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BMS3031 > CANCER > Flashcards

CANCER Flashcards

1
Q

What are the known risk factors for cancer?

A
  • Tobacco
  • Reproductive factors
  • Certain microbes (e.g. Sarcoma virus, HPV–> viral proteins degrade tumor suppressor genes)
  • Alcohol
  • Occupational exposure
  • Obesity
  • Radiation
  • Unhealthy diet
  • Family history
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2
Q

What process leads a normal cell to becoming a cancer cell?

A
  • Transformation
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3
Q

What can both epigenetic and genetic changes lead to in terms of cancer?

A
  • Loss of tumour suppressor genes (e.g. P53)_

- Expression of oncogenes e.g. mutant EGFR

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4
Q

Which gene is lost in 50% of cancers and halts the cell cycle OR induces apoptosis to delete damaged DNA?

A
  • P53
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5
Q

What are the typical phenotypic differences in normal versus cancer cells? -

A

CANCER CELLS:

  • Large number of DIVIDING cells
  • Small cytoplasmic volume relative to nuclei
  • Variation in cell size and shape
  • Loss of normalised cell features
  • Disorganised arrangement of cells
  • Poorly defined tumour boundary
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6
Q

What are the three overall steps of carcinogenesis?

A
  • Initiation
  • Promotion
  • Progression
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7
Q

What occurs in the process of initiation (carcinogenesis)?

A
  • There is a genetic alteration which can be spontaneous or induced by carcinogenic factors.
  • This leads to a dysregulation in the biochem signalling pathways (cell proliferation, cell survival and differentiation)
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8
Q

What occurs in the process of Promotion (carconogenesis)?

A
  • These are EPIGENETIC changes
  • Preneoplastic cells accumulate
  • Can be altered by chemoprotective agents
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9
Q

What occurs in the progression phase of carconogenesis?

A
  • This is the final stage of transformation.

- MORE genetic changes occur that allow for invasion and metastasis to occur

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10
Q

What plays a major role in supporting the cell transformation of a cancer cell?

A
  • The microenvironment
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11
Q

What is an example of the steps of a cancer cell metasitaising?

A
  • Primary tumor formation
  • Localised invasion
  • INVASION
  • Transport through circulation
  • Arrest in microvessles of various organs
  • Extravasation
  • Formation of a micrometastasis
  • Colonisation (formation of a macrometastasis)
  • METASTASIS
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12
Q

What are the 6 Hallmarks of cancer?

A
  • Sustaining proliferation signalling
  • Evading growth suppressors
  • Activating invasion and metastasis
  • Enabling replicative immortality
  • Inducing angiogenesis
  • Resisting cell death
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13
Q

What are the positive and negative regulators of proliferation?

A
  • POSITIVE: Proproliferation signalling (ECM,) Integrin signalling (EGFR binding to Ligand EGF)
  • NEGATIVE: E-Cadherin (promotes ANTI proliferation signalling)
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14
Q

What are three main things that occur in H1: Sustained proliferative signalling?

A
  1. Cancer cells can synthesise growth factors (autocrine fashion, positive feedback loop)
  2. Overexpression of growth factor receptors (this makes the cell HYPER responsive to pro proliferation signals e.g. HER2 in breast cancer)
  3. The growth factor receptors mutate/truncate (this leads to ligand INDEPENDENT activation of signalling e.g. EGFR mutation in lung cancer)
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15
Q

Is the expression/activity of E-cadherin gained or lost in cancer?

A
  • It is LOST/REDUCED
  • This is because E-cadherin normally suppresses proliferation via cell-cell contact inhibition
  • When this is lost, the cells grow ontop of each other, and thus increases in prolferation
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16
Q

What is the main thing that occurs in H2: Evading growth suppressors?

A
  • Cancer cells are resistant to anti-proliferative signals via E-Cadherin loss
  • This means that the cells proliferate and grow on top of one another
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17
Q

What is E-Cadherin?

