessive’ rule/”two-hit hypothesis”?

A

p53 acts as a tetramer
One mutated copy of p53 can lead to LOF of p53 because the incorporation of just one non-functional p53 into the tetramer results in LOF of p53

106
Q

Where do mutations in p53 generally occur?

A

In the DNA binding region

107
Q

Li Fraumeni syndrome

A

Inherited disorder

Predisposes sufferers to cancer as a result of inheritance of a mutated p53 gene

108
Q

p53 is inactivated by…

A

…environmental carcinogens e.g. benzo(a)pyrene in cigarette smoke
aflatoxin

Cancer (4 decks)

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