Tumor Virology Flashcards
What are the 5 oncogenic DNA viruses that cause cancer in humans?
Esptein-Barr Virus (EBV) Human herpes virus 8 AKA KSHV Human papillomavirus 16 and 18 (HPV16 and HPV18) Merkel's Cell Polyomavirus MCV Hepatitis B virus (HBV)
What are the 2 oncogenic RNA viruses that cause cancer in humans?
Hepatitis C virus (HCV)
Human T-lymphocyte retrovirus (HTLV)
What cancers do the DNA viruses cause? Esptein-Barr Virus (EBV) Human herpes virus 8 (HHV8) Human papillomavirus (HPV16 and HPV18) Hepatitis B virus (HBV)
EBV: Burkitt’s lymphoma, nasopharyngeal carcinoma, Hodgkin disease, gastric carcinoma
HHV8 AKA KSHV: Kaposi sarcoma, multicentric castlemen disease, primary effusion lymphoma
HPV16 and HPV18: cervical carcinoma, other anogenital carcinomas, oropharyngeal carcinoma, non-melanoma skin cancer
HBV: hepatocellular carcinoma
What cancers do the RNA viruses cause?
Hepatitis C virus (HCV)
Human T-lymphocyte retrovirus (HTLV)
HCV: hepatocellular carcinoma
HTLV: adult T cell leukemia/lymphoma
Viruses that cause cancer are identified as?
oncogenic viruses
HHV4 is another term for what virus?
Human herpes virus 4= Epstein-Barr virus
Most of the oncogenic viruses that affect humans are of what genome?
DNA
There is ______oncogenic RNA viruses than oncogenic DNA viruses.
The majority of oncogenic RNA viruses belong to which family?
Out of this family which is the only virus that is associated with human cancer.
more oncogenic RNA viruses than oncogenic DNA viruses
Retroviridae
Human T cell leukemia virus 1 (HTVL-1)
What is the only non-retroviral RNA virus than induces cancer in humans?
Hepatitis C virus (HCV)
Approximately ____% of human cancers worldwide are caused by oncoviruses infection with more than ______% of cases occurring in the developing world.
12%
85%
Rate of virions of EBV is high but cancer prevalence is low. What does this statement support?
Oncoviruses are necessary but NOT sufficient for human cancer development. So the cancer incidence is much low than viral prevalence in human populations.
Viral cancers area associated with that kind of infections?
persistent infection
Viral cancers are associated with persistent infection and occur many years after acute infection.
Environment and host cofactors such as what are involved in the cancer development?
immunosuppression, genetic predisposition, or mutagen
Induction is cancer in humans is a _________process.
Multistep
In vitro studies with oncogenic viruses have shown that the first step is ____________, which is a development of ___________cells in cell culture. Oncogenesis is a development of tumor in animal cells.
transformation
immortal
Transformed cells may or may not be oncogenic.
What are the differences between normal and tumor cells in terms of growth and biochemical aspect?
normal cells: finite life span, contact inhibition, normal nutrient transport, oxidative respiration, anchorage dependent and growth factor dependent
tumor cells: immortal, loss of contact inhibition, increased nutrient transport , aerobic glycolysis (Warburg effect), anchorage INdependent and growth factor INdependent
Even in the presence of O2 tumor cells still undergo aerobic glycolysis as opposed to oxidation. What is this called?
Warburg effect
Most DNA viruses are lytic or cytopathic. Cytopathic effects should not be lethal. Why?
If the cytopathic effect was lethal then the virus would not be able to replicate as they will be killed as well. Virus are obligate parasites and need the host to replicate. Thus the cells should survive the infection.
Lytic infection
Most cells in the adult organism are __________AKA non-dividing. For initiation of growth, the cell has to receive a mitogenic signal from environment. After binding to the specific membrane receptor this signal activates a cascade of cytoplasmic _________ that transduce the signal to nuclear ___________. They phosphorylate _________, which is a protein that allows cell cycle progress through a restriction point.
quiescent
kinases
cyclin dependent kinases (CDK)
Retinoblastoma (Rb) protein
What is an inhibitor of cell cycle progression and how is it inhibited?
