Unit 1 - Oncogenic Viruses Flashcards
what are the main differences between normal cells and malignant cancer cells? how can they be induced experimentally?
- tumorigenicity (make tumors if transplanted to animals)
- undifferentiated
- immportal (replicate w/o limit)
- not contact inhibited
- resistant to apoptosis
- abnormal Xm
all features induced experimentally by viruses
what is myc?
proto-oncogene transcription factor to control growth of human cells
what is src
proto-oncogene for membrane signaling of GF binding to control growth of human cells
what is ras
proto-oncogene signal transduction from surface receptors to control growth of human cells
what is sis
proto-oncogene platelet-derived growth factor to control growth of human cells
what is erb B
proto-oncogene growth factor receptor to control growth of human cells
what is fms
proto-oncogene growth factor receptor to control growth of human cells
what is LMO2
proto-oncogene for hematopoiesis to control growth of human cells
how are p53 and pRB involved in the cell cycle?
- p53 repairs DNA damage or induces apoptosis, but if inhibited then the cell cycle continues to cause cancer
- Rb inhibits E2F, but if inhibted then E2F is able to induce uncontrollable replication
thus, inactivation of P53 and/or Rb allows cells to proliferate and accumulate other mutations (often from DNA tumor viruses)
damage to DNA is managed by three things
- pause in cell cycle
- repair of DNA damage
- resumption of cycle or death by apoptosis
what oncogene is overexpressed in human acute myeloblastic leukemia?
mos
what oncogene is overexpressed in human CML?
abl
what oncogene is overexpressed in human acute promyelocytic leukemia?
fes
what oncogene is overexpressed in human acute lymphocytic leukemia?
LMO2
what oncogene is overexpressed in human ovarian cancer
myb
what oncogene is overexpressed in human breast cancer?
her-2 (sometimes) and neu
how can some oncogenes be overexpressed?
by amplification, mutation, or translocation
in what cancers is P53 often mutated?
breast bladder prostate liver lung skin colon
how do RNA oncogenic (retro)viruses transform cells?
two important mechanisms
- some contain concogenes and express them in infected cells
- some insert promoter into Xm and cause expression of regional oncogenes
how do oncogenic DNA viruses transform cells?
encode proteins that disturb cell cycle (by degrading cell cycle genes)
-example is p53 and pRB can both be inactivated by viral proteins
what is the SV40 virus?
primate virus that causes cell transformation and cancer in rodents
- transforms human cells to malignant state
- expresses T antigen that inactivates p53 and pRB (T Ag must be expressed continually for tumor to grow)
- was contaminant of early polio vaccines, but recipients didn’t get cancer
what are adenoviruses?
a group of human viruses of various serotypes
- some cause cell transformation and cancer in rodents (if injected in newborns)
- E1A and E1B are analogous to T Ag and are always expressed in transformed cells
- only cause colds and sore throats in humans
what does SV40 have to do with polio?
the live attenuated polio vaccine was originally made in monkey kidney cells
- it was found that these would induce sarcoma in hamsters
- new SV40 transformed hamster and human cells
- immunized children shed virus for several weeks in stool, and transformed human cells make tumors in animal recipients
what kind of specificity do oncogenic viruses show?
species-specific
what is the only example of non-species specificity in terms of oncogenic viruses?
a mouse leukemia virus was modified to transduce stem cells in newborns with IL-2 receptor deficiency
-4/9 developed T cell leukemia due to insertion of virus adjacent to LMO2 oncogene (hematopoiesis to control growth of human cells)
what is breast cancer of mice caused by?
mouse mammary tumor virus
what is leukemia of cats caused by?
feline leukemia virus (FeLV)
what are lymphomas of chickens caused by?
Marek’s disease virus
what cancer and other condition does the papillomavirus cause?
Cervical cancer and warts
what cancer and other condition does the Epstein-Barr virus cause?
