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Cellular & Molecular Pathology > Molecular basis of cancer > Flashcards

Molecular basis of cancer Flashcards

1
Q

define cancer

A

a group of diseases involving abnormal cell growth with the potential to invade or spread to other parts of the body

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2
Q

what two ways can stored information in the cell of a metazoan be affected to create cancer?

A

altered/currupted OR misused

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3
Q

Cancers are classified according to what three criteria?

A
  • tissue of origin
  • level of malignancy
  • genetics
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4
Q

When the tissue of origin is epithelial, what is the name of the cancer?

& what percentage are they

A

Carcinoma

>80%

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5
Q

When the tissue of origin is mesenchymal tissue, what is the cancer called?

& what percentage are they

A

Sarcomas

~1%

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6
Q

When the tissue of origin is Hematopoetic tissue, what is the cancer called?

& what is the percentage they make

A

Lymphoma/ Leukemia

~10%

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7
Q

When the tissue of origin is Neuroectoderm, what is the cancer called?

& what percentage does it make up

A

Blastoma/ Melanoma

~5%

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8
Q

wht are the two parts of TMN staging?

breifly describe each

A

Staging = characteristics of a tumour
Grading = characteristics of tumour cells

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9
Q

What are levels of malignancy?

A

Mild hyperplasia
Advanced hyperplasia
Carcinoma in situ
Invasive carcinoma
Metastatic carcinoma

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10
Q

What three ways can cancer come about?

genetic & non genetic

A

Sporadic: no family history
Familial: mutation is unknown
Hereditary: mutation is known

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11
Q

What percentage of cancers are hereditary?

A

5-10%

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12
Q

what are the four stages in classification of the tissue of origin of breast cancer?

breifly describe advance of cancer in the milk duct

A

Mildly hyperplastic tissue:
More advanced hyperplasia: Lumen is visible but small, cancer cells contained
Ductal cacinoma in situ: No lumen, bleeding, no spread yet
Invasive ductal carcinoma: basement membrane broken, detachment of cells from main lump, invasding surrounding fat tissues

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13
Q

What are the 6 hallmarks of cancer?

A
  • self sufficiency in growth signals
  • insensitivty to antigrowth signals
  • sustained angiogenesis
  • evading apoptosis
  • limitless replicative potential
  • tissue invasion and metastasis
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14
Q

What is considered the ultimate hallmark of cancer?

And why?

A

Almost all the other hallmarks of cancer you see in other diseases, the only real hallmark is metastasis

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15
Q

Why is cancer a disease of clonal selection?

A

when a cell mutates, it can give it a survival advantage and so are selected for based on the selction pressure and clonally expand until the next mutation arrives to confer another advantage and then these cells are clonally expanded. this continues multiple times

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16
Q

What is an Oncogene?

How does it cause cancer?

A

A gene that has the potential to cause cancer

Mutation or overexpression of protooncogenes

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17
Q

what are the three ways of oncogene activtion?

Give 2 examples for each

A
  1. Activating mutations (eg Ras, CDK4)
  2. Gene amplifications (eg Myc, MDM2, Her2)
  3. Translocations (eg Myc/IgH)
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18
Q

What is MDM2?

A

An important negative regulator of the p53 tumour suppressor gene

Mouse double minute 2

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19
Q

Breifly how does Ras cause cancer

in terms of oncogene mutation

A

Mutation activating oncogene

Ras is a bottleneck for survival signals

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20
Q

Describe the activation of the Ras gene

A

Inactive Ras is bound by GDP
Upstream stimulatory signal and Ras activation is triggered by GEF (unbinding GDP)
Downstream signalling brings GTP to bind to Ras - it is now active

Often a blockage caused by an oncogenic mutation at this point prevents Ras inactivation

GTP hydrolysis and Ras inactivation is induced by GAP

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21
Q

What are the three Ras genes?

A

K-Ras
H-Ras
N-Ras

On different chromosomes, function similarly but differ in expression

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22
Q

Breifly how does EGRF2 (HER2) cause cancer

in terms of oncogene activation

A

Oncogene activation through amplification

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23
Q

How does HER2 (EGRF2) work?

And what happens when the oncogene is activated?