Rb protein
by phosphorylation
This protein is a sensor for DNA damage and hypoxia, promotes cell cycle arrest, promotes apoptosis, and activates DNA repair, prevents mutations. This protein has the most mutated gene in all human cancers. What is this protein and what is its role? What is it’s half-life and how is it stabilized?
p53, a tumor suppressor
half-life= 30 min
stabilized by dsDNA damage
Inhibition of p53 enables uncontrolled cell growth and genetic instability. It is a most altered gene in human cancers.
Binds to the specific –sequence of DNA and activate gene expression (example: p21 WAF1)
p53 is constantly produced in the cell. But it is a short-live protein with t1/2= 30 min. It binds to ubiquitin-ligase MDM2, poly-ubiquitinated and degraded in proteasome.
What are the two best known host cell factors (checkpoints) targeted by viral proteins? What are their roles?
p53 and Rb family members
They both act as tumor suppressors during the cell cycle.
Compare the homology between oncoproteins in DNA viruses with host cell proteins.
In most cases they do not have homology with host cells proteins. They are completely foreign/viral.
EBNA1 (nuclear antigen) is an oncoprotein for what virus?
Epstein-Barr Virus (EBV)
X protein is an oncoprotein for what virus and targets what?
Hepatitis B Virus (HBV)
p53
E5, E6, and E7 are DNA virus oncoprotein for what virus? Which ones target p53 and Rb?
Human Papillomavirus
E6 targets p53
E7 targets Rb
Oncoproteins of EBV do not target p53. True or false?
TRUE!!!
LMP2 (latent membrane protein 2) targets Src.
A T angiten oncoprotein from what virus targets Rb, p53, and Src?
Merkel cell polyomavirus
k-bZIP, ORF 50 (open reading frame), vCyclin, and LANA are DNA oncoproteins for what virus and which ones target Rb, p53, or Src?
Kaposi Sarcoma herpes virus (KSHV)
k-bZIP and ORF 50 target p53. LANA targets Rb.
None targets Src.
Cell target protein PI3K is targeted by what DNA viral oncoprotein?
LMP1 (latent membrane protein 1) from EBV
What is a mutagen?
an agent, such as radiation or a chemical substance, that causes genetic mutation.
DNA viruses oncogenes or oncoproteins induce cell transformation in what conditions? They are necessary but __________for human cancerogenesis.
in vitro
not sufficient
This family of DNA viruses is a large family (about 150 genotypes) of small (8kb), non-enveloped, icosahedral viruses with double-stranded circular DNA. They infect epithelial cells.
Papillomavirdae
More than 40 HPV types can be easily spread through what mechanisms? What are the treatments? What are vaccines for prevention?
through direct sexual contact by vaginal, anal, and oral sex
There is currently no medical treatment for persistent HPV infections.
Genital warts, benign respiratory tract tumors, and cancers resulting from HPV infections can be treated surgically.
Gardasil, Gardasil 9 and Cervarix.
HPV infections are the most common sexually transmitted infections in the United States. About 14 million new genital HPV infections occur each year.
Most HPV infections occur without any symptoms.
Low risk HPVs cause what?
High risk HPVs such as HPV16 and HPV18 cause what?
Low risk HPVs benign warts.
HPV16 and HPV18 causes cervical papilloma and dysplasia.
85% of cervical papilloma contain what kind of DNA?
contain integrated HPV-DNA
HPV contains what kind of DNA?
double-stranded circular DNA
HPV encodes 8 early genes (E1-E8) and two late or structural genes (L1 and L2). Which genes are braking for integration and being deactivated thus preventing viral replication?
E1 and E2
E1, E2–> viral multiplication
E5, E6, E7–> tumor genesis
E5, E6, E7 DO NOT brake.
What is the role of E5, E6, and E7 as DNA viral oncoproteins?
E5 – activates epidermal growth factor (EGF) receptor
E6 – binds p53 and targets it for degradation
E7- binds and activated Rb
HPV is the most cancer causing virus passed through sex. True or false?
TRUUEEE!!!