Burkitt’s lymphoma, naso-pharyngeal cancer, and mononucleosis
-in vitro transforms human B cells with continual expression of some viral genes
what cancer and other condition does the hepatitis B virus cause?
hepatocellular carcinoma and hepatitis B
- liver cancer incidence is higher in countries with endemic HBV infection (Asia)
- prospective studies show greater risk with cirrhosis or higher level expression of viral genes
- universal immunization of newborns in Taiwan and Alaska has reduced incidence by 50%, and completely eliminated (rare vaccine can prevent)
what cancer and other condition does the Kaposi’s sarcoma herpesvirus (HHV8) cause?
Kaposi’s sarcoma (KSHV, HHV8)
- associated with Kaposi’s sarcoma in patients with HIV and AIDS
- 10% in E. Europe, <1% in N. Europe
- can be latent in B cells
- tumors contain KSHV DNA and express KSVH proteins through uncertain mechanism
what cancer and other condition does the human T cell leukemia (lymphotrophic) virus cause?
leukemias/lymphomas (HTLV-1/2); RNA virus but with no oncogene
- 1 in 20 infected people get T cell leukemia after many years (prevalent in Caribbean)
- 1 is integrated into genome of all leukemic cells
- tax gene causes overexpression of IL-2 and its receptor, but expression declines over time
- HBZ gene that dysregulates RNA metabolism persists
- genetic changes accumulate
what are the three main groups of human papillomaviruses? what are examples of types in each?
over 100 types, divided into three groups:
- low risk (4, 6, 8) = warts
- intermediate (11) = laryngeal papillomas
- high risk (16, 18) = cervical, pharyngeal, penile cancer
how are E6, E7, and E2 related to high risk HPV?
E6/7 function in the same way as T Ag of SV40 (must be expressed continuously)
- E6 binds P63 that leads to degradation by ubiquitin pathway
- E7 binds non-phosphorylated Rb that prevents interaction with E2F
- transfection of cells with E6/7 causes immortalization
- co-transfection with mutated ras leads to transformation
- E2 suppresses both E6 and E7, but if integration then loss of function, and over-expression of 6/7
how are E6 and E7 related to low risk HPVs?
similar to high risk HPV E6/7, but low affinity binding that doesn’t cause cancer, only warts
what is the pathogenesis of cervical cancer?
E6/7 proteins are expressed continuously
normal epithelium CIN I/II CIN III (where HPV/DNA integration takes place –> 50% get cancer (Xmal instability –> activation of cellular oncoproteins and/or neutralization of tumor suppressors)
-although progerssion is very slow and requires many years
*CIN = cervical intraepithelial neoplasia
HPV vaccine?
there are two, and both consist of empty virus capsids
-reduce incidence of progression to CIN I/II
elaborate on Burkitt’s lymphoma
contains EBV and expresses genes constantly (transforms B cells in culture)
- endemic in African malaria/AIDS belt
- affects pre-pubertal boys
- maxilla is most common site
- tumors express latent viral Ag of uncertain function, with overexpressed translocated oncogene myc
elaborate on naso-pharyngeal cancer
contains EBV and expresses genes continually
- endemic in South China, Vietnam, Arctic Eskimos
- environmental co-factors involved (likely food preservatives)
- IgA Ab to EBV capsin antigen may predict tumors or recurrences
B cell lymphomas in western world
most are EBV-negative
- in rare cases, EBV is present and some genes expressed
- seen in patients with AIDS or long-term immunosuppression (SCID or graft recipients)
- may regress if immune function is restored
pathogenesis of HBV-liver cancer association
-what viral gene is important?
tumor cells contain integrated HBV, but no consistent expression of any viral protein in cancer cells and no activation of cellular oncogene
- virus X gene plus ras can transform liver cells in culture
- -transactivates many cellular genes
- -x-gene-deleted mutant virus cannot transform cells
what is the one vaccine that can prevent viral induced cancer?
the hepatitis B vaccine can prevent HBV and HCV
