6/22- Viruses and Human Malignancies Flashcards
Overview
What are some infectious agents that can cause malignancy?
- HBV, HCV
- HPV
- H. pylori
- EBV
- HHV 8
- HTLV 1
- Opisthorcis and clonorchis
- S. haematobium
- Merkel cell polyomavirus
(Adenoviruses cause tumors in other animals but have not been associated with human tumors)
How do viruses cause cancer?
Directly:
- Introduce vONC or affect function of cONC
- Interfere with tumor suppressors
- Genomic instability (DNA damage, dysregulation of DDR)
Indirectly:
- Alter host immune response
- Stimulate chronic inflammation
What is the affect of HAART on HIV-Associated Cancers?
- Improved immune function of HIV+ people
- Reduced risk of AIDS progression
- Greatly improved survival for people infected with HIV
- Decrease in AIDS-defining cancers
- Increase in other cancers
What cancers are associated with AIDS?
AIDS-defining cancers:
- Kaposi Sarcoma
- Non-Hodgkin lymphoma
- Cervical cancer
What other types of cancers actually increased in HIV/AIDS pts on HAART?
Non AIDS-defining cancers
- Anal cancer
- Hodgkin Lymphoma
- Liver cancer
- Lung cancer
What are some of the hallmarks of cancer?
- Sustaining Proliferative Signaling
- Evading Growth Suppressors
- Activating Invasion and Metastasis
- Enabling Replicative Immortality
- Inducing Angiogenesis
- Resisting Cell Death
- Deregulating Cellular Energetics
- Avoiding Immune Destruction
- Genome Instability and Mutation
- Tumor Promoting Inflammation
What is cellular transformation?
- Stable, heritable change in cell growth control
- Associated with changes in growth patterns, membrane structure and function, biochemical activity, and tumor formation.
What is the role of viruses in cellular transformation?
- Affect structure or function of cellular oncogenes and tumor suppressors
- Damage DNA
- Interfere with DNA damage repair
- Introduce viral oncogenes
- Alter host immune responses
What are the criteria for a causal relationship when looking at the association of virus infection with tumor formation?
- Infection precedes onset of tumor
- Persistence of virus or viral nucleic acid
- Geographic distribution of infection with virus similar to that of associated tumor
- Prevention of infection should prevent development of the tumor
- In vitro and in vivo models
What other factors should be considered in analyzing virus/cancer association?
- Host: genetics; immune status
- Pathogen
- Environment/exposures: UV, tobacco, aflatoxin, diet, sexual activity, etc.
(Viruses are seldom complete carcinogens, and transformation is usually a multi-step process)
What are proto-oncogenes?
Normal cellular genes whose protein products influence cell growth and differentiation of the cell
What are examples of oncogenes?
- Growth factors (GF)
- GF Receptors
- Signal transducers
- Apoptosis regulators
- Transcription factors
- Chromatin remodelers
Activation of oncogenes may cause what?
- Structural change: rearrangement mutation
- Altered expression: microRNA
What are tumor suppressor genes?
Negative regulators of cell growth
Recall: stages of cell cycle:
- G1: determination of readiness to commit to DNA synthesis. Cells are held in check by p53 and RB
- Syn = DNA synthesis
- G2: error correction If the fcts of p53 or RB are disrupted, then genetically damaged cells can undergo mitosis
What are some mechanisms of transformation for RNA tumor viruses?
- Cell-derived oncogene is carried in the viral genome (transducing retroviruses)
- Cellular proto-oncogene is activated or deregulated by integration of viral DNA (insertional activation; cis-activating retroviruses)
- Virus-encoded regulatory protein dysregulates transcription of cellular regulatory genes (transactivating retroviruses); seen in humans
What cancer is associated with HTLV-1
Leukemia/Lymphoma
- Adult T-cell lymphoma (ATL) in 1-4% of carriers
Where is HTLV-1 common found?
- S. Japan
- Central Africa
- NE S. America
- Caribbean
- Southeast US
- Australia
- Papua New Guinea
Transmission of HTLV-1?
- Sexual
- Breast feeding
- Blood exposure (cellular fraction)
What is this?
Adult T-cell lymphoma
Classification of Adult T-cell lymphoma how?
What is this?
HTLV-1 associated Adult T-cell lymphoma (ATL)
- Widespread cutaneous leukemic infiltrates
- Nodules, papules, plaques, patches, and erythroderma
Pathogenesis of HTLV-1 and leukemia/lymphoma?