Everyone needs to get vaccinated EVEN men. She told us a story of a man who kept marrying and killing his wife. He was a carrier for HPV.
What other viruses or infectious agents have been implicated as cofactors with human papillomavirus 16 for cervical cancer?
herpes simplex virus type 2
human cytomegalovirus
chlamydia
multiple sexual partners and early age of first intercourse
E6 and E7; proteins induced genomic instability
Compare HPV and HHV in terms of braking and integration into host chromosomal DNA.
HPV brakes and integrates.
HHV including EBV and KSHV do not brake and integrate.
Herpesviruses are large enveloped viruses with linear double-stranded DNA. HHV4 AKA Epstein-Barr virus infects B-cells and ____________.
During cell transformation, cells contain a small number of ________________ EBV genomes, that replicate only during cell division.
epithelial cells
circular plasmid like
EBV has three latency patterns. In this latency pattern, the virus express a lot of viral proteins (6 nuclear proteins and 3 membrane proteins such as EBNA1-6 and LMP1, LMP2A, and LMP2B respectively) which stimulate B-cell proliferation. It is very immunogenic and infected cells are eliminated by CTLs. This latency pattern is associated with Hodgkin’s lymphoma in HIV-1 positive and post-transplant patients.
EBV latency III
which drives positive selections of infected B-cells to the Latency II pattern
EBV has three latency patterns. In this latency pattern, few viral proteins (EBNA1, LMP1, and LMP2A) are expressed and cells are differentiated to resting memory B cells. This latency pattern is also associated with Hodgkin’s lymphoma.
EBV latency II
memory B cells are easily activated
EBV has three latency patterns. In this latency pattern, there is only expression of ENBA1, that connects viral genome replication with host genome replication and allows viral episome to be segregated and retained in dividing cells. This latency pattern is also associated with Burkitt’s lymphoma.
EBV latency I
What are some clinical presentations of EBV infection?
- B cell lymphoma (Burkitt’s lymphoma, Hodgkin’s lymphoma, post transplant lymphoproliferative disease)
- Non B-cell malignancies (nasopharyngeal carcinoma and gastric cancer-epithelial cell cancers; T and NK cells lymphomas)
- the vast majority of immunocompetent individuals have an asymptomatic infection
EBV with latency I is associated with this type of lymphoma. This lymphoma (a cancer of the lymphoid system) consists of tumors with a similar size and morphology population of medium-sized B cells with high proliferative and apoptotic activity which express B cell antigens CD20, CD22, CD19. This characteristically involves the jaw or other facial bones, distal ileum, cecum, ovaries, kidney, and breast. It can be treated with chemotherapy (EPOCH with rituximab). However, its rapid response to chemotherapy can be hazardous to the patient as a phenomenon called “tumor lysis syndrome”. A cofactor is Plasmodium falciparum infection (malaria) which may increase chromosomal translocation of c-myc gene in B cells.
Burkitt’s lymphoma
tumor lysis syndrome occurs when tumor cells get lysed so fast that you get an accumulation of dead cells and these dead cells can stimulate and immune response
EBV with latency II is associated with this type of lymphoma. This lymphoma is cancer of the lymphatic system. It is characterized by the orderly spread of disease from one lymph to another and by the development of systemic symptoms with advanced disease. Microscopically, multinucleated Reed-Sternberg cells (RS cells) are the characteristic histopathological finding. This lymphoma can be treated with radiation therapy, chemotherapy, or hematopoietic stem cell transplant. It occurs most frequently in two age groups: 15-35 and over 55 years old. It is more common in males than females.
Hodgkin’s lymphoma
Burkitt’s lymphoma do not have orderly spread.
EBV with latency III is associated with this type of lymphoma in a specific population of patients. Cofactor for this type of lymphoma is immunosuppression. In contrast to many other lymphomas this lymphoma is most common in patients with higher CD4 T cell counts.
Hodgkin’s lymphoma in HIV-1 positive and post-transplant patients
HHV8 is also known as ________________and is a characteristic opportunistic disease associated with what disease? What type of cells does it affect?