A
  • Transmembrane protein
  • Tumor suppressor gene
  • Connects epithelial cells at adherins junctions
  • Suppresses proliferation via cell-cell contact inhibiton
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18
Q

What is the main event that occurs in H3?

A
  • Resisting cell death
  • Cancer cells avoid cell death from apoptosis
  • This is due to the loss of P53 thus P53 induced apoptosis cannot occur
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19
Q

What occurs in P53 induced apoptosis?

A
  • When cells are stressed, (e.g. DNA mutations) P53 expression allwod Bax/Bak to form oligomers (apoptosome) and Cyt C release leads to intrinsic cell death (apoptosis)
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20
Q

What is the main event that occurs in H4?

A
  • Inducing angiogenesis
  • Tumours >1-2mm secrete pro-angiogenic facotrs e.g. VEGF and FGF
  • These bind their receptors on endothelial cells thus promoting angiogenesis
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21
Q

What does oncogene expression in cancer cells allow for?

A
  • Promotes the secretion of angiogenesis factors

- tumour hypoxia also promotes this

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22
Q

What is angiogenesis essential for?

A
  • Waste removal and nutrient/oxygen supply for tumours
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23
Q

What is the main event occuring in H5?

A
  • Enabling replicative immortaility
  • The cancer cells avoid senescence (senescence means to stop dividing)
  • The cancer cells do this by expressing telomerase (regenerates the telomeres)
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24
Q

What is the main event that occurs in H6?

A
  • H6 is Avtivation o invasion and metastasis
  • there is LOCAL invasion, extravasation and growth at distant tissue site.
  • Activation of EMT (Epithelial to Mesenchymal transitio–> E-Cadherin downregulated)
  • Increased expression of proteins that PROMOTE cell invasion (e.g. MMPs- matrix mellanoproteases and also Rac)
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25
Q

After the cancer has metastasised, does it stay as a mesenchymal state?

A
  • NO
  • It transitions BACK into an epithelial state
  • If this is BLOCKED, then metastasis is prevented from occurring further.
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26
Q

Do cancer cells lack contact inhibition?

A
  • YES
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27
Q

Do cancer cells induce angiogenesis?

A
  • YES
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28
Q

Do cancer cells LACK differentiation?

A
  • YES
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29
Q

Are cancer cells immortal?

A
  • YES
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30
Q

What is the formation of a new blood vessel called?

A
  • Angiogenesis
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31
Q

Which phase of carcinogenesis does angiogenesis occur in?

A
  • Progression
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32
Q

If two patients that phave breast cancer both have increased VEGF expression, what does this mean?

A
  • That they will be likely to have primary tumors that are larger than 2mm
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33
Q

In two patients with breast cancer, the patient A has lower E-cadherin expression, and increased MMP expression compared to the patient B, does this mean that they will have a poorer prognosis?

A
  • Most likely yes

- Because MMPs are associated with metastasis and the other patient had no change in their MMP expression

34
Q

In two patients with breast cancer, one is showing the signs of metastasis (stage IV, increased MMP expression and lower E-Cadherin). Are they likely to have an increased expression of Telomerase?

A
  • YES

- Telomerase is one of the last things to occur (avoiding senescence)

35
Q

What are the two general ways that cancer can be generated?

A
  1. Expression of an oncogene (from a proto-oncogene mutation)
  2. Loss of expression of a tumor suppressor gene
36
Q

In a proto oncogene, do one or both alleles need to be mutated to cause pathology? -

A
  • Only ONE
37
Q

In a tumor suppressor gene, do one or both alleles need to be mutated to cause pathology?

A
  • BOTH
38
Q

What are two types of tumor suppressors?

A
  • Tumor suppressor genes

- DNA mis-match repair enzymes

39
Q

What is the normal function of proto-oncogenes?