Multifactorial
- Associated with monoclonal integration of virus into CD4+ leukemic T cells (site varies for each pt); little viral antigen expressed
Tax gene
-regulatory gene, transactivates cellular genes resulting in upregulation of genes associated with cell growth (supported by in vitro and in vivo models of Tax-mediated transformation and tumorigenicity)
Possible mechanisms of HTLV-1 and tumor formation?
- Inactivation of p53 and Rb (Tax-mediated)
- Inhibition of DNA repair
- Inactivation of cyclin-dependent kinase inhibitors
- Stimulation of cell cycle progression
- Enhancement of genomic instability
Treatment for ATL?
- Combination chemotherapy +/- anti-CCR4 MoAb
- IFN-a + Zidovudine (although dz is not felt to depend on active viral replication)
- Allogenic bone marrow transplantation
HCV is associated with what malignancy?
- Cirrhosis and hepatocellular carcinoma (HCC)
- HCV is the #1 infectious cause of chronic liver dz in the US
What is this?
Heptocellular carcinoma
Pathogenesis of HCV and hepatocellular carcinoma?
- Related to chronic inflammation (cirrhosis)
- Dz typ develops after 2+ decades of infxn
- Serum AFP levels often very high
Other (non-hepatocellular carcinoma) related malignancies with HCV?
Splenic lymphoma with villous lymphocytes (B cell lymphoma)
- HCV plays an indirect role
- Primary mechanism is immunostimulation of B cells
- Tumor may regress after treatment with IFN
What are some methods of transformation by DNA viruses causing tumors?
- Transforming genes are essential for viral replication (Exception: HHV8)
- DNA tumor virus oncogenes have no cellular homologs (Exception: HHV8)
- DNA transforming proteins complex with normal cell proteins and alter their function
- A copy of all or part of the viral DNA is integrated into chromosome
- Quiescent cell stimulated to enter cell cycle
- Interruption of cellular tumor suppressor gene products
- Activation of cellular tyrosine kinase activity
- Inhibition of cellular apoptosis
Where is the incidence of primary HCC?
What malignancy is associated with HBV?
Primary HCC- Primary hepatocellular carcinoma
A study has shown more than a 200-fold increased risk of HCC in patients who were ___.
A study has shown more than a 200-fold increased risk of HCC in patients who were HBsAg+.
(If had antigen presence of HBV/infection with HBV, had 223x chance of getting HCC)
Pathogenesis of HBV in causing primary HCC?
Probably multifactorial:
- Random integration of viral sequences is detected in most tumors.
- Trans-activating gene products (X gene; PreS2) and chronic inflammation may play a role.
Prevention and Detection of HBV-associated HCC?
Prevention:
- Vaccinate!
- Treat persistent infections
Screening:
- Serum alpha-fetoprotein
- Routine hepatic US for persistently infected pts
What malignancies are associated with EBV?
- African Burkitt’s Lymphoma
- Nasopharyngeal carcinoma
Others:
- A subset of Hodgkin’s lymphoma
- B-cell immunoblastic lymphoma
- T-cell lymphomas and lethal midline granuloma
Burkitt’s lymphoma is primarily seen where? In what patients?
Geography: Africa
Clinical: childhood lymphoma
Nasopharyngeal carcinoma (NPC) is primarily seen where? In what patients?
Geography:
- S China
- SE Asia
- Alaska
Clinical:
- 50-70 yo
- Epithelial tumor
- High IgA vs. VCA
Pathogenesis of EBV causing Burkitt’s lymphoma/NPC?
- Increased c-MYC transcription (Burkitt’s)
- Anti-apoptotic proteins
- Disruption of p53 and RB by EBNAs
- Growth promoting effects of LMPs
What is this?
Lymphoma
Two types of Burkitt’s lymphoma?
African Burkitt’s lymphoma:
- Monoclonal, poorly differentiated lymphocytic Lymphoma
- Frequently associated with EBV
Sporadic Burkitt’s lymphoma:
- Abdominal and lymphoid
- Infrequently associated with EBV
EBV stimulates abnormal cells to proliferate; EBV is not essential for the development of BUrkitt’s
What are other factors affecting EBV/lymphoma association?
- EBV and malaria are co-factors for development
What is this?
“Starry Sky” of Burkitt’s lymphoma
- Small, non-cleaved malignant cells interspersed with macrophages
What malignancies are associated with HHV8?
- Kaposi’s Sarcoma
- Castleman’s disease (lymphoid tumor)
- Primary effusion lymphoma
Pathogenesis of HHV8 in causing malignancies?
HHV 8 encodes homologues of cellular genes (Bcl-2, G protein-coupled receptor, IL6 and MIP1) whose expression may enhance tumor formation
- Cytokines, chemokines, antiapoptotic factors, and molecules that inhibit the immune response promote proliferation and tumor growth
What are these?
