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22 Cards in this Set
- Front
- Back
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Cellular Genes Regulate Cell Cycle
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Virus-induced transformation alters expression or function of proto-oncogenes, tumor suppressors, or both.
Four general mechanisms: -induction of a cellular oncogene -expression of a viral oncogene -inactivation of cellular tumor suppressors -indirect promotion of cell division and genetic instability (often due to inflammation) |
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Key cellular growth regulators
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Retinoblastoma susceptibility protein pRb
-E2F complexed with RB and is inactive -If RB is phosphorylated, E2F is released and can act as transcription factor for replication genes Tumor suppressor p53 -Upregulates p21 inhibits kinases leading to cell cycle arrest -Upregulates Bax which leads to apoptosis |
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Human papilloma virus: structure, disease, cancer associated
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Virus
-Typical small DNA tumor virus -Non-enveloped, environmentally stable particle -More than 80 distinct human types Disease -Warts --Benign hyperplasia of the epithelia --Common, flat, palmo-plantar, genital, laryngeal --Flat / colored skin (epidermodysplasia verruciformis (EV)) Cancer (associated with “high risk” types) -Cervical carcinoma (types 16, 18 > 6, 11, 31, 35) -Skin carcinoma in EV patients (types 5, 8 > 20, 47) -By bypassing cellular growth controls --pRb and p53 |
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HPV tropism
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Either cutaneous or mucosal and either low or high disease risk
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Human papilloma virus infection
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-Exquisite selectivity for skin or mucosal epithelium
-Virus enters through micro lesions in cornified layer -Virus infects basal cells -Viral genes drive cellular differentiation and DNA replication -Viral DNA replicates in terminally differentiated cells: no viral DNA pol! -Virus particles are released with released cells and by breakdown of the keratin filament system |
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HPV Pathogenesis
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Most common sexually transmitted infection
-75% of sexually active females will acquire infection with at least one strain -Second largest cause of cancer death in women Majority of all infections resolve without disease within 12-18 months Viral persistence associated with increased risk of cervical epithelial cell abnormalities (positive “Pap” smear; 1928): koilocytotic cells 100% of cervical cancers are HPV positive, but most occur >3-5 years after infection |
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Progression to Cancer Following HPV Infection
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HPV infection usually from age 15-25
10% progress to precancer -subset of these become metastatic carcinomas |
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Oncogenic transformation by human papilloma virus
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Critical HPV early genes promote replication
E7 -Binds pRb and releases active E2F; enables viral DNA replication -"High risk" forms have greater affinity and induce pRb degradation E6 -Binds and modifies cellular ubiquitin ligase E6-AP -E6-AP targets p53 for degradation -blocks cell death until replication is complete Viral DNA is episomal at early stages of cancer, but is integrated in advanced cancer Integration event preserves viral E7 and E6 genes which bypass cellular growth control mechanisms Viral genes required for completion of replication (E1, E2, capsid L genes) are disrupted upon integration |
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HPV DNA integration Leads to Sustained E6, E7 Expression and Cellular Transformation
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LSIL (low grade squamous intra-epithelial lesion)
-CIN 1 (cervical intraepithelial neoplasia): HPV infection, virus production HSIL (high grade squamous intra-epithelial lesion) -CIN 2: No virus production -CIN 3: High E6 and E7, viral integration leads to carcinomas |
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Most oncogenic infections with the small DNA tumor viruses are defective
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HPV as episome (normal)
-E7 releases E2F from RB and E6 induces p53 degradation -viral replication commences, E6/E7 turned off -cell death HPV integrated into host genome -E7 releases E2F from RB and E6 induces p53 degradation -viral replication cannot occur, E6/E7 expressed continuously -uncontrolled cell proliferation |
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HPV spread & risk factors
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particles shed in mucosal secretions
-remain infectious on dry skin surfaces -present on genital surfaces (penis, scrotum, vulva) and fingers/fingernails -condom use may not prevent spread Age: 15-25 highest incidence -infection highly prevalent in males and females ->75% of sexually active individuals with no disease symptoms --50-75% are high-risk infections Risk factors of acquisition: -Total number of sexual partners -recent sexual partners -promiscuous sexual partners -oral contraceptive use -smoking -history of herpes or vulvar warts |
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Approaches to HPV Control: infection prevention, screening, therapy
