#5 Oncogenesis Flashcards
Oncoviruses are necessary but NOT _____for cancer devo.
sufficient
Many/most people infected with a given virus do not devo the cancer that the virus can cause
Viral cancers appear in context of ________infections. Occur many years to decades after acute infection
persitant/chronic
Immune system can play a _____ or a prote______ctive role in virally induced oncogenesis
deleterious
protective
see human visus associated cancers in association with
immunosuppresion/chronic inflammation
How viruses causes indirect cancer
Chronic infection causes cirrhosis, inflammation, tissue damage, high levels of cell division to increase chance of mutation to derail growth control
How do viruses directly cause cancer
stimulate cells to enter S phase and make viral proteins to contineu to direct cell to ovvride normal controls on growth
How can we tell if a cancer we’re seeing epidemiologically is viral related
we’ll see it in an immunosuppresed population
aggressive skin cancer in elderly/immunocompormised
Merkel Cell carcinoma
Mech of merkel cell carcinoma
common deletion renders virus unable to complete replication cycle; persistnat infecction
common deletion renders virus unable to complete replication cycle; persistnat infecction
Merkel cell carcinoma
Papillomaviurs is member of:
genome:
infectects:
papovavirus
dsDNA
mucosal/epithelial~ hands/feet/genital
this has ~100 sub types with 1/3 infecting genital strand
papillomavirus
E1 and E2 of HPV mediate:
E1 and E2 mediate replication and transcription of viral DNA
E4 of HPV will:
E4 distrupts cytokeratins to facilitate virus egress~ helps virus out of the tissue
L1 and L2 of HPV
compose the capid
distrupts cytokeratins to facilitate virus egress~ helps virus out of the tissue
E4
mediate replication and transcription of viral DNA
E1 and E2
E5, 6, and 7 of HPV
intersect with key elements of cellular growth control, are associated with oncogenesis
E5 in HPV
stimulates constituitive GF replicating signal thus the cell no longer needs the GF receptor to signal replication
stimulates constituitive GF replicating signal thus the cell no longer needs the GF receptor to signal replication
E5
E6 and E7 in HPV
neutralize major ‘brakes’ that regulate cell cyle—p53 and Rb—thus uncouple cell division from key regulatory controls
neutralize major ‘brakes’ that regulate cell cyle—p53 and Rb—thus uncouple cell division from key regulatory controls
E6 and E7
Cousre of HPV
Inocculation of epitherlium→ hand/foot/throat or cervix→ Local multiplication→ wart
–resulotion(latency) OR –cell transformation
Life cycle of papillomavirus is tied to the differenation state of
keratinocytes
Stage of HPV virions fucking you up
a. Early gene expression in the basal layer of E1, E2, E6 and E7
b. Late gene expression and viral genome amplication: in the spinous layer
c. Virion assembly and release in the cornified layer
a. Early gene expression in the_____ layer of E1, E2, E6 and E7
basal
Late gene expression and viral genome amplication: in the ____ layer
spinous
Virion assembly and release in the _____layer
cornified
HPV stimulation of cell cycle causes cell in _______ to replicate
stratum spinosum
the spinosum is spitting out hpv
Where are cells supposed to regulate?
the stratum basal
BASICALLy, the basal layer
is the engine of the cell cycle: move the clel cycle ahead by phosphorylating key substrates
CDKs
CDK regulation
by enZ synthsis, degredation of cyclins, phosphorylation events, inhibtiors
key brake that blocks progression to S phase
Rb
Rb-P is in its’
inactive state… lets cell go G1–> S
how do we P Rb?
accumulate Cdk/cylcins and phosphorylate it
____ protein of papillomavirus binds to Rb—targets it for proteosomal degradation
E7
—E7 like syltherin… sneaky snake bastard
guaduain of genome to prevent proguression to S phase by making cyclins or inducing apoptosis
p53
the killer of p53 by targeting upiquitin to it!
