Brainscape's Knowledge GenomeTM

Browse over 1 million classes created by top students, professors, publishers, and experts.


See full index

B353 > L6, Infectious Agents and Cancer > Flashcards

L6, Infectious Agents and Cancer Flashcards

1
Q

What percentage of cancers are reportedly attributed to infectious diseases? Which are the two most prevalent?

A
  • Around 15% of cancers
  • H.pylori and HPV
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
2
Q

List 6 cancers with strong infectious drivers:

A
  • Cervical cancer (HPV)
  • Liver cancer (Hep. B and C)
  • Lymphomas (viruses)
  • Stomach cancer (H.pylori)
  • Rarer cancers cause by parasitic infections
  • HIV enables several cancers including Karposi’s sarcoma
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
3
Q

Early discoveries in tumour virology (1910-1981)

A
  • Rous: transmission experiments for avian sarcomas, discovered RSV
  • Identification of papillomavirus in rabbit
  • Discovery of murine leukaemia retrovirus
  • Adenovirus and SV40 induce tumours in rodents
  • First human tumour virus (EBV -> Burkitt’s lymphoma)
  • Origin of Src oncogene
  • AIDS-related cancers -> KS and non-Hodgkin’s lymphoma
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
4
Q

Rous sarcoma experiment

A
  • Removed sarcoma from breast muscle of affected chickens
  • Broke down and ground the tissue with sand
  • Collected filtrate from fine-pore filter (retaining only small viral particles and removing cell matter)
  • Injected filtrate into young chickens who eventually developed sarcomas
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
5
Q

How can viruses directly drive carcinogenesis? (x3)

A
  • DNA damage response and subsequent mutation due to integration of viral DNA into cellular DNA (retroviruses; HPV, EBV etc)
  • Modified viral oncogenes after integration into host cell DNA
  • Modified host genes integrated into viral genome act as oncogenes
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
6
Q

How can viruses indirectly drive carcinogenesis? (x5)

A
  • Detection of virus by PAMPs/DAMPs can induce chronic inflammation
  • Oxidative stress (ROS/RNS, mitochondrial stress, ER stress pathway)
  • Immunosupression by virus (HIV-1/2)
  • Prevention of apoptosis
  • Induction of chromosomal instability and translocations
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
7
Q

Structure of RSV:

A
  • env: surface glycoprotein (facilitating uptake through interacting with host)
  • gag: protein coat
  • pol: reverse transcriptase
  • lipid bilayer acquired from infected cell
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
8
Q

Retrovirus lifecycle:

A
  • Entry into cell and shedding viral envelope
  • Reverse transcriptase makes DNA/RNA and then DNA/DNA double helix
  • Integration of host DNA copy into host chromosome
  • Assembly of many new virus particles, each containing reverse transcriptase, into protein coats
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
9
Q

RSV monolayer experiment:

A

Studying how virus conveys cancer

  • Cell monolayer infected with RSV particle
  • Changed behaviour of cell; foci lose contact-contact inhibition so are no longer being signalled to cease growing once monolayer complete
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
10
Q

Temperature mutant RSV experiments:

A
  • Normal morphology cells infected with ts RSV mutant at 37 degrees -> produced transformed morphology
  • At increased temperature (41 degrees), transformed morphology was lost -> normal morphology
  • Shifting temperature back down restored cancerous phenotype
  • As such, the cancerous phenotype requires presence of active viral proteins
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
11
Q

Proposed model for source of v-src:

A
  • RSV has extra gene, src in genome compared to ALV
  • Host cell chromosomal DNA contains c-src which integrates with dsDNA provirus (from ALV virion), once transcribed as v-src is packaged into capsid as RSV
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
12
Q

Give the role of the Src oncogene: Mechanism of activation?

A

Src produced a protein kinase which signals for proliferation

  • In inactive form, C-terminal tail is phosphorylated
  • C terminal tail dephosphorylation activates activation loop, triggering autophosphorylation of src-activator
  • Activation loop phosphorylated and catalytic cleft thus exposed -> ACTIVE -> signals proliferation
  • In normal cells this is initiated in certain conditions whereas in v-src oncogenes it is constitutively activated
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
13
Q

What makes v-Src oncogenic compared to the gene in a healthy cell?

A
  • Lacks Tyrosine-527 on c-terminal tail; not inactivated by phosphorylation
  • Constitutively active
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
14
Q

How does ALV induce cancer?

A
  • Insertional mutagenesis
  • ALV: Slowly transforming retrovirus
  • Provirus inserts randomly into host genome
  • Very occasionally, inserts upstream of c-myc (1 in 10 million)
  • Induction of cancer is a rare event
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
15
Q

HPV and cervical cancer: Statistics

A
  • 4th most common cancer in women worldwide
  • 86% of cases in the developing world
  • Issue of transmission; compared ot breast cancer, much higher prevalence in 18-44
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
16
Q

HPV vaccinations:

A
  • Vaccine programmes introduced in early 90s
  • Cohorts with higher vaccination rates have historically better incidence rates (*partly predicted values)
  • Depends on lifetime of vaccination -> how long does protection last (expected around 10 years)?
17
Q

HPV characteristics:

Type of virus, key subtypes

A
  • dsDNA virus
  • Many subtypes, some innocuous (cause warts)
  • Show tissue tropism
  • High risk HPVs 16 and 18 cause cervical cancer
18
Q

HPV genome:

A
  • Early genes E1 to 7 (where E6 and E7 are oncoproteins) carry out viral replication
  • Late genes (L1, 2) produce capsid proteins
19
Q

HPV life cycle:

A
  • Microabrasions permit virus into tissue
  • Virion penetrates to stem cells in epithelial basement membrane -> inhabit differentiating cells and proliferate themselves
  • Not initially part of host genome; at an unknown point, virus enters host genome, uses E6 and E7 to drive carcinogenesis whilst reproducing
  • Tumour cells do not usually produce virions; this is an exception
20
Q

