Viral Oncogenesis Flashcards
What is cancer characterized by?
An accumulation of mutations due to uncontrolled cell growth which ultimately deregulate the cell cycle, DNA repair machine and cell differentiation
Proto-oncogenes
Promote progression of the cell cycle
Oncogene
Mutated to promote unchecked cell growth (cancer)
What are the DNA virus families which are capable of oncogenesis?
Papilloma Polyoma Adeno Herpes Hepandna Pox
What are the RNA virus families which are capable of oncogenesis?
Adult T-cell leukemia (HTVL)
What is a direct acting oncogenic virus?
The virus introduced a new transforming gene into the cell
What is an indirect acting oncogenic virus?
The virus alters the expression of pre-existing cellular genes
What is an onco-protein?
Proteins with the ability to become oncogenic and interact and inactive cellular tumor suppressors
Will all people infected with oncogenic viruses get cancer and why?
No because transformation is a rare process
What type of infections does a transforming virus set up?
Long term/persistent
If someone is infected with an oncogenic virus, what is the key factor to being forming tumors?
Viral infection in sufficient amount
How does a virus act as cofactor for tumor formation?
Provide certain steps in process of transformation (but not all)
If there are viral genetic material expressed in every cell what does that indicate?
Indicates viral genes are necessary for maintaining a transformed state
If the viral infection is only necessary to begin the transformation process what does that mean?
Viral genes drive tumor initiation but does need to stay for the transformation to continue
What are the two ways that tumor causing retroviruses cause tumors?
Carry transduced cellular oncogenes that play no role in replication
Act through indirect mechanism (location of viral gene insertion)
Are the transforming genes from tumor-causing DNA match the homologs to the host genome?
No
Which type of virus will cause the majority of human cancers?
DNA
What are some of the mechanisms involved in tumorogenesis?
Expression of viral oncoproteins can alter different cellular proteins
Indirect mechanism of tumor formation where viral proteins interact with other cellular processes
Episome
When a DNA virus maintains their genome outside of the host genome
How many different genera exist in the Human Papillomavirus (HPV)?
16
What tissues are HPV likely to infect?
Epithelial cells in skin and mucous membranes
Which HPV types are considered “low-risk”?
6 and 11 (ano-genital warts)
Which HPV types are considered “high-risk”?
16 and 18 (genital and oral cancer)
What is the prognosis for most HPV infections?
Cleared in 2-3 years
Where does the primary infection of HPV occur and how?
Basal cells by micro-cuts in the skin
When does the HPV viral load increase?
When the basal cells proliferate into prickle cells (early viral genes expressed)
What is it referred to as when infected ells differentiate into later stages?
Terminal sequence
Which are the transformative onco-proteins that are high-risk HPV types?
E6 and E7
What are the most important proteins in cell cycle checkpoints and that E6 and E7 bind to in producing tumors?
p53 and retinoblastoma protein (Rb)
What are the normal functions for p53?
Tumor suppressor
Induces growth arrest and G1/S phase of cell cycle upon detection of DNA damage
Becomes phosphorylated to be active
What is p53’s inhibitor?
MDM2
What occurs if DNA damage appears in the cell cycle?
MDM2 and p53 are phosphorylated to induce DNA repair
What shape must multiple p53 take to form an active state?
4 - a tetramer
Which protein does E6 bind to?
p53
When bound to E6 what happens to p53?
It cannot function as a transcriptional activator causing the cell cycle to progress regardless of DNA damage
What is the normal function of Rb?
When hypophosphorylated it binds to E2F transcription factors and blocks them from binding to DNA
Halts the cell cycle at G1/S
When phosphorylated will release E2F which then bind to DNA and begins transcript of cell cycle genes
Which protein does E7 bind to?
Rb
How does E7 induce tumors in the cell cycle?
The E7 sequesters Rb which does not allow E2F to block transcription
What are some other factors that can induce tumors in HPV?
Prolonged chronic infection
Integration of viral DNA into host genome
Modulation of cyclins and CDK inhibitors
Reactivation of telomerase
Genomic instability
Blocking apoptosis
What is Kapsoi’s sarcoma?
Mutlifocal neoplasm characterized by dark purple lesions
Caused by Kaposi’s sarcoma associated herpes virus (KSHV)
Classic Kaposi’s s sarcoma
Mostly found in the elderly male patients of Mediterranean decent with very slow progression
Endemic Kaposi’s sarcoma
Commonly found in HIV-negative children in Africa
Expressed a very aggressive lymphadenopathy
Iatrogenic Kaposi’s sarcoma
Post-transplant pts undergoing immunosuprressive therapies
AIDS-associated Kaposi’s sarcoma
Most common cancer found in AIDS pts in the US and Europe
Most aggressive
KSHV is _____ but not _____ to cause cancer.
Necessary, sufficient
What is the major viral protein and mechanism for KSHV transformation?
Latency-associated nuclear antigen 1 (LANA 1)
Binds well to p53 blocking transcription and pro-apoptosis activities
What are the mechanisms of KSHV to cause cancer?
Supressing function of p53 and Rb
Induction of chromosome instability
Dysregulation cellular apoptotic pathways
Inducing secretion of growth factors
What are the ways KSHV plays a systemic role in promoting tumor growth?
Immune evasion - interferes with complement system, interferon signaling and antigen presentation
Angiogenesis - stimulating cytokine release from infected cells
What are the cancers associated with EBV?
Burkitt's lymphoma Hodgkin's disease T-cell lymphoma Nasopharyngeal carcinoma Gastric carcinomas Lymphoproliferative disorders
What is the key factor in EBV transformation?
Expression of latent genes EBNA2 and LMP2
EBNA2
Acts as a transcriptional activator fir many downstream genes
Upregulates other late genes and promoters in viral genes
Upregulates B cell antigens CD21 and CD23 in host genes
Can alter cell expression of host cell oncogene c-MTC
LMP1
Thought to act as a constitutively active member of the TNF receptor superfamily
Looks like CD40 so can active B cells causing proliferation without a stop signal
Activates anti-apoptotic and cytokine genes and cell surface proteins are altered
What are the general hallmarks of a retroviral infection?
Non-lytic (except lenti)
Genetic material inserted at random within host genome (except lenti)
Viral genetic material remains within the cellular DNA for the life of the cell
Implicated in certain types of cancers like lymphomas and sarcomas
Acute transforming retrovirus
Virus carries an oncogene which is incorporated into the host genome under the viral promoter
Oncogene does not play a direct role in viral replication
Slow transforming retrovirus
Does not carry and oncogene
Tumor formation through variety of mechanisms depending on where the viral genome is inserted into host genome