Kaposi sarcoma
AIDS= acquired immunodeficiency syndrome
B cells, endothelial cells, monocytes, epithelial cells
Multiple pigmented (purple-brownish) sarcoma of skin is a typical presentation of this sarcoma? It is also transmitted from mother-to-child or sexually and usually consists of a localized tumor that can be treated either surgically or through irradiation.
Kaposi sarcoma
For patients with AIDS-KS what is the most effective therapy to reduce HIV infection? AIDS patients receiving this therapy may have up to a 90% reduction in Kaposi’s sarcoma occurrence.
combined antiretroviral therapy (ART)
This virus is a small enveloped virus with circular partly double-stranded DNA. It infects only human and chimpanzee, and has a strong tropism for liver. The incubation period is about 3 months. Its oncogenic protein is X protein which binds to p53.
hepatitis B virus
Like HPV they integrate into the transformed cell.
HHVs do NOT integrate into the transformed cell.
The blocking of p53 is not sufficient for the production of tumors. True or false?
True!
normally its more than 5-6 mutations that can lead to tumors.
This is a worldwide infection where transmission is through direct blood transfer, mother-to-child, and sexual contact. The virus enters the bloodstream, travels to the liver and infects hepatocytes. Acute infections cause viral hepatitis and chronic infections cause chronic hepatitis, liver cirrhosis, or hepatocellular carcinoma. There is no available treatment for acute infections but there are anti-viral drugs and IFN-alpha-2a for chronic infection (suppression of viral replication reduces btu doesn’t eliminate the risk of HCC). What is this virus?
Hepatitis B virus
Pegylated interferon alfa-2a is an immunosuppressive drug and antiviral drug that can treat hepatitis B or C.
There a lot of serological test developed for testing the different stages of Hepatitis B virus. True or false?
True!!
It test for acute or chronic infection or respondant status to treatment.
Serological tests:
hepatitis B surface antigen (HBsAg)
hepatitis B surface antibody (anti-HBs)
total hepatitis B core antibody (anti-HBc)
IgM antibody to hepatitis B core antigen (IgM anti-HBc)
hepatitis B antigen (HBeAg)
hepatitis B antibody (HBeAb or anti-HBe)
Measurement HBV DNA is useful in monitoring of efficiency of drug treatment
Blood cell cytology can show high number of atypical small non-aggregated cells and T lymphocytes with poly lobated nuclei and “flower cells”. The presentation and symptoms are most often correlated with the GI system. What is the most likely condition?
Adult T cell leukemia
is an aggressive malignancy of mature activated T cells caused by human T-cell lymphotropic virus type I
GI symptoms such as persistent vomiting due to mass formations in the liver pressing on GI and stomach
Most RNA viruses that induce tumors are retroviruses. What is the most important, necessary step in the viral replication for retroviruses?
Integration
without integration there is no progeny viruses or viral replication
What type of viruses typically produce viral proteins that interact with p53 and Rb?
DNA viruses
Most gene therapies belong to what group of oncogenic retroviruses?
non-transducing or non acute retroviruses
What is the property shared by all retroviruses?
their genomes encode a mutated cell oncogenic protein
Which group of oncogenic retroviruses are used for cell transformation and production of cell cultures?
transducing retroviruses
Non-transducing retroviruses activate proto-oncogenesis by integration into a host genome leading to:
Mutation within proto-oncogene
Mutation within regulatory domain (promoter)
Mutation in the tumor suppressor gene
This is called a ______________.
Proviral promoters can activate transcription of nearby genes (which is why it is called ________________ or activate transcription by fusion to host promoter.
Transformation can occur if the nearby gene is an cellular oncogene.
insertional mutagenesis
cis-acting provirus
Non-transducing retroviruses don’t integrate randomly into genome, but they integrate preferentially in to the “hot-spots” in the genome. Most of the hot- spots are located near ______________.
cellular oncogenes
Human T-Cell Leukemia Virus-1 (HTLV-1) belongs to what group of oncogenic retroviruses?
HTLV causes adult T-Cell leukemia/lymphomas (ATLL).
ATLL is slowly developing (20-30 years) after infection.
