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PED3006 Carcinogenesis > Cellular And Molecular Biology Of Cancer > Flashcards

Cellular And Molecular Biology Of Cancer Flashcards

1
Q

What are the general features of a benign cancer

A

Locally confined in non vital organs
Differentiated (resemble tissue of origin)
Loss of normal patterns of growth

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2
Q

What are the general features of a malignant cancer

A

Invades other tissues
Spreads too distant organs via blood and lymphatic system
Loss of differentiated morphology

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3
Q

What are the main hallmarks of cancer

A

Sustaining proliferative signalling
Evading growth suppressors
Activating invasion and metastasis
Enabling replicative immortality
Inducing angiogenesis
Resisting cell death

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4
Q

What are the enabling hallmarks of cancer

A

Deregulating cell energetic - can use anaerobic glycolysis
Avoiding immune destruction

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5
Q

What are the enabling characteristics of cancer

A

Genome instability and mutation i.e abnormal kayrotypes
Tumour-promoting inflammation

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6
Q

What evidence is there for the genetic basis of cancer

A

Loss of growth control is heritable
DNA damaging agents are generally carcinogenic
Genetic predisposition to some cancers is hereditary

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7
Q

How can the X-linked G6P markers be used to distinguish between normal and cancerous cells

A

Random X- inactivation generates a mosaic in normal tissues

Use of A and B markers to distinguish between the alleles

Tumours express only 1 allele whereas surrounding tissue can express either allele

Shows clone of tumour cells surrounded by normal mosaic tissues

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8
Q

Name some cancers that have viral aetiology in humans

A

HPV - cervical cancer
Hepatitis B/C - liver cancer
Epstein-Barr virus - nasopharyngeal cancer

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9
Q

How are tumour causing viruses classified

A

DNA viruses
Long latency retroviruses (LTRs)
Acutely transforming retroviruses (ATRs)

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10
Q

What are the types of cancers mainly associated with viruses

A

Sarcomas or leukaemia’s

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11
Q

What happened to the morphology of the fibroblast colony when ATRs are introduced

A

Disordered colony morphology
Loss of contact inhibition
Can grow independently of cell attachment

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12
Q

What did in vitro transformation assays show in regards to viral genes

A

Suggest theres a direct viral gene that is involved/expressed that is responsible

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13
Q

What are the genes necessary for a virus to replicate

A

Gag; encodes fro viral core
Env; encodes for viral envelope glycoproteins
Pol: RNA dependent DNA polymerase

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14
Q

What gene was discovered in viruses that was not necessary for replication

A

Src

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15
Q

What is the role of Src

A

Essential for the transforming/oncogenic effect of the virus

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16
Q

How do oncogenes differ with viruses

A

Carry different oncogenes with products located in different parts in the transformed host cell
Exhibits a range of different biochemical functions

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17
Q

What suggest that viral oncogenes are transducer from normal cellular genes

A

Homologous to host genomic sequels (approx 80%)

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18
Q

What could be the reason for the absence of intronic sequences in viral DNA

A

Picked up as reverse transcripts of cellular mRNA that become co-integrated with viral cDNA
Proved a growth or survival advantage

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19
Q

Why do long latency retroviruses cause tumours that take a longer time to develop?

A

Do not carry oncogenes
Produce genetic alterations in the host cells

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20
Q

Describe the enhancer effect

A

Integration of viral DNA downstream instead of upstream of the exons

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21
Q

What is the most important part of viral DNA

A

LTR: as long as that is present to obtain the TFs that drive expression

Don’t need any other coding region to drive the tumour

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22
Q

Describe the karyotype of tumour cells

A

Show frequent abnormalities in number and structure

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23
Q

Describe gene amplification

A

The fain of multiple copies of a chromosomal region
Can manifest as HSRs or double minutes
Over-expression of genes in that region confer a selective growth advantage