E6
666 like the devil and now the cell is immoral! aghh!
two naughty function of E6
blocks p53 and increase telomerae
More then 99% of cervical cancers specimens show evidence of infection with ‘high risk’ strains of HPV strains
HPV 16 (50-60%)
HPV 18 (10-20%),
HPV6
HPV 11
See correlation btwn high risk strains and activity of_______proteins in vitro assays of cell transformation
E6 and E7
a. high risk; E6 + E7 can immortalize
keratinocytes
Early stage of acute and persistent HPV infection, viral DNA is maintained as
episome
-stays as a little extra chromo on its own then gets integrated into host DNA
Devo of carcinoma associated with integration of DNA into the host as what is retained?
E6 and E7 (always retained in cancer cells)
Integration disrupts expression of ________, which is transcriptional repressor, allow increased levles of E6 and E7
E2 gene
*Replication of integrated DNA triggers DNA amplications and chromosomal abnormalities
Our transcriptional repressor that is disrupted during integration of HPV into genome
E2
______ _______ key step towards oncogeneis in HPV
Genome integration
LSIL is
low grade squamous intraepitheilal lesion
HSIL
HIgh grade squamous intraepithelilal lesion
CIN
cervical intraepithelial neoplasia
productive infection we see ______
with low E7 and low viral DNA
LSIL; productive infection
Cellular Gene Deregulation:
we see increased:
E7 and viral DNA
Cervical cancer: DNA integration we see a break in ______
with high levels of
basal membrane
E7
Normal cervix→ to HPV invected cervix: seen in 370 million and often
cleared
HPV infected cervix→ to Low grade SIL: in about 70 million and can______ or move to ______
regress
HG-SIL
causes that precipitate moving from LSIL to HG-SIL
(especially if they smoke, OC use, viralload, coinfections)
HG-SIL (in 10 million) can regress or move on to
cervicle cancer:
in .5 million cases and can’t go back
How do we progress from HG-SIL to cervical cancer
occurs in viral integration methylation
- **E6/E7 mRNA is present as we______
* **___ will disappear as we move to cancer
progress
L1
cytological evidence of displasia or neoplasia; detect koilocytotic cells (vacuolated cytoplasm) which are rounded and appear in clumps
Pap smear
Pap smear that show evidence of displasia or neoplasia looks like:
detect koilocytotic cells~~~ round and clumpy
Step 1: Release nucleic acid: clincial specimes are combined with a base solution which release target
DNA
Step 2. Hybridize RNA probe with Target DNA: target DNA combines with specific RNA probes creating
RNA:DNA hybrids
- Capture Hybrids: multiple RNA:DNA hybrids captured onto solid phase coated with universal capsure _____ specific for RNA:DNA hybrids
antiBs
- Label for detection: captured hybrids dectected with multiple antiBs conjugated to ______. Signal then amplified 3000 fold
alkaline phosphatase
- Detect, read and interpret results: bound alkaline phosphates detected with ________ substrate. Upon cleavage by alkaline phosphatase, substartes produce light measure on luminometer in ______
chemiluminsent
Relative Light Units (RLUs)
Vaccine issues
a. need mucosal infection d/t route of infection
b. need to recognize multiple high risk strains
c. admin of vaccine that includes oncogenes not possible
d. societal issues: is this a vaccine to prevent cancer or STD
Capsid protein L1 will induce:
humoral innuminty
recombinant L1 can be made in culture
b.L1 self-assembles into_____ that resemble virions and induce appropriate immunological response
“VLPs”
Vaccine contains purifed VLPs
induces protective, humoral immunity
antiBs present at mucosal surfacee prevent incoming HPV from establishing infection
Guardasil
1. prevents precancerous lesion and warts: HPV
6, 11, 16, and 18
Gardasil admin age
- can be administerd as young as 9 and as old as 26
Type of vaccine Gardasil is?
when and why do you use it?
HPV is leading cause of cervicle cancer
should be given before onset of sexual activity but either way get vaccinated
this is a tetravelant vaccine
Cervical cancer stats FYI
- 15,000/year in US infected with cervcle cancer and 4,100 die per year d/t this
- 500,000 new cases /yr worldwide and see 250,000 deaths
- second or thrid most common cancer among women
- Vaccines for pre-adolescent girls with VPL vaccine and vaccine for men to deplete high risk HPV from popuation
- HPV is associated with penile cancers, vulvar cancers and anal cancer~ %25 of oroparnyeal cancers
