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Virology > Unit 3 - Viruses and Cancer > Flashcards

Unit 3 - Viruses and Cancer Flashcards

1
Q

What is Cancer?

A

Cancer: Uncontrolled growth of abnormal cells in the body

  • 10^14 cells in the body; chance of individual cell becoming cancerous is ~3x10^-14
  • Cancer can develop in almost any organ or tissue (more than 100 types of cancer)
  • Cancer caused about 13% of all human deaths worldwide (7.9 million) in 2007
  • rates are rising as more people live to an old age
  • Three most common cancers in men: Prostate, lung, and colon
  • Three most common cancers in women: Breast, colon and lung
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2
Q

What are the causes and risk factors in cancer?

A

Causes and Risk Factors:

  • Carcinogens (asbestos)
  • Behavior (alcohol use, smoking)
  • Hormones (HRT)
  • Psychological stress (?)
  • Heredity
  • Radiation and UV light
  • Physical inactivity/obesity
  • Viral infections (10-20% of cancers worldwide
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3
Q

What is the history of cancer viruses and tumors?

A
  • Cancer has afflicted humans throughout history?
  • Hipposcrates observed carcinomas (460-370B.C.)
  • Percival Pott (1775): chimney sweeps and scrotal cancer caused by soot
  • 18th century: 1st cancer hospital in Reims, France; cancer as contagious disease
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4
Q

What and Who was involved in Early cancer Research?

A
  • Ellerman and Bang (1908): demonstrated that “filterable agents” (viruses) could produce tumors in chickens
  • Peyton Rous (1911): demonstrated that a cell-free, bacteria-free filtrate could cause sarcomas (slow-growing solid tumors) in chickens

The transmissible agent was a retrovirus, later named Rous sarcoma virus (RSV)
1st identified oncogenic virus (“oncovirus”)

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5
Q

What is Bishop and Varmus?

A
  • RSV genome: gag, pol, env, and src
  • Discovered that the src gene is found in the normal DNA of chickens (and later mammals and humans).
  • Their work demonstrated that oncogenes are cellular genes that were hijacked by viruses from cells.
  • Cause cells to become transformed or cancerous
  • 1989 Noble Prize
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6
Q

What is a viral oncogene (v-onc)?

A

It is a viral gene responsible fo roncogenicity of the virus

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7
Q

What is Proto-oncogene?

A

Proto-oncogene: cellular genes that promote normal growth and cell division

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8
Q

What is cellular oncogene?

A

Cellular oncogene: mutated form of proto-concogene that causes tumor formation

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9
Q

What are Tumor suppressor gene?

A

Tumor Suppressor gene: gene that inhibits conversion of normal cell into a cancer cell

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10
Q

What is Transformation?

A

Transforation: Change in the morphological, biochemical, or growth protperites of a cell

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11
Q

What is Metastasis?

A

Metastasis: when a cell or clump of cells separates from a tumor and spreads to another location.

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12
Q

How is the Eukaryotic Cell cycle and cancer involved in one another?

A
  • Interphase (G1, S, G2)
  • Mitosis
  • Cytokinesis
  • “Checkpoints” to monitor and regulate the cell cycle
  • G1/S and G2/M
  • Regulatory molecules
  • Cyclins & cyclin-dependent kinases (CDKs)
  • Dysregulation of cell cycle components may lead to tumor formation
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13
Q

What are Telomeres?

A
  • DNA sequences found at the end of chromosomes
  • Telomeres become shorter during normal aging
  • Short telomere signals cell to stop dividing
  • Telomerase: enzyme that synthesizes telomeric DNA (“TTAGGG“) on the ends of chromosomes
  • Cancer cells contain increased levels of telomerase activity
  • Telomere length never shortens and cell never stops dividing
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14
Q

What are the properties of Cancer or Transformed Cells In vitro (cell culture)?

A
  • Genetic changes—polyploidy, high levels of telomerases
  • Immortalization
  • Metabolic changes—grow rapidly
  • Lack of contact inhibition—cells pile up
  • Anchorage independent—loss of adhesion
  • Require less serum in medium to grow
  • Loss of cell cycle control
  • Changes in membrane structure and function
  • Tumor-associated carbohydrate antigens
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15
Q

What is involved in properties in Cancer cells in vivo?