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Prevention of infection
-delay of sexual activity, decreased number of sexual partners -vaccination Screening for infection-associated pre-cancerous cells -“Pap” smear -Poor sensitivity (50-60% effective) -Impractical in developing countries -Age of first Pap test controversial -Molecular screening for high-risk genotypes of HPV possible, but not routine (no male screening!) Therapy -Removal of precancerous/cancerous lesions surgically -therapeutic vaccination? |
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The HPV Vaccines
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Subunit vaccine produced in yeast or insect cells
-contains only the HPV capsid protein, L1 -L1 spontaneously self-assembles into virus-like particles (VLPs) Quadrivalent (Gardasil) or bivalent (Cervarix): -HPV16, 18: 70% of all cervical cancer (Cervarix targets only these) -HPV 6, 11: 90% of external genital warts (Gardasil only) Safe and effective -Nearly 100% effective at preventing pre-cancerous lesions caused by HPV 16 and 18 -Does not prevent transient infection with these strains -Limits infection to suprabasal epithelium and prevents lateral spread across cervix -Speeds clearance of infection -Does NOT prevent cancer caused by pre-existing infection |
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Target groups: HPV vaccine
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Routine Vaccination of Females Aged 11-12
-FDA approved as early as 9 Catch-Up Vaccination of Females Aged 13-26 Years 3 doses required for full efficacy Approved for use in boys to prevent genital warts Recent CDC recommendation that all boys 11-12 be vaccinated to prevent -genital warts -head and neck cancers -transmission to female sexual partners |
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Five Human Polyomaviruses
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JC virus from brain of a patient with progressive multifocal leukoencephalopathy (PML) (1971)
-PML in immune compromised, esp. HIV+ BK virus from urine of kidney recipient (1971) -BK nephropathy in renal transplant setting KI virus from respiratory secretions (2007) WU virus from respiratory secretions (2007) -no clear disease MC virus from integrated copies of the genome in Merkel cell carcinoma (2008) |
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Merkel cell virus: virus, disease, cancer
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Virus
-Recently discovered human polyomavirus -Closest relative is African green monkey virus Disease -Unknown; none in most hosts? Cancer (Merkel cell carcinoma) -Rare skin cancer of mechanoreceptor cells -1200 cases per year in USA -Presents late in life (immunosuppression?) -By bypassing cellular growth controls --pRb and p53 inhibited by viral Large T protein --viral genome integrated; replication defective |
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Adenovirus
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"Adenoid degenerative agent" discovered at the NIH (Rowe, 1953)
Influenza-like respiratory epidemics, conjunctivitis, gastroenteritis, tonsilitis Over 50 species identified by serology Some adenoviruses cause tumors when injected into newborn rodents (nonpermissive host) -E1A: E2F release from pRB -E1B-55K: p53 degradation |
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Oncoproteins of the small DNA tumor viruses target pRb
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E7 protein of Human papilloma virus
Large T antigen of Polyoma viruses E1A protein of Adenovirus |
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Oncoproteins of the small DNA tumor virus target p53
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E6 targets p53 degradation in Papilloma virus
E1B-55K targets p53 degradation in Adenovirus E1B-19K blocks Bax and prevents apoptosis in Adenovirus Large T antigen of Polyoma virus |
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Cancer and viruses: an accidental outcome
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No virus life cycle requires tumorigenesis
tumorigenic viruses don’t intend to cause cancer; they seek to replicate and spread -cell cycle is triggered to promote a cellular environment favorable to large-scale DNA replication -cell death is blocked to allow completion of viral replication permissive virus infections eventually result in cell death due to overwhelming cell stress, “lysis,” or immune-mediated killing -dead cells can’t become tumors Virus-derived cancers require a genetic or physiologic “accident” in the virus or host |
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What kinds of accidents result in tumorigenic virus infection?
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Viral :
-Deletion of viral genes required for replication -Retention of genes that trigger cell division --pRb and p53 antagonism common theme Host : -infection with a zoonotic virus that cannot replicate in host cells, but that can alter cell cycle progression -mutations in oncogenes or tumor suppressor genes (cofactors) -immune suppression resulting in inability to eliminate infected cells |
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HPV and cervical carcinoma overview
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Infection is very common
The majority of infections clear spontaneously High risk strains cause most cancers Cancer requires viral integration and sustained expression of E6 and E7 oncogenes Effective vaccines protect from persistent infection, cervical intraepithelial neoplasia, and likely from carcinoma |
