Chapter Outlines

Chapter 10      Viruses and Cancer

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10.1 History of Cancer Viruses and Tumors
  • Cancer has afflicted humans throughout history.
    • Hippocrates observed carcinomas
    • Chimney sweeps and scrotal cancer
    • Reims, France, first cancer hospital
  • About 20% of human cancers associated with viruses
Early Cancer Research on Rous Sarcoma Virus (RSV)
  • 1908 Wilhelm Ellerman and Olaf Bang demonstrated that "filterable agents) could produce tumors in chickens.
  • 1911 Peyton Rous demonstrated a bacteria-free filtrate caused sarcomas in chickens.
    • The agent was Rous Sarcoma Virus, a retrovirus.
  • Michael J. Bishop and Harold E. Varmus
    • Discovered that the src gene of RSV is found in the normal DNA of chickens.
    • Their work demonstrated that oncogenes are cellular genes that were hijacked by viruses from cells!
10.2 Cancer Today
  • At least six viruses are thought to contribute to cancers:
    • Hepatitis B virus
    • Hepatitis C virus
    • Human Papillomavirus
    • Epstein Barr virus
    • Kaposi's sarcoma-associated herpesvirus
    • Human T-lymphotropic virus types I and II
Cancer Biology Terms
  • Oncogene -a gene that has the potential to convert a normal cell to a cancerous or transformed cell
  • Viral oncogene (v-onc): a viral gene responsible for the oncogenicity of the virus
    • Retroviruses may carry altered cellular genes that are tumor promoters
  • Proto-oncogene: cellular genes that promote the normal growth and division of cells.
Cancer Biology Terms
  • Tumor suppressor genes: genes that suppress or inhibit the conversion of a normal cell into a cancer cell. These genes cause cancer when they are turned off.
  • Cell transformation: the change in the morphological, biochemical, or growth properties of a cell.
  • Cancer: a term for diseases in which abnormal cells divide without control.
  • Metastasis: when a cell or clump of cells separates from a tumor and spreads to another location.
Properties of Cancer or Transformed Cells in vitro (in laboratory cultured cells)
  • 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
Properties of Cancer or Transformed Cells in vivo (e.g. in tumors from patients)
  • Increase in oncogene expression
  • Loss of tumor suppressor gene function
  • Changes in DNA methylation patterns
  • Increased or unregulated level of growth factors
  • Cells divide uncontrollably
  • Increased levels of enzymes involved in nucleic acid synthesis and lytic enzymes
  • Reactivation of telomerases
  • Immune evasion
Cancer is a Multi-Step Process
  • Cells bypass apoptosis
  • Cells circumvent the need for growth signals
  • Cells escape immunosurveillance
  • Cells (tumors) command their own blood supply
  • Cells may metastasize
  • Tumor suppressor genes lose function
10.3 Molecular Mechanisms of Virally Induced Tumor Formation by RNA Tumor Viruses
  • The retrovirus genome
    • gag, pol, env and maybe a v-onc
Molecular Mechanisms of How Retroviruses Can Cause Cancer: Proviral Integration
  • Insertional inactivation
  • Integration of proviral DNA containing a v-onc
  • Insertion of a Viral Promoter Upstream of a Proto-oncogene.
  • Insertion of a Viral Oncogene May Promote the Growth and Division of Cells
  • Cellular Oncogenes Promote the Normal Growth and Division of Cells.
  • C-onc's damaged by Carcinogens May Lead to Cellular Transformation
Human Endogenous Retroviruses (HERVs)
  • 8% of the human genome consists of HERVs
  • Most sequences are defective and incapable of producing gene products.
  • Are HERVs involved in cancer? Autoimmunity? Neurological Diseases?
10.4 Human Retroviruses
  • Human Foamy Virus
  • HTLV-1
    • (most people infected are asymptomatic carriers)
  • HTLV-2
  • HIV-1 (Chapter 16)
  • HIV-2 (Chapter 16)
10.5 DNA Tumor Viruses