A
  • Increased oncogene protein expression due to amplifications, translocations, or mutations
  • Loss of tumor suppressor gene function due to deletion or mutation
  • Cells divide uncontrollably
  • Increased levels of enzymes important for nucleic acid synthesis
  • Increased telomerase activity
  • Malignant cells avoid host immunosurveillance
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16
Q

What the the different Assays to Detect Transformation?

A
  1. Focus-forming assay
  2. Soft agarose assay
  3. Reduced serum requirement
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17
Q

What is a Forcus Forming assay?

A

Focus-forming assay: transformed cells lose contact inhibition and grow on top of each other in dense piles (foci)

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18
Q

What is a Soft agarose assay?

A

Soft agarose assay: transformed cells can divide and form colonies when suspended in agarose

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19
Q

Wha tis reduced serum requirement?

A

Reduced serum requirement: transfomred cells can grow in media containing reduced serum (low 0.5% vs. normal 10%)

20
Q

Since cancer is a Multistep process, what is involved in that multistep process?

A
  • Cells bypass apoptosis
  • Cells circumvent the need for growth signals
  • Cells escape immunosurveillance
  • Cells (tumors) command their own blood supply
  • Cells may metastasize
  • Tummor suppressor genes lose function
21
Q

What are some of the viruses that are related to cancer?

A
  • Viruses are associated with 10-20% of cancer worldwide
  • At least six viruses are thought to contribute to cancers
  1. Hepatitis B virus
  2. Hepatitis C virus
  3. Human Papillomavirus
  4. Epstein-Barr virus
  5. Kaposi’s sarcoma-associated herpesvirus
  6. Human T-lymphotropic virus types 1 and 2 (HTLV-1 and -2)
22
Q

What are the molecular mechanisms of virally-induced tumor formation by RNA tumor viruses?

A

Retrovirus genome

  • pol encodes reverse transcriptase (RNA→DNA), integrase, Rnase H, and protease
  • gag encodes matrix and core structure proteins
  • env encodes “spike” proteins that are embedded in envelope and are critical for attachment
  • Repetitive (R) and unique (U) sequences enable DNA copy of genome to be inserted into host DNA

Some retroviruses contain an additional gene (v-onc)

  • not an essential gene
  • hijacked from genome of host cells during evolution
  • encodes a protein capable of inducing cellular transformation
23
Q

What are the molecular mechanisms of how retroviruses can cause cancer?

A

Random integration of provirus into host cell DNA:

  • Insertion within/near a cellular oncogene (c-onc)
  • Insertional activation: abnormal expression of c-onc leads to uncontrolled growth
  • Insertional inactivation of cellular tumor suppressor gene leading to uncontrolled cell division
  • Integrated v-onc may become activated and transcribed
  • Promoting normal cell growth and division; tumor formation
24
Q

What are Human Retroviruses and how many have been identitfied?

A

Five human retroviruses have been identified:

  1. Human foamy virus
  2. HTLV-1
  • Sexually transmitted (male → female)
  • Most people infected are asymptomatic carriers
  • 2-5% chance of developing Adult T-cell Leukemia (ATL)
  1. HTLV-2
    * Hairy Cell Leukemia
  2. HIV-1*
  3. HIV-2*
25
Q

What are DNA Tumor Viruses?

Who discovered it?

How do DNA tumor viruses differ from RNA tumor viruses?

What are oncogenes of DNA tumor virese essential for?

A
  • Richard E. Shope (1930s): discovered 1st DNA tumor viruss

Rabbit fibromas and papillomas; filterable agent caused tumors

  • DNA tumor viruses differ from RNA tumor viruses

Structure
Genome organization
Replication strategies

  • Oncogenes of DNA tumor viruses are essential viral genes used in replication

Those from small DNA tumor viruses do not have cellular homologs
Most target tumor suppressor genes

  • % of transformation < 1:100,000 infected cells
26
Q

What is Epstein-Barr Virus (EBV)?

A
  • Also known as human herpes virus 4 (HHV-4)
  • Named after Anthony Epstein and Yvonne Barr
  • Isolated from lymphoma samples collected by Dennis Burkitt (1964).

==Burkitt’s lymphoma
=== Aggessive, malignant cancer similar to leukemia

  • Teens usually infected with EBV
  • causes mononucleosis (“the kissing disease”)

==Sore throat
==Swollen glands
==Fatigue
==Lack of appetite
==Headache
==White patches in the back of the throat
==Usually not life-threatening

  • 95% of the population in the US. between the ages of 35 and 40 are persistently infected with EBV.