A
  • Needed for cell survival

- Do this via growth factor receptors (EGFR) and signalling proteins (B-RAF)

40
Q

What type of mutation occurs with a proto-oncogene? -

A
  • Turns it into an oncogene

- Activating mutation –> ‘gain of function’

41
Q

What type of mutation occurs with tumor suppressor genes?

A
  • Inactivating mutations

- Loss of function

42
Q

What is an example of an inherited cancer that involves a loss of function mutation in tumor suppressor genes?

A
  • Rb gene (retinoblasstoma–> eye tumors)
43
Q

How does Retinoblastoma work?

A
  • BOTH Rb alleles are inactivated
  • NORMALLY pRb binds to E2F (Transcription factor)
  • This inhibits the cell entry into S phase
  • The inactivation of Rb PROMOTES cell cycle and DNA synthesis
44
Q

How do the cancers HPV and SV40 promote cell growth?

A
  • Bind to an inhibit the pRb that normally prevents the cell from entering S phase
  • Thus cells continually enter S phase and replicate
45
Q

What is the ‘two hit hypothesis’?

A
  • that the loss of TWO tumor suppressor genes is required for the development of cancer
  • Known as a ‘loss of heterozygosity’
46
Q

Apart from regulation of the cell cycle, what else can Tumor suppressor genes promote?

A
  • Cell adhesion
  • DNA repair
  • Apoptosis
47
Q

True or false: P53 is activated via stress and regulates transcription

A

-TRUE

48
Q

Is p53 an oncogene or tumor suppressor gene?

A
  • Tumor suppressor gene!
49
Q

What can 4 examples of proto-oncogenes include?

A
  1. Growth factors
  2. Growth factor receptors
  3. Intracellular transducers
  4. Transcription factors
50
Q

What does the hyperactivation of EGFR lead to?

A
  • Aquisition of cancer hallmarks
  • e.g. sustained proliferative signalling
  • Evasion of growth suppressors
  • Resisting cell death
51
Q

In cancer, how are RTKs activated?

A
  • Normally, they are activated by the ligand binding
  • BUT HYPERACTIVE SIGNALLING IN CANCER
  • Can be due to AUTOCRINE SECRETION of growth factors which lead to ligans dependent hyperactive signalling
  • OR activated in a ligand INDEPENDENT manner
  • Can be due to DUPLICATION of the kinase domain
  • This leads to hyperactivated signalling
52
Q

What are three different mechanisms by which proto-oncogenes can be converted to oncogenes?

A
  • dominant point mutations
  • Localised reduplication (gene amplification)
  • Chromosomal translocation
53
Q

What occurs as a result of point mutations of a proto-oncogene?

A
  • Mutant protein (oncogene)
  • Constituitivley active -
  • Only ONE allele required to be mutated
54
Q

What occurs as a result of localized reduplication of DNA segment (proto–> oncogene) ?

A
  • If the gene amplification occurs in a DNA segment that INCLUDES a proto oncogene, then there will be overexpression of the wild type protein
55
Q

What occurs as a result of chromosomal translocation involving proto oncogenes? -

A
  • The growth regulatory gene is under the control of a different promoter
  • This causes an increased expression of wild type mutant protein.
56
Q

What is the result of methylation of CpG islands or histones normally, and is this the same in cancer cells?

A
  • Repression of transcription
  • NO cancer cells are different
  • They have a different methylation profile (different epigenetics)
57
Q

What is the hypothesis of the mutator phenotype?

A
  • Loss of a genome caretaker gene (DNA repair enzyme or TSG) leads to instability in precancerous lesions
  • This drives tumor development by INCREASING the spontaneous DNA mutation rate
    e. g. P53
58
Q

What is the Oncogene-induced replication stress hypothesis?

A
  • That oncogene expression INCREASES the proliferation rate in precancerous lesions
  • This induces DNA replication stress leading to MORE mutations
  • Hyper proliferative cells have a GROWTH advantage.
    e. g. RTK, EGFR
59
Q

What is the rough life cycle duration of Keratonocytes?