  • History: Richard E. Shope discovered the first DNA tumor viruses: rabbit fibromas.
  • DNA tumor viruses differ from RNA tumor viruses.
    • Structure
    • Genome organization
    • Replication strategies
  • Oncogenes of DNA tumor viruses are essential viral genes in replication.
  • The oncogenes of small DNA tumor viruses (adenoviruses and SV-40) do not have cellular homologs.
Epstein-Barr Virus (EBV)
  • Also known as Human Herpes Virus 4 (HHV-4)
  • Named after Anthony Epstein and Yvonne Barr
  • They isolated EBV from lymphoma samples collected by Dennis Burkitt (1964).
    • The lymphoma was called Burkitt's Lymphoma.
  • Teen usually infected with EBV (causes mononucleosis, the kissing disease).
  • The initial signs of infection are:
    • Sore throat
    • Swollen glands
    • Fatigue
    • Lack of appetite
    • Headache
    • White patches in the back of the throat
  • 95% of the population in the US. between the ages of 35-40 are persistently infected with EBV
  • EBV persistently infects B lymphocytes.
  • Burkitt's Lymphoma
    • Most common in people who suffer from conditions that weaken their immune system e.g. chronic malaria or AIDS.
      • Most common in children in central Africa.
    • Burkitt's lymphoma (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 of chromosomes 8, 14, 22, or 2.
Kaposi's Sarcoma
  • Also referred to as Human Herpesvirus: 8 (HHV-8)
  • Causes Kaposi's sarcoma (rare skin cancer).
  • Discovered at the cause of Kaposi's sarcoma in 1994 by Patrick Moore and Yuan Chang.
  • Kaposi's sarcoma occurs most often in elderly men of Mediterranean, Middle Eastern or Eastern European decent and AIDS patients (50% risk).
Hepatitis B Virus (HBV)-and Hepatitis C Virus (HCV)-Related Hepatocellular (Liver) Cancer (HCC)
  • Causes chronic hepatitis which can progress to cirrhosis and liver cancer (HCC or hepatoma).
  • Infects the hepatocytes of the liver.
  • HCC tumors in patients infected with HBV usually harbor integrated viral DNA.
  • HBV vaccine was the first vaccine to prevent a "cancer."
Human Papillomaviruses (HPV)
  • HPV infections most common among sexually active adults and adolescents.
  • There are over 100 different types of HPV's (low, medium and high-risk).
  • Low-risk types cause warts or papillomas (e.g. genital warts).
  • High-risk types cause cervical, vulva, vagina, anus and penis cancers (e.g. types 16 and 18).
  • HPV replication: viral life cell is linked to epithelial cell differentiation
  • Cells of benign tumors contain episomal forms of HPV-16 DNA whereas cells of malignant tumors contain Integrated DNA (E6/E7 involved in oncogenesis)
Papillomavirus Structure and Genome
  • Small (52-55 nm in diameter)
  • Nonenveloped
  • Icosahedral-shaped
  • Circular dsDNA genome (~8000 bp in length)
    • HPV Vaccine Production
    • 2nd vaccine available to prevent a cancer!
    • Merck GARDASIL -licensed by FDA in 2006
    10.6 Animal DNA Tumor Viruses 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.
  • Adenovirus Structure
  • 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).
    • Simian Virus-40 (SV-40)
    • Isolated from primary African green monkey kidney cells by Sweet and Hilleman during safety testing of the poliovirus vaccine in 1960.
    • Did not cause CPE.
    • Frequent contaminant of rhesus monkey kidney cell culture cells.
    • SV-40 is a Polyoma Virus
      • T
    • Two other polyomaviruses are 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.
    • SV-40 is well-characterized.
    • SV-40 Characteristics
      • Small (45 nm in diameter)
      • Nonenveloped
      • Icosahedral-shaped
      • 3 capsid proteins (VP1, VP2, VP3)
      • dsDNA genome (5.2 kb in length)
        • 2 sets of genes (expressed early and late)
        • ORIs
        • Promoters
        • Enhancer sequences
    • Large and Small T-antigens

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