Why doesn’t everyone get Burkitt’s lymphoma?

27
Q

What is Burkitt’s Lymphona and Who gets it?

A
  • Burkitt’s lymphoma (BL) is most common in children in central Africa (30-60% of malignant tumors).
  • They suffer from conditions that weaken their immune system (e.g., chronic malaria or AIDS).
  • EBV persistently infects B lymphocytes.
  • BL is a solid tumor of B lymphocytes.
  • BL affects the jaw and very rapidly spreads to the soft tissues and the parotid glands.
  • The DNA of BL tumors contain genetic aberrations
  • Chromosomal translocations resulting in abnormal regulation of the c-myc gene.
28
Q

What is the Geographic Distribution of Burkitt’s Lymphoma?

A
  • Tropical zones of Africa, New Guinea, and South America
  • Related to temperature (60°F minimum), altitude (< 1,500 meters), and rainfall
29
Q

What is Kaposi’s Sarcoma-Associated Herpesvirus (KSHV)?

A
  • Also referred to as human herpesvirus-8 (HHV-8)
  • Cause of Kaposi’s sarcoma (1872)
  • Rare skin cancer
  • Virus discovered as the cause of Kaposi’s sarcoma in 1994
  • Viral genome encodes a cyclin and a Bcl2 homolog
  • Kaposi’s sarcoma occurs most often:
  • Elderly men of Mediterranean, Middle Eastern, or Eastern European decent (10-15 males: 1 female)
  • AIDS patients (50% risk)
30
Q

What is Hepatitis B virus (HBV)?

A
  • HBV causes chronic hepatitis that can progress to cirrhosis and liver cancer (HCC).
  • Liver cancer is 5th most common cancer
  • HBV infects the hepatocytes of the liver.
  • HCC tumors in patients infected with HBV usually harbor integrated viral DNA.
  • HBV transmitted by infected blood/body fluids
  • HBV vaccine was the first vaccine to prevent a cancer.
  • Taiwan: carrier state reduced from 9.8% to ~1% in 10 yrs
31
Q

What are Human Papillomaviruses (HPV)?

A
  • HPV infections are most common among sexually active adults and adolescents.

Most prevalent sexually transmitted disease in the world today

  • There are over 100 different types of HPVs (low, medium, and high-risk).

Low-risk types are benign and cause warts or papillomas (e.g., genital warts, warts on hands and soles of feet).
High-risk types cause cervical, vulva, vagina, anus, and penis cancers (e.g., types 16 and 18).
4- to 20-year latent period between infection and cancer

32
Q

What is HPV Replication?

A

Viral Life Cell is linked to epithelial cell differentiation

  • HPVs infect basal epithelial cells via entry though a break in the skin
  • Genome replication and virion assembly occur in nuclues of epithelial cells
33
Q

Why care about HPV and oncogenesis?

A
  • HPVs may cause 16% of female cancers worldwide and 10% of all cancers
  • HPV-16 (50%), HPV-18 (15%), HPV-45 (8%), and HPV-31 (5%) DNA found in nearly all cervical cancers
  • HPV genome integrated into host cells
  • Inactivate tumor suppressor genes p53 and pRb
  • 555,00 new cases of cervical cancer annually, with 310,000 deaths
  • Vaccination recommended for both girls and boys
  • HPV can be found in semen
  • high-risk HPV types are responsible for a large proportion of cancers of the mouth and pharynx in males
34
Q

What is involved in HPV vaccine Production?

A

Merck GARDASIL—licensed by FDA in 2006 (HPV-6, 11, 16, and 18)
GSK CERVARIX—licensed by FDA in 2009 (HPV-16 and 18)
Prevents ~70% of cancers

HPV-16/18 virus-like particles (VLPs) produced in yeast

35
Q

What are Animal DNA Tumor Virus?

A
  • Adenoviruses
  • Isolated from human adenoids of children by Rowe in 1953
  • Many types of adenoviruses
  • 47 types identified by 1989
  • Some adenoviruses can cause malignant tumors in baby rodents (e.g., hamsters and mice).
  • Adenovirus E1A and E1B genes transform rodent cell lines.
36
Q

What is the Adenovirus Strucutre?