After ATLL detection, survival is 6-24 months
Clinical manifestations include hypercalcemia, lymphadenopathy, skin lesions caused by infiltration of leukemic cells, spleen and liver involvement and immune suppression
Long Latency Retroviruses
HTLV infects T-cells and monocytes. This virus is endemic in areas of the Caribbean basin, Africa, South America, Australia and Japan. Global prevalence (~20 millions).
Viral genes are expressed in all ATLL clones. True or false?
FFALLLSSEEE!!!
Viral genes are not expressed in all ATLL clones. Expression of viral genes is necessary for initiation of transformation but not for its maintenance.
Long latency oncogenic retroviruses such as HTLV have long tumor latency, for example 20-30 years in HTLV. What is the oncogenic protein and what is its function?
Tax which is a trans-acting protein and stimulates cell division and blocks mitotic spindle assembly.
Viral protein (TAX), plays a role in the latent transforming of T-lymphocytes. It has multiple effects on cellular factors which leads to deregulation of the cell cycle. Transformation of T cells does not lead itself to oncogenesis.
So it conducts chromosomal aberration and genomic instability.
Why does Adult T cell leukemia (ATLL) have a poor prognosis with an average survival of only months after diagnosing?
Human T cell leukemia virus type 1 causes ATLL.
HTLV-1 is a member of the long latency viruses of oncogenic retrovirus and they have LONG tumor latency, 20-30 years for HTLV-1.
What is the most common chronic blood borne infection and the leading cause of liver transplantation in the US? What is the genome and family of this virus?
Hepatitis C virus
-small, enveloped, positive sense RNA virus part of the Flaviviridae
- HCV only infects human and monkey.
- HCV does not enter nucleus.
- HCV can’t interact with cell-cycle proteins in nuclear.
- Multiple viral proteins are involved in disease progression (E1, E2, NS2, NS3, NSSA, and Core)
There is no vaccine available for HepC.
What two viruses cause hepatocellular carcinoma and what are the differences between the two?
Hepatitis B and C
Hepatitis B virus:
- transmission is through blood, mother-to-child, sexual contact
- highest risk group are infant of infected mother, sex partner of infected person
- infection is acute or chronic
- vaccination is available
Hepatitis C virus:
- transmission is through blood and blood products
- highest risk group are drug users, HIV-1 positive, immunosuppressed patients
- infection is mostly chronic
- no available vaccine
BOTH have similar symptoms of fever, joint pain, fatigue, nausea, loss of appetite, vomiting, abdominal pain, jaundice(yellowing of the skin or whites of the eyes), cirrhosis, hepatocellular carcinoma
BOTH can be detected by (ALT/AST), serologic tests that are immunoassays for antibodies and antigens, Nucleic acid-based tests
_________infections of HCV can lead to the development of hepatocellular carcinoma (HCC) by repeatedly causing the body’s own immune system to attack the liver cells, infected and non-infected by the virus.
The constant cycle of damage followed by repair can lead to mistakes during repair which in turn lead to carcinogenesis through___________.
The mechanism of HCC is a combination of direct and indirect mechanisms, which results in chronic oxidative DNA damage that promotes the development of mutations.
Chronic
cirrhosis
Pathogenesis of HCV infection:
- HCV infection
- Chronic hepatitis
- cirrhosis (20-25 years)
- HCC (25-30 years)
HCV _______apoptosis but upregulates proliferation, dysregulated ______metabolism, chronic inflammation, angiogenesis, ROS, epithelial and mesenchymal transition, and genome ___________.
HCV inhibits apoptosis.
HCV upregulates lipid metabolism and genome instability mutations.
A 42-year-old man was admitted to the Emergency Department because of a painless swelling and moderate bleeding, located in his right tonsil. Oral examination showed a purple swelling in the upper pole of his right tonsil. His was HIV positive. His CD4 lymphocyte count was 207 cells/μL and HIV viral load was >100,000/mL. He underwent a tonsillectomy with complete excision of the tumor. The histopathological analysis identified a spindle cell sarcoma.
What are the two most important host tumor suppressor proteins which are targeted by this tumor-associated pathogen?
P53 and Rb