A

In a normal cell - cross phosphoyrylation (by the tyrosine kinase domasin) after ligand binding - ligand dependent binding

In a cancer cell– ligand independent firing (via mutation affecting structure or overexpression)

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24
Q

Patients with breast cancer live long if the Her2 gene is not ________

A

amplified

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25
Q

Breifly describe how Myc causes cancer

in terms of oncogene activation

A

Onocogene activation through translocation

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26
Q

Reciprical translocation between two chromosomes creates _______________

A

… a fusion gene

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27
Q

In Burkitts lymphoma, what translocation occurs?

A

The myc gene is moved onto chromosome 14 (instead of 8) and the IgH gene is moved to chromosome 8 (from 14)

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28
Q

What chromosome is myc usually on?

A

Chromosome 8 (long arm)

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29
Q

Most cancers related to B cells is a result of what type of mutation

A

Translocation

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30
Q

What ways can proto-oncogenes be converted to oncogenes?

A

Deletion or point mutation in coding sequence
Gene amplification
Chromosome rearrangement

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31
Q

In terms of the resultant protein

Deletion or point mutation in coding sequence of a protooncogene results in what

A

Hyperactive protein made in normal amounts

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32
Q

In terms of the resultant protein

What does gene amplification of a proto-oncogene result in

A

Normal protein greatly overprodced (overexpression)

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33
Q

What does chromosomes rearrangement of a proto-oncogene result in

A

Nearby regulatory DNA sequence causes normal protein to be overproduced
Fusion to actively transcribed gene greatly overproduces fusion protein: or fusion protein is hyperactive

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34
Q

What are tumour suppressor genes?

How do they cause cancer?

A

A gene that regulates a cell during cell division and replication

Causing cancer by loss of function (when mutated or deleted)

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35
Q

What are the 2 classes of tumour suppressor genes?

Give 4 examples for each

A

1- Gatekeeper genes encode a system of checks and balances that monitor cell division and death (Rb, p53, APC, p16).
2- Caretakers are responsible for genomic integrity (MLH1, MSH2, BRCA1, BRCA2).

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36
Q

Whats the difference between the distribution of mutations on oncogenes vs tumour suppressor genes?

A

Oncogene mutations are often clustered in the same place whereas on tumour suppressor genes they are more spread

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37
Q

What is the Knudson hypothesis?

aka the two hit hypothesis
when was it proposed?

A

The hypothesis that most tumour suppressor genes require both alleles to be inactivated, either through mutations or through epigenetic silencing, to cause a phenotypic change. It was first formulated by Alfred G. Knudson in 1971

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38
Q

Why is it more likely for bilateral retinoblastoma to develop in those who have a familial form of the disease?

A

Because you can more easily end up with two mutate alleles.

If you already have one mutated allele due to familial or hereditary genes then you are far more likely to develop the second somatic mutation and get bilateral retinoblastoma

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39
Q

What gene is known as the master guadian of the genome?

A

TP53 (or p53)

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40
Q

What is p53?

A

A transcription factor that controls cell divison, apoptosis and DNA fidelity

41
Q

What class of tumour suppressor gene is p53?

A

a gatekeeper

a stress response protein that sense stresses in the cell

41
Q

What class of tumour suppressor gene is p53?

A

a gatekeeper

a stress response protein that sense stresses in the cell

42
Q

If a cell has mutated Ras but normal p53 what is observed in terms on cancers observed?

A

very little or no cancers because p53 gatekeeping mechanism is stopping cancers developing

43
Q

If a cell has mutated Ras but normal p53 what is observed in terms on cancers observed?

A

very little or no cancers because p53 gatekeeping mechanism is stopping cancers developing

44
Q

What possible stresses could a cell face that are addressed by p53?

A

lack of nucleotides
uv radiation
ionizing radiation
oncogene signalling
hypoxia
blackage of transcription

45
Q

what ways does p53 address stresses to the cell?

A

cell cycle arrest (followed by senescence or return to proliferation)
DNA repair
block of anhiogenesis
apoptosis

46
Q

what occurs in mice who have had both TP53 genes knocked out

A

all develop tumours and die

47
Q

whats unique about the structure and function of p53

A

it acts as a tetramer

47
Q

whats unique about the structure and function of p53

A

it acts as a tetramer

48
Q

In addition to mutations how else is TP53 inhibited?