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24
Q

Describe chromosomal translocation

A

Interchange of segments from different chromosomes

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25
What happens when extracellular growth factor molecules bind to specific receptor proteins
Triggers a cascade of signalling events inside the cell Involves protein kinases that attach phosphate groups
26
What amino acids do kinases phosphorylate
Tyr, Ser or Thr
27
What happens after the phosphorylation cascade transfers the signal to the nucleus
Regulates cell cycle proteins and txn factors
28
When can a gene, that’s involved in the growth transduction step, become an oncogene
When a mutation = product becomes constitutively active even in absence of positive growth signal Gene is over-expressed due to green amplification or promoter alteration
29
What is PDGF
Platelet derived growth factor = potent growth factor Released from platelets -> response to normal wound healing
30
How does PDGF act in virally transformed cells
Autocrine growth stimulatory factor for infected cells Local paracrine effect on neighbouring stromal tissue
31
What once genes are related to fibroblast growth factor (FGF)
Hst int2 FGF3/4/19
32
Describe Hst
Derived from human stomach cancer Encodes 205 amino acid protein
33
Describe int2
Identified from murine mammary tumour virus (MMTV) Encodes a 245 amino acid protein Homologous to FGF3
34
Describe FGF3/4/19
Amplified in breast, head, neck and bladder cancers
35
What oncogenes have products related to growth factor receptors
erbB or EGF- receptor family erbB1 erbB2
36
Describe the EGF-receptor
Intracellular tyrosine kinase domain activity stimulated by EGF binding
37
What other ligands does the EGFR have
TGF-a Acts a an autocrine growth stimulator in some tumours
38
Describe EGFR signalling
Ligand binding = receptors dimerise + activate intracellular kinase activity Tyrosine kinases cross phosphorylate their partner Phosphorylated residues are docking sited for signalling proteins
39
What is the significance of EGFR over-expression in human cancer
Several cancers show abnormally high EGFR expression Often associated with green amplification
40
Describe EGFR expression in breast cancer
Inverse correlation with oestrogen receptor expression Indicator of poor prognosis
41
Describe EGFR expression in bladder cancer
Increased expression in late stage invasive tumours Indicator of likely recurrence, invasive progression and poor survival
42
Describe EGFR as therapeutic target
Specific inhibits or EGFR tyrosine kinase developed and have activity against a number of cancers
43
Describe erbB2 oncogene
Sequence and overall structure similar to EGFR Only binds ligands as part of a heterodimer with other receptors
44
Describe c-erbB2 in breast cancer
Frequent and over-amplification and over expression of erbB2 Associated w higher incidence of early relapse and poor survival
45
What is Herceptin
Humanised anti-erbB2 monoclonal antibody Binds to extracellular of the HER2 receptor
46
Which domain of EGFR is the most conserved
Tyrosine kinase domain n
47
Which is the preferred homodimer for other members of erbB family
ErbB2. Enhances proliferation signals from all the other receptors
48
Describe the mechanism of activation of the RAS G-protein family
Single misses e gain of function point mutations Always found at the same specific points - codons 12/13 or 59/61 or 63
49
What are the properties of the RAS gene product
Inner plasma membrane attachment required fro transforming activity Localisation to inner membrane requires post-translational modifications
50
What is farnesyl transferase
Modifies RAS gene products post translation
51
Describe the KRAS-G12C mutation
Mutant cysteine Renders proteins susceptible to specific irreversible binding with cysteine reactive small molecules
52
Describe how the KRAS-G12C mutation can be targeted
Allosteric binding to the Switch-II domain locks KRAS in the inactive GDP-bound form
53
Describe the Src homology regions on cell surface receptors
SH2 and SH3 are non-catalytic conserved region s Found on many cytoplasmic signalling proteins
54
Describe SH2 domain
Bind to tyrosine phosphorylated proteins
55
Describe SH3 domain
Link to adapter proteins that couple tyrosine kinase receptors to specific target proteins
56
How does Grb2 bind to a receptor
Via tyrosine phosphorylated regions of activated receptors - via SH2 domain and Sos
57
Describe Son of Sevenless (SOS)
Guanine nucleotide release factor Interacts w RAS to displace GDP nucleotide GDP replaced by GTP to activate RAS
58
What cancers have EGFR overexpression
Colorectal Pancreatic Lung cancer Non-small cell lung cancer
59
What cancers have Ras mutations
Pancreatic Papillary thyroid cancer Colon cancer Non-small cell lung cancer
60
What cancers have B-Raf mutation
Melanoma Papillary thyroid cancer Colon cancer
61
What are the 3 nuclear oncogenes encoding TFs
Jun fos MYC
62
Describe Jun and fos
AP1 TFs complex
63
Describe MYC
TF family
64
Describe nuclear oncogenes that encode TFs
Normal expression highly regulated Expressed at low levels in quiescent cells Rapidly switched on in response to growth signals
65
Where do nuclear oncogenes that encode TFs function
At the nuclear and of the growth signal transduction pathway Covert primary stimuli to long-terms responses
66
Name 2 cell cycle control proteins
Cyclins Cyclin-dependent kinases
67
Describe cell cycle proteins
+tive regulations of cell cycle progression Deregulated expression is frequently seen in cancer - can act as oncogenes
68
Describe CDKs
Induce other proteins to perform their function by phosphorylating key residues
69
Describe cyclins
Bind to CDKs to control their kinase function
70
Name the 5 DNA repair pathways
Direct repair NHEJ HR Mistmatch repair NER
71
What kind of repair pathway targets O6 methyl lesions caused by alkylation
Direct repair
72
What repair pathway removes alkylation, deamination or oxidation
Base excision repair
73
What are the 2 types of double strand repair pathways
NHEJ and HR
74
What type of repair pathway targets DNA damage that distorts the helical structure
NER
75
What repair pathway corrects replication errors in Newley synthesised DNA
Mismatch repair
76
Describe direct repair
MGMT removes O6 methyl lesions on guanine Binds to lesions and removes it Is the deactivated and degraded
77
Describe base excision repair
Glycolyses remove modified base and generate an AP site Endonuclease cut the DNA and remove a few bases APE1 hydrolyses AP site Uses opposite strand and a DNApol fills in gap Strands religated
78
What has a key role in BER
PARP Recognise when somethings wrong in the DNA
79
Describe NHEJ
Ku80 distal and Ku70 proximal to break DNA-PKcs recruited -> Kus become active = DNA ends brought together Ligase joins the break NHEK proteins removes and ligation proceeds -> autophosphorylation by DNAPKcs
80
Describe HR
Requires a template strand High fidelity repair that occurs only in S/G2 phase Needs ATM to recognise the damage and BCRA proteins to process some damage
81
What happens if there is no BRCA during HR repair
DNA can be repaired but not as high fidelity = mutagenic error prone DNA
82
What are the 2 types of NER
Global genome Transcription-couples
83
Describe NER
Recognition of damaged site Binding and recruitment of factors Excision of damaged DNA Gap filling and religation
84
What genes are involved in NER
XP gene s If 1 missing, others can take on the role but wont be as efficient
85
Whats the difference between NHEJ and HR
NHEJ just puts the DNA back together tot allow DNA replication = doesn’t ensure integrity HR is high fidelity and ensures integrity NHEJ can occur at any point but HR only when cells replicate
86
Describe mismatch repair
Repairs lesions in newly synthesised DNA Results ins mall mismatches or insertion and deletion loops

PED3006 Carcinogenesis (9 decks)

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