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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
Q

What happens when extracellular growth factor molecules bind to specific receptor proteins

A

Triggers a cascade of signalling events inside the cell
Involves protein kinases that attach phosphate groups

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26
Q

What amino acids do kinases phosphorylate

A

Tyr, Ser or Thr

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27
Q

What happens after the phosphorylation cascade transfers the signal to the nucleus

A

Regulates cell cycle proteins and txn factors

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28
Q

When can a gene, that’s involved in the growth transduction step, become an oncogene

A

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

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29
Q

What is PDGF

A

Platelet derived growth factor = potent growth factor
Released from platelets -> response to normal wound healing

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30
Q

How does PDGF act in virally transformed cells

A

Autocrine growth stimulatory factor for infected cells
Local paracrine effect on neighbouring stromal tissue

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31
Q

What once genes are related to fibroblast growth factor (FGF)

A

Hst
int2
FGF3/4/19

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32
Q

Describe Hst

A

Derived from human stomach cancer
Encodes 205 amino acid protein

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33
Q

Describe int2

A

Identified from murine mammary tumour virus (MMTV)
Encodes a 245 amino acid protein
Homologous to FGF3

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34
Q

Describe FGF3/4/19

A

Amplified in breast, head, neck and bladder cancers

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35
Q

What oncogenes have products related to growth factor receptors

A

erbB or EGF- receptor family
erbB1
erbB2

36
Q

Describe the EGF-receptor

A

Intracellular tyrosine kinase domain activity stimulated by EGF binding

37
Q

What other ligands does the EGFR have

A

TGF-a
Acts a an autocrine growth stimulator in some tumours

38
Q

Describe EGFR signalling

A

Ligand binding = receptors dimerise + activate intracellular kinase activity
Tyrosine kinases cross phosphorylate their partner
Phosphorylated residues are docking sited for signalling proteins

39
Q

What is the significance of EGFR over-expression in human cancer

A

Several cancers show abnormally high EGFR expression
Often associated with green amplification

40
Q

Describe EGFR expression in breast cancer

A

Inverse correlation with oestrogen receptor expression
Indicator of poor prognosis

41
Q

Describe EGFR expression in bladder cancer

A

Increased expression in late stage invasive tumours
Indicator of likely recurrence, invasive progression and poor survival

42
Q

Describe EGFR as therapeutic target

A

Specific inhibits or EGFR tyrosine kinase developed and have activity against a number of cancers

43
Q

Describe erbB2 oncogene

A

Sequence and overall structure similar to EGFR
Only binds ligands as part of a heterodimer with other receptors

44
Q

Describe c-erbB2 in breast cancer

A

Frequent and over-amplification and over expression of erbB2
Associated w higher incidence of early relapse and poor survival

45
Q

What is Herceptin

A

Humanised anti-erbB2 monoclonal antibody
Binds to extracellular of the HER2 receptor

46
Q

Which domain of EGFR is the most conserved

A

Tyrosine kinase domain n

47
Q

Which is the preferred homodimer for other members of erbB family

A

ErbB2.
Enhances proliferation signals from all the other receptors

48
Q

Describe the mechanism of activation of the RAS G-protein family

A

Single misses e gain of function point mutations
Always found at the same specific points
- codons 12/13 or 59/61 or 63

49
Q

What are the properties of the RAS gene product

A

Inner plasma membrane attachment required fro transforming activity
Localisation to inner membrane requires post-translational modifications

50
Q

What is farnesyl transferase

A

Modifies RAS gene products post translation

51
Q

Describe the KRAS-G12C mutation

A

Mutant cysteine
Renders proteins susceptible to specific irreversible binding with cysteine reactive small molecules

52
Q

Describe how the KRAS-G12C mutation can be targeted

A

Allosteric binding to the Switch-II domain locks KRAS in the inactive GDP-bound form

53
Q

Describe the Src homology regions on cell surface receptors

A

SH2 and SH3 are non-catalytic conserved region s
Found on many cytoplasmic signalling proteins

54
Q

Describe SH2 domain

A

Bind to tyrosine phosphorylated proteins

55
Q

Describe SH3 domain

A

Link to adapter proteins that couple tyrosine kinase receptors to specific target proteins

56
Q

How does Grb2 bind to a receptor

A

Via tyrosine phosphorylated regions of activated receptors
- via SH2 domain and Sos

57
Q

Describe Son of Sevenless (SOS)

A

Guanine nucleotide release factor
Interacts w RAS to displace GDP nucleotide
GDP replaced by GTP to activate RAS

58
Q

What cancers have EGFR overexpression

A

Colorectal
Pancreatic
Lung cancer
Non-small cell lung cancer

59
Q

What cancers have Ras mutations

A

Pancreatic
Papillary thyroid cancer
Colon cancer
Non-small cell lung cancer

60
Q

What cancers have B-Raf mutation

A

Melanoma
Papillary thyroid cancer
Colon cancer

61
Q

What are the 3 nuclear oncogenes encoding TFs

A

Jun
fos
MYC

62
Q

Describe Jun and fos

A

AP1 TFs complex

63
Q

Describe MYC

A

TF family

64
Q

Describe nuclear oncogenes that encode TFs

A

Normal expression highly regulated
Expressed at low levels in quiescent cells
Rapidly switched on in response to growth signals

65
Q

Where do nuclear oncogenes that encode TFs function

A

At the nuclear and of the growth signal transduction pathway
Covert primary stimuli to long-terms responses

66
Q

Name 2 cell cycle control proteins

A

Cyclins
Cyclin-dependent kinases

67
Q

Describe cell cycle proteins

A

+tive regulations of cell cycle progression
Deregulated expression is frequently seen in cancer
- can act as oncogenes

68
Q

Describe CDKs

A

Induce other proteins to perform their function by phosphorylating key residues

69
Q

Describe cyclins

A

Bind to CDKs to control their kinase function

70
Q

Name the 5 DNA repair pathways

A

Direct repair
NHEJ
HR
Mistmatch repair
NER

71
Q

What kind of repair pathway targets O6 methyl lesions caused by alkylation

A

Direct repair

72
Q

What repair pathway removes alkylation, deamination or oxidation

A

Base excision repair

73
Q

What are the 2 types of double strand repair pathways

A

NHEJ and HR

74
Q

What type of repair pathway targets DNA damage that distorts the helical structure

A

NER

75
Q

What repair pathway corrects replication errors in Newley synthesised DNA

A

Mismatch repair

76
Q

Describe direct repair

A

MGMT removes O6 methyl lesions on guanine
Binds to lesions and removes it
Is the deactivated and degraded

77
Q

Describe base excision repair

A

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
Q

What has a key role in BER

A

PARP
Recognise when somethings wrong in the DNA

79
Q

Describe NHEJ

A

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
Q

Describe HR

A

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
Q

What happens if there is no BRCA during HR repair

A

DNA can be repaired but not as high fidelity
= mutagenic error prone DNA

82
Q

What are the 2 types of NER

A

Global genome
Transcription-couples

83
Q

Describe NER

A

Recognition of damaged site
Binding and recruitment of factors
Excision of damaged DNA
Gap filling and religation

84
Q

What genes are involved in NER

A

XP gene s
If 1 missing, others can take on the role but wont be as efficient

85
Q

Whats the difference between NHEJ and HR

A

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
Q

Describe mismatch repair

A

Repairs lesions in newly synthesised DNA
Results ins mall mismatches or insertion and deletion loops

PED3006 Carcinogenesis (9 decks)

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