A

oncogenic viruses also target and inhibit p53

49
Q

Give some examples of tumour virusses that perturb p53

A

Adenovirus
HPV
HCMV
Epstein-barr

HPV= human papillomavirus
HCMV= human cytomeglovirus

49
Q

Give some examples of tumour viruses that perturb p53

A

Adenovirus
HPV
HCMV
Epstein-barr

HPV= human papillomavirus
HCMV= human cytomeglovirus

50
Q

what are the 6 main stages of invasion-metastasis

A

1- breaking down basal membrane
2- EMT and intravasation
3- Anoikis resistance (transport though circulation)
4- extravasation
5- colonisation and MET (formation of macrometastasis)
6- dormancy-proliferation

51
Q

what two indicators show that the cancer has metastasised?

A

stiffness in the tumour
loss of basement membrane

52
Q

what are matrix metalloproteinases?

how are they involved in metastasis

A

Enzymes that are capable of degrading all kinds of extracellular matrix proteins

  • they play a critical role in invasion via cleavage of ECM and cell adhesion molecules
52
Q

what are matrix metalloproteinases?

how are they involved in metastasis

A

Enzymes that are capable of degrading all kinds of extracellular matrix proteins

  • they play a critical role in invasion via cleavage of ECM and cell adhesion molecules
  • existing MMPs help create a larger region of MMP activity to help invade the basement membrane
53
Q

what are the two types of matrix metalloproteinases?

A
  • transmembrane type MT-MMPs: cleavage by furin during secretion, accumulation in invadopodia
  • secreted MMPs: extracellular cleavage by other MMPs and plasmin, binding to ECM
54
Q

what are invadopodia

A

actin-rich membrane protrusions, which possess the ECM degrading activity (MMPs)

55
Q

What is Anoikis

A

a form of programmed cell death that occurs in anchorage-dependent cells when they detach from the surrounding extracellular matrix (ECM).

56
Q

Give four features of developmental EMT

A

1 - committed migratory cells do not divide
2 - migratory cells should be resistant to apoptopic stimuli
3 - committed migratory cells should retain the ability to give rise to more than one type of cell (stem cell properties)
4 – anoikis resistance

56
Q

Give four features of developmental EMT

A

1 - committed migratory cells do not divide
2 - migratory cells should be resistant to apoptopic stimuli
3 - committed migratory cells should retain the ability to give rise to more than one type of cell (stem cell properties)
4 – anoikis resistance

56
Q

Give four features of developmental EMT

A

1 - committed migratory cells do not divide
2 - migratory cells should be resistant to apoptopic stimuli
3 - committed migratory cells should retain the ability to give rise to more than one type of cell (stem cell properties)
4 – anoikis resistance

57
Q

What is the Epithelial-mesenchymal transition (EMT)

A

a reversible genetic trans-differentiation program when epithelial cells lose E-cadherin and other epithelial markers and acquire expression of mesenchymal markers resulting in enhanced cell motility and invasiveness

(detach car from the train)

58
Q

what key difference between epithelial and msenchymal cells makes EMT and important process in cancer progression

(EMT)

A

Mesenchymal cells can stand and survive as single cells
Epithelial cells act as a group

59
Q

Give the 5 pathways to EMT

A

1-Cadherin switch
2-Mucin downregulation
3-Loss of epithelial cell polarity
4-Increased matrix metallo-protease expression
5- Increased mesenchymal markers
(such as vimentin)

59
Q

Give the 5 pathways to EMT

A

1-Cadherin switch
2-Mucin downregulation
3-Loss of epithelial cell polarity
4-Increased matrix metallo-protease expression
5- Increased mesenchymal markers
(such as vimentin)

60
Q

give 3 examples of epithelial markers

A

E-cadherin
beta-catenin
gamma-catenin

60
Q

give 3 examples of epithelial markers

A

E-cadherin
beta-catenin
gamma-catenin

61
Q

give 3 examples of mesenchymal markers

A

fibronectin
vimentin
N-cadherin

62
Q

what three cell types assemble to enable cancer cells to invade endothelial walls into capilaries

A

carcinoma cells, macrophages, endothelial cells

63
Q

what interactions lead to intravasation

A

reciprocal interactions between tumour associated macrophages (TAMs) and tumour cells leads to intravasation

cancers cells stimulated by EGF released by macrophage partners

64
Q

why do cancer cells sometimes circulate with platelets

A

survival is greatly enhanced if the cancer cells can attract an entourage of blood platelets to escort them through the rapids (hydrodynamic forces in circulation) into safe pools within the tissues