A
  • 80 nm in diameter
  • Nonenveloped
  • Icosahedral-shaped
  • Knobbed penton fibers projecting outward
  • dsDNA (36–38 kb in length)
  • Can infect a wide variety of cell types
  • chosen as a gene therapy vector
37
Q

What is Simian Vaculoating Virus-40 (SV-40)

A
  • Isolated from primary African green monkey kidney cells by B.H. Sweet and M.R. Hilleman during safety testing of the poliovirus vaccine in 1960
  • Did not cause cytopathogenic effect (CPE) in cells
  • Frequent contaminant of rhesus monkey kidney cell culture cells
  • SV-40 is a well-characterized polyomavirus.
38
Q

What are the characteristics of SV-40?

A
  • Small (45 nm in diameter)
  • Non-enveloped
  • Icosahedral-shaped
  • Three capsid proteins (VP1, VP2, VP3)
  • dsDNA genome (5.2 kb in length)

Two sets of genes (expressed early and late)
Origin of replications (ORIs)
Promoters
Enhancer sequences

  • Large and small T-antigens

Large T antigen interacts with tumor suppressor genes, inactivating cell cycle control

39
Q

What is the SV-40 structure and Genome?

A
  • Two other polyomaviruses found in humans
  • Jamestown Canyon virus (JCV)
  • BK virus (BKV)
  • Both JCV and BKV cause tumors in animals and in about 5% of AIDS patients.
40
Q

Discuss the Virus File 10-5 and the SV-40 Controversy

A
  • Early lots of poliovirus vaccine were contaminated with SV-40.
  • SV-40 can cause tumors in rodents.
  • Vaccinees who received contaminated vaccines produced antibodies against SV-40.
  • SV-40 DNA has been found in the DNA of tumor cells of rare cancers.
  • Can SV-40 cause cancer?
  • Some scientists are working on a vaccine against large T antigen.
41
Q

What is Human Endogenous Retroviruses (HERVs)?

A
  • 8% of the human genome consists of HERVs.
  • Sequences containing gag, pol, env, and LTRs
  • Most sequences are defective and incapable of producing gene products.
  • Are HERVs involved in cancer? Autoimmunity? Neurological diseases?
42
Q

What are Oncolytic Viruses?

A

Cancer Therapy: The last 150 years

  • Surgery
  • Radiation therapy
  • Chemotherapy
  • mustard gas
  • aminopterin

Immunotherapy

Virotheraphy

43
Q

What is involved in virotherapy in the 21st centure the oncolytic virus should?

A

The oncolytic virus should:

  • not be a human pathogen. This reduces the chance of pre-existing immunity that would inhibit its therapeutic effectiveness.
  • not cause toxicity or severe side effects to normal tissues and cells.
  • be able to be genetically manipulated to facilitate the introduction of therapeutic or suicide genes and/or genes used to monitor its viral spread through the tumor or cancerous mass/tissues
  • have a rapid life cycle such that it can replicate in cancer cells, lyse the cancer cells, and spread to other cancer cells quickly.
44
Q

Virotherapy continued

A
  • can be administered systemically (e.g., intravenous injection) to treat patients with metastatic disease.
  • can eradicate the tumor and also establish anti-tumor immunity to contain metastases.
  • does not enter the nucleus of its target cell or cannot recombine with the host cell genome to minimize the risk of virus–host genetic recombination events.
  • naturally replicates in specifically in tumor tissue but not normal tissues or cells (e.g., Adenoviruses, mumps virus)should be susceptible to an antiviral drug.
  • should be well characterized in terms of viral genome and protein function.
  • the viral mechanism of oncolytic action and tumor specificity should be well-characterized.
45
Q

What are the fundamental Concepts of Viruses and Cancer?

A
  • Cancer develops when cells in part of the body begin to grow out of control
  • Cancer is a multi-step process.
  • 20% of all human cancers are associated with viruses
  • Transformed cells undergo phenotypic, genetic, and metabolic changes in culture and in vivo.
  • Retroviruses can cause cancer via the integration of a provirus into the host genome within or near cellular oncogenes.
  • Human DNA tumor viruses include EBV, KSHV, HPV, and HBV.
  • Animal DNA tumor viruses include adenovirus and SV-40.
  • Current treatments for cancer include radiation, chemotherapy, immunotherapy.
  • Virotherapy is an experimental form of cancer therapy in which viruses are used to target and destroy cancer cells.

Virology (23 decks)

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