A
  • 40 days
60
Q

What is the main risk factor for melanoma and non melanoma skin cancer?

A

-UV light

61
Q

What dramatically increases the change of developing a basal cell carcinoma?

A
  • More than 5 cases of blistering sunburn in childhood.
62
Q

Does UVA or UVB radiation induce cyclobutane pyrimidine dimers (DNA lesions)?

A
  • UVB light induces these lesions
63
Q

Why are the DNA repair mechanisms so important when being exposed to UV light for only 1 hour?

A
  • Because in this hour, roughly 360 000 CPDs will form (Cyclobutane Pyrimidine Dimers)
  • This means there are 100 per second!
  • Therefore very important to repair this
64
Q

What is the effect of the cyclobutane dimers?

A
  • They cause a PHYSICAL kink in the DNA strand

- This means that when the polymerases enter to make the second strand, they can’t read it properly

65
Q

How are CPDs formed (cyclobutane pyrimidine Dimers)?

A
  • UV light absorbed by double bond in C and T bases (breaks the bond)
  • The open bond then allows for a new bond to be formed between adjacent thymines
66
Q

What are 6,4 photoproducts?

A
  • They are DNA lesions
  • Occur 3X less frequency than CPDs
  • After UVB radiation, Covalent bond forms between C6 of 5’ base AND C4 of 3’ base.
67
Q

How does the body deal with UV induced DNA lesions?

A
  • NER enzymes (Nucleotide Excision Repair) –>e.g. UVrA-D
  • These recognise and remove the damaged DNA from UV light.
  • e.g. They recognise the dimer (kink in DNA) and cut it out
  • DNA polymerase then FILLS the gap and nick is sealed by DNA liagase
68
Q

What is the hallmark of UVB-induced DNA damage?

A
  • CC–> TT mutation
69
Q

When the UVB DNA damage is not repaired, what occurs?

A
  • The DNA strand with the lesion (CBD) contains CC nucleotides and is copied
  • This means the new copied strand contains AA from CC
  • This means that the copied strand will pair with TT thus , CC–» TT mutation
70
Q

What types of mutations can occur in SSC (Squamous cell carcinoma)?

A
  • Mutations in GTPase Ras, and P53
71
Q

Which singalling pathway does Ras activate?

A
  • MAPK
72
Q

What is a marker of the MAPK pathway activation?

A
  • pERK (phosphorylated Erk)
73
Q

Is SSC present in the lungs and colon as well as the skin?

A
  • YES
74
Q

In SSC, which mutations are thought to occur in the initiation phase?

A
  • RAS and P53 mutations as a result of DNA photoproducts
75
Q

In SSC, what is thought to occur in the promotion phase?

A
  • Signalling pathways allow for the activation of AP-1 and COX2 expression
  • This mans there is a benign papolloma formation
76
Q

In SSC, what occurs in the Progression stage?

A
  • Consituitive COX-2 and AP-1 expression, genetic instability
  • This leads to malignant conversion and metasitasis
77
Q

What is the issue when applying COX-2 inhibitors for the treatment of Squamous cell carcinoma?

A
  • They increase the risk of a heart attack
78
Q

What is Xeroderma Pigmentosa?

A
  • Autosomal recessive
  • Loss of function mutation in NER enzymes
  • This means that the body is HIGHLY sensitive to IV light
  • Leads to SEVERE blistering thus GREATLY increased chance of developing melanoma early
79
Q

What can Basal cell carcinoma be associated with genetically?

A
  • Mutation in the Patched tumour suppressor gene (Hedgehog signalling)
80
Q

What is Gorlin syndrome (BSNS)?

A
  • Individuals are born with a mutant PTCH allele
  • Loss of function mutation which means that the Hh signalling pathway is hyperactivated
  • This leads to expanasive basal cell carcinoma, benign tumours in heart etc.
81
Q

What is the normal function of patched?

A

It is a tumour suppressor gene that suppresses smoothened

BMS3031 (6 decks)

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