65
Q

metastatic cells that retain .____________. status survive in circulation

A

Mesenchymal status

66
Q

give 5 features specific to cancer stem cells

A
  • high tumourigenicity
  • drug resistant
  • highly metastatic
  • self-renewal
  • anoikis resistance

non stem cells have low tumourigenicity, are drug sensitive and have low metastatic status

67
Q

what is the difference in CD24 and CD44 levels between cancer stem cells and non-stem cells

A

cancer stem cells have low CD24 and higher CD44
non-stem cells have very high CD24 and low CD44

change in CD24 important in identification of cancer

68
Q

what signalling molecule is key ininducing and direction EMT-MET cycles

A

TGFbeta

68
Q

what signalling molecule is key ininducing and direction EMT-MET cycles

A

TGFbeta

69
Q

what two pathways are there to extravasation

A

rolling and arrest
trapping and microclot (with platelet assistance)

70
Q

what receptors and ligands are involved in the rolling stage that precedes extravasation

A

(tumour cell) ligands - CD44, CEA, PODXL
(endothelial cell) receptors - E-selectin, P-selectin

71
Q

What receptors and ligands are involved in the arrest stage the precede extravasation?

follows rolling

A

(tumour cell) ligands - integrins
(endothelial cell) receptors - ICAM1, VCAM1

71
Q

What receptors and ligands are involved in the arrest stage the precede extravasation?

follows rolling

A

(tumour cell) ligands - integrins
(endothelial cell) receptors - ICAM1, VCAM1

71
Q

What receptors and ligands are involved in the arrest stage the precede extravasation?

follows rolling

A

(tumour cell) ligands - integrins
(endothelial cell) receptors - ICAM1, VCAM1

72
Q

describe the role of platelets in the trapping extravasation pathway

A
73
Q

what is the rate limiting step in metastasis?

A

colonisation

74
Q

what happens after extravsation in the the progression of cancer?

occuring in the secondary organ

A

in the secondary organ mesenchymal cancer cells either remain dormant or undergo MET to form secondary tumours

enabling them to start dividing again

74
Q

what happens after extravsation in the the progression of cancer?

occuring in the secondary organ

A

in the secondary organ mesenchymal cancer cells either remain dormant or undergo MET to form secondary tumours

enabling them to start dividing again

75
Q

what stage are dormant cancers in?

A

Dormant cancer cells sit in the tissues as mesenchymal cells. once MET occurs they start to divide again and cancer comes back

76
Q

if there is no micrometastasis then what is the chance of survival?

in breast cancer

A

75% for 10 years

77
Q

inefficiency of colonisation might be explained by what hypothesis?
formulated by who? when?

A

the seed and soil hypothesis formulated by Dr Paget in 1889

if they come from a tissue that was embryonically similar to the seconda

77
Q

inefficiency of colonisation might be explained by what hypothesis?

A

the seed and soil hypothesis formulated by Dr Paget in 1889

if they come from a tissue that was embryonically similar to the seconda

78
Q

what is the seed and soil hypothesis?

formulated by Dr Paget in 1889

A

‘’…seeds are carried in all directions but they can only live and grow if they fall on congenial soil’’

explains the inefficiency of colonisation (formation of macrometastasis)

79
Q

what is the explanation for the seed and soil hypothesis?

A

Organ trophism

80
Q

what type of circulation can cancer cells disseminate through?

A

the portal venous system
venous circulation
arterial circulation

81
Q

what protein is key in inducing EMT-MET cycles?

A

TGFbeta

82
Q

what is the proposed mechanism of MET

A

activation of microRNAs to inhibit EMT transcription factors (ZEB1, ZEB2OR TWIST)

82
Q

what is the proposed mechanism of MET

A

activation of microRNAs to inhibit EMT transcription factors (ZEB1, ZEB2OR TWIST)

83
Q

other than mutations, what other way can p53 be mutated

A

oncogenic viruses target and inhibit p53

83
Q

other than mutations, what other way can p53 be mutated

A

oncogenic viruses target and inhibit p53

84
Q

what mutational events occur along the progression of colon cancer?

A

normal epithelium is transformed into a hyperplastic epithelium by the loss of APC
DNA hypomethylation occurs to cause adenoma formation
activation of K-ras and loss of 18q TSG contribute to progression of adenoma from early to intermediate to late stage.
FInally loss of p53 means switch to a carcinoma and then invasion and metstasis

Cellular & Molecular Pathology (12 decks)

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