Symptoms of Kaposi’s Sarcoma
- Characterized by development of vascular nodules in skin, mucous membranes, or viscera
- Endemic KS is indolent with lesions primarily located on extremities; epidemic KS is aggressive, and lesions can be widespread.
What is this?
Histological view of Kaposi’s Sarcoma (HHV 8)
- KS lesions consist of spindle cells of endothelial origin with slit-like vascular spaces, extravasated RBCs, and inflammatory cells
Which genotypes of HPV are associated with the development of cancers?
16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 68, 73 and 82
HPV tumors are responsible for __ of all human tumors, including what?
HPV tumors are responsible for 5-10% of all human tumors, including: epithelial/mucosal cancers:
- Cervical carcinoma (basically 100% of cervical cancers are associated with HPV!!)
- Penile cancer
- Anal cancer (most, > 90% are HPV-associated)
- Vulvar cancer
- Head and neck tumors
Cervical cancer is the __ cancer-related cause of death in the female population?
Cervical cancer is the #2 cancer-related cause of death in the female population
What is a big accompanying risk factor for the development of cancers with HPV?
Co-infection with HIV
What is this?
HPV- associated cervical carcinoma
- Left: cervical lesion
- Right: histopathology
Pathogenesis of HPV-Associated Cancers?
- Mechanism
- Cofactors
- Risk for Acqusition of Infection
Mechanism:
- Disruption of p53 and Rb functions by E6 and E7 gene products, respectively
Cofactors: HSV 2, CMV, HIV, Chlamydia Risks for
Acquisition of Infection:
- Young age
- Increased number of sexual partners
- Early age of first sexual intercourse
- Uncircumcised male/partner
- Smoking
- Oral contraceptive use
Cervical cancer screening recommendations for women at low risk?
Vaccines to prevent HPV-associated cancers?
Vaccines composed of virus-like particles reduced the incidence of HPV-16 infection and cin among healthy young women
- In a recent study, a vaccine based on HPV oncoproteins E6 and E7 improved clinical responses in women with grade 3 vulvar intraepithelial neoplasia
Polyomaviruses are associated with what malignancies?
Sequences or proteins of several Polyomaviruses (PVs) have been detected in several human tumors:
- BKV
- JCV
- Merkel Cell PV (MCPV)
- SV40
SV40, BKV, and JCV (or their early proteins) can induce tumors in animal models and can immortalize human cells
MCPV large T antigen targets Rb
- The role PVs play in the development of human cancer is uncertain
What is this?
Merkel cell carcinoma (associated with polyomavirus)
What is Tasmanian Devil Facial Tumor Disease?
Clonal, transmissable, derived from Schwann cells
Question:
All but which one of the following viruses has been associated with human tumors?
A. Adenovirus
B. Hepatitis B virus
C. Human herpesvirus 8
D. Human papillomavirus
?
Case:
A 39 year old Caribbean immigrant presents with fatigue and weight loss. Physical exam reveals diffuse papular and nodular skin lesions and an enlarged spleen.
CBC reveals lymphocytosis with 6% abnormal CD4+ lymphocytes. The patient is also found to be anemic and hypercalcemic.
What is the most likely etiology of this person’s illness?
A. HIV 1
B. EBV
C. HTLV 1
D. HHV 8
?
Case:
A 64 year old male presents with a history of right upper quadrant pain and weight loss. Past medical history is remarkable for traumatic rupture of the spleen several decades previously requiring massive transfusion. He subsequently developed chronic hepatitis C.
US shows an hepatic mass; serum AFP is elevated. What is the most likely mechanism for tumor development in this case?
A. Chronic inflammation
B. Viral E6 and E7 oncoproteins interrupted p53 and Rb functions
C. Increased c-myc transcription
D. Viral Tax gene expression
?
Case:
A 6 year old African child presents with a history of a rapidly growing mass in the lower jaw. Biopsy reveals lymphoma.
Which of the following tumors has NOT been associated with the virus that is associated with this child’s tumor?
A. Nasopharyngeal carcinoma
B. Hodgkin’s disease
C. Post-transplantation lymphoproliferative disorder
D. Hepatocellular carcinoma
?
Case:
A 20-year old woman presents for routine gynecologic exam. On colposcopic exam (after application of 3% acetic acid), you note abnormal-appearing cervical mucosa. Biopsy reveals low-grade cervical intraepithelial neoplasia associated with HPV 16.
After appropriate management you recommend that she no longer requires immunization because she is now immune to HPVs that can cause cancer.
A. True
B. False
?
