What are the common features of the cancer-causing viruses?
- persistently infecting, lasting years in patients
- geographically, culturally-restricted
-viruses are more common than the tumors they cause (infection alone is not sufficient to cause cancer - infection is only one hit in multi-hit carcinogenesis)
- viruses operate directly ie) virus genome or parts of the genome are in the tumor cells EXCEPTION: HIV and HCV
what percentage of cancers are associated with viral infections?
which is most common in women?
10-20% of CA are associated with viral infection s
Women -- cervical cancers
[HPV --> warts = epithelial dysplasia; others cause epithelial carcinoma]
Men -- liver cancers
How many different types of HPV infections are there?
What are they associated with?
There are over 100 HPV types -- each type of wart is associated with a distinct type of HPV
Type classification is based on relatedness of the HPV DNA genomes (less than 50% puts HPV viruses into different HPV type)
types are very specific to the types of HPV infection that is presented
Condyloma accumunata - HPV, sexually transmitted via mucosal
There is cutaneous, mucosa, cutaneous and/or mucosal and cutaneous associated with epidermodysplasia verruciformis (rare)
Each type of wart has a particular HPV type. HPVs are very similar structurally but their DNA sequences vary. An HPV is set apart from other types by having less than 50% DNA genome relatedness (as based by DNA hybridization tests).
whats the difference between high grade and low grade mucosal HPV infections?
Why is it important to distinguish the type?
HPV in the mucosal group are divided into high and low risk categories
High risk: 16, 18 --> cervical intraepithelial neoplasia --> cervical squamous cell CA, adenocarcinoma, oropharyngeal CA;
LOW RISK: HPV 6, 11, 13, 32..... smaller risk of cervical squamous CA; usually associated with benign genital lesions, respiratory papillomatosis, oral focal epithelial hyperplasia
The type classification matters, because each type causes a distinct type of wart disease/morphology, some being cutaneous and some mucosal.
A cutaneous HPV cannot cause a mucosal wart.
*a mother with a cutaneous HPV wart will NOT transmit it as an anogenital condyloma to her child*
A child should NOT have condylomas since condylomas arise from sexually transmitted HPVs-might want to suspect sexual abuse
How does the HPV virus infect?
HPV = naked, very stable DS-DNA virus that infects through breaks in the epithelial layers (must be able to reach the basal cells!) / gains access to the basal layer of skin via cuts and abrasions--> the basal layer of cells have the "HPV receptors" for the virus --> virus infects, delivering the viral genome into the cell; DNA enters the nucleus and remians there as an episome --> HPV replication cycle is tied to epithelial cell differentiation-ie) when the basal keritinocytes differentiate to form teh spinosum layer, the HPV genome replicates up to 50 episomal copies per cell -- Episomal HPV DNA + new virions produced in more differentiated cells; as the dead cells sloth off the corenum layer of skin, the viruses are released
=> cervical intraepithelial neoplasia --> integrated HPV DNA but no virus production => invasive CA
episome = DNA not associated with the host genome
Virus particles are not produced in the granulosum layer, they are produced in more differentiated cells, virus capsid proteins are produced.
when do the HPV genes get expressed?
DNA is introduced as an episome to the BASAL LAYER
First set of genes = E "early" genes...shortly after basal keratinocytes are infected, they are produced. These are the gene products that contribute to the dysplastic state of the cell
Late gene products = "L" are transcribed only at terminally differentiated cells, they form the capsules in which the virion particles are packaged in
FIRST MAKE THE GENOMES, THEN MAKE THE STRUCTURAL PROTEINS
How does HPV cause epithelial cancers?
Episomes "accidentally" integrate into the host chromosome of the differentiating cells. Cell transformation comes from abortive events that rarely take place, and stochastically after infection of the basal cells
What does E6 and E7 bind to?
What does this cause?
E6 - p53
E7 - Rb
E6 and E7 are viral oncogenic proteins but do not opperate as DIRECTLY pro-oncogenic agents --> block the actions of p53 and rb
P53 and Rb are tumor suppressors - they are check points within the cell cycle, typically arrest cell at G1-S boundary; they are RECESSIVE, so the elimination of one often have no effect - why they have the recessive nature of 2 allelles. BOTH --> uncontrolled progression through the cycle
It is continued overexpression of E6 and E7 genes that contribute to cell immortalization
What is the difference between normal cells and infected cells?
Normal cells have low levels of p53. Viral infections, such as HPV infection, or DNA damage, such as caused by irradiation, or cell stresses, such as caused by mutagens, will induce signal transductions that bring about increased p53. The higher levels of p53 will set up new gene expression profiles (p53 is a transcription factor). Amongst the new gene products are some that will halt the cell cycle at the G1 / S boundary. There are other gene products that are pro‐apoptotic, and the cells will go into programmed cell death (better to kill the damaged cells than to let them propagate).
vaculated cytoplasm with halos around
Koilocytes (hallmark) - usually developes eyars after
Pap or DNA probe for HPV
SURGICAL: Indications to remove warts- pain, cosmetic reasons, or in the case of laryngeal papillomasà remove airway obstructions
- Surgical cryotherapy or electro cautery, remove warts
- Podophyllotoxin cream [podophyllotoxin; aka PPT; is a plant-derived toxin that damages DNA to kill HPV-infected cells]
- Imiquimod cream [imiquimod is a synthetic TLR7 agonist that induces proinflammatory cytokines, notably interferons, which attract antiviral effector cells to destroy warts] – wart is resolved faster
- Cidofovir [cidofovir is a nucleoside analog that blocks DNA polymerases; standard use is to reduce herpes infections but topical cidofovir has been shown to reduce some HPV-induced warts]
What is the vaccine against HPV made up of and what strands does it help protect?
contains VIRUS-LIKE PARTICLES...induces IgG!
not recommended for pt with yeast allergies
Contains four HPV VLPs: 6, 11, 16, 18 (some cross protection)
Give in 3 injections
protects against 70% of the cervical CA
Ineffective if pt already has CIN