E7 mechanism:

A
  • High risk E7 binds to Rb and targets it for proteasomal degradation
  • Rb no longer binds and inhibits E2F
  • E2F target genes upregulated -> cell cycle entry and proliferation
21
Q

E6 mechanism:

A
  • Targets p53 for proteasomal degradation (ubquitin)
  • Complex requires both E6 and E6A to target p53
22
Q

Further tumour promoting effects of E6 and E7:

3 key hallmarks of cancer implicated

A
  • E6 derepressed expression of hTERT (telomerase component)-> enabling replicative immortality
  • E6 stimulates expression of VEGF (angiogenic factor)
  • E6 and E7 stimulate genomic instability
23
Q

H.pylori bacteria in cancer

A
  • Estimated to cause up to 90% of stomach cancers
  • Causes chronic inflammation
  • Carcinogenesis is driven in part by chronic inflammation and resultant genotoxic stress but also specific of virulence factors e.g. CagA
23
Q

Further infections linked to cancer (3 examples)

A
  • Southeast asian liver fluke causes liver cancer
  • Bilharzia causes bladder cancer
  • H.pylori causes stomach cancer
24
Q

Cancer and ER stress: Features of cancer cells, role of ER and UPR in cancer, relevance for field…

A
  • Common biochemical characteristics in tumours include: Hypoxia, high [GSH], certain proteinases, peroxide and ER stress
  • Higher rate of protein synthesis coupled with deregulated proliferation vs chromosome abnormalities in cancer impose stress on the ER
  • UPR: unfolded protein response, helps to balance protein production with demand; deregulated in cancer
  • Ensuing inflammation, cell markers and involvement in EMT -> relevant to invasiveness and motility
  • All of these features are frequently targeted in modern approaches e.g. theranostics in which diagnoses via fluorescence is coupled with therapeutic agents like camptotecin and its derivatives (various benefits, see C363)
25
Q

Role of CagA in H.pylori

A
  • Pleiotropic effects…
  • Can disrupt the cell cytoskeleton, cell polarity and cell junctions in addition to being mitogenic and pro-inflammatory
26
Q

Role of CagL in H.pylori:

A
  • Allows H.pylori to bind to integrins on the basolateral surface -> integrated into cells
  • As a result, TypeIV secretion system injects peptidoglycan and CagA into the cell, stimulating an inflammatory response
27
Q

Morphological changes in H.pylori infected cells:

A
  • Hummingbird phenotype
  • Cell-cell junctions altered
  • Cell elongation facilitates invasion
28
Q

+ Key feature of HPV positive cervical cancers

A
  • Found to express E6 and E7 (viral oncogenes)
  • These two components are the only parts of the viral genome that are consistently expressed in cervical carcinomas
  • These oncoproteins fulfil roles in two stages: tumour initiation (key focus) but also malignant progression (by inducing genomic instability etc)
  • This is often a slow progress with malignancies arising years to decades after original infection
29
Q

+ How do basal cells divide in epithelial basal layer

A
  • Asymmetric division perpendicular to basal membrane
  • One daughter retains basal cell characteristics and one is committed to differentiation -> withdraws from cell division cycle, subsequently pushed upwards within stratified tissue
30
Q

+ Why is evading anoikis important in the HPV life cycle? How is this thought to be carried out?

Experimental evidence:

A
  • Differentiated keratinocytes must retain the ability to reproduce DNA and divide beyond the basal membrane
  • Thought to be regulated by association with p600 protein of E7 through an amino terminal domain -> depletion of p600 known to cause loss of anchorage-independent growth
  • Just one of many delicate cancer promoting activities of the E6 and E7 viral oncogenes
31
Q

+ Give the name of the two cancer causing liver flukes, where are liver flukes most prevalent?

How is it often contracted?

A
  • O. viverrini
  • C. sinensis
  • Globally, incidence varies greatly, highest in Northeast Thailand
  • Typically ingested through raw/fermented fish containing infectious ‘metacercaria’ of the pathogen
32
Q

+ What type of cancer do liver flukes typically cause?

Technical name + key feature of this cancer type

A
  • Cholangiocarcinoma
  • Malignant neoplasm of biliary duct system
  • Difficult to diagnose (‘silent killer’) due to relatively silent clinical progression
33
Q

+ Key pathological changes of liver fluke infection

O.viverrini distribution among hosts:

A
  • Distribution of O.viverrini is highly dispersed in human hosts; generally light infection but small percentage of people have heavy infection and high risk of disease
  • Primarily damages the bile duct -> acute inflammation (IL-6) upon infection -> hyperplasia -> adenomatous formation, scarring, fibrosis -> cancer
  • Chronic infection more prone to carcinogenesis by ROS/RNS induction after initial inflammation
  • Analogous to liver cirrhosis but found in bile duct (instead of HCC)
  • Treatment against the liver fluke itself is actually thought to be a risk factor especially upon repeat infections and treatments (praziquantel)
34
Q

+ Governmental intervention against liver fluke

A
  • Mass drug administration (MDA) by Thai government
  • 1980s
  • Reduced prevalence of O.viverrini from 80% to 15-20% by 1997
35
Q

+ H. pylori virulence factors:

A
  • CagA -> Act.s ERK1/2 -> IL-8 and NFKB ->…-> atropic gastritis
  • VacA -> cyt c release in mit -> apoptosis
  • HtrA -> cleaves junctions (cadherins etc)
  • CagL -> binding to integrins on basolateral surface

B353 (15 decks)

Brainscape helps you reach your goals faster, through stronger study habits.
© 2024 Bold Learning Solutions. Terms and Conditions