Infectious Agents in Human Cancers

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Contents
Infectious Agents in Human Cancers How Infections
Cause Cancer
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Infectious agents in human cancers

• There are four conditions to prove that a disease
  is caused by a specific pathogen
• Kochs postulates
• Must be detected in the disease tissue
• Must be isolated from the diseased host and grown
  in lab.
• The lab.-grown pathogen must cause the disease
• The pathogen isolated from the newly infected
  host must be identical to the original pathogen

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Cancer viruses were initially discovered in
animals

• In 1908, Wilhelm Ellerman and Olaf Bang
• Leukemia can be transmitted by injecting the
  blood from chicken which has the disease
• in 1933, Richard Shop
• Transmitting skin cancer
• Containing oncogenic virusShope papillomavirus
• Table 7-1

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Infectious Agents in Human Cancers
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Infectious Agents in Human Cancers
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The Epstein-Barr Virus is Associated with
Burkitts Lympohma and Several Other
Proliferative Disorders of Lymphocytes

• In 1950s
• Many viruses had been found to cause cancer in
  animals
• No human examples had found
• Examples Burkitts lymphoma
• Disease distribution (Fig. 7-1)
• Suggested by a mosquito-borne infectious pathogen
• Discovered the virus particles by EM
• Epstein-Barr virus (EBV)

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• Ambiguous question
• 90 peoples have been infected (EBV)
• Malaria depress the immunity function
• AIDS lymphoma
• Hodgkins disease one major type of lymphoma
  also involved EBV
• By the presence of Reed-Sternberg cells (two
  nuclei)
• EBV also trigger a nonmalignant proliferation of
  lymphocytes
• As infectious mononucleosis
• Rare disease symptoms production

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Infectious Agents in Human Cancers
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Infectious Agents in Human Cancers
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EBV infection is also associated with
nasopharyngeal carcinoma and a few other
epithelial cancers

• nasopharyngeal carcinoma
• common in southeast Asia
• Not in elsewhere of the world
• Hereditrary or dietary factors?
• Stomach, breast cancer
• Some evidence suggests that the presence of EBV
  may influence the behavior of cancer cells
• One protein from EBV can bind with Nm23-H1
• Nm23-H1 production by metastasis suppressor
  genes
• can inhibit cells migration
• EBV is the first oncogenic virus to be identified
  in humans

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Human papillomavirus (HPV) is the main cause of
cervical cancer

• Cervical cancers is common in prostitutes(??) but
  unknown in nuns (??)
• In 1980s, to prove the evidence of HPV and
  cervical cancer
• HPV is a heterogenous family (gt100 different
  types HPV 1, 2, 3.)
• HPV 16 is detected in half of all cervical
  cancers
• Rare cancers by HPV 18, 45, 31 (F. 7-3)
• Infection ? cervical dysplasia ? cancer
• Cigarette smoking can enhance the risk
• Immune dysfunction can increase the risk

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Infectious Agents in Human Cancers
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The hepatitis B (HBV) and hepatitis C virus (HCV)
are responsible for most liver cancers

• At least six hepatitis viruses have found
• Two types are strongly linked to liver cancer
• HBV a DNA virus
• HBV infected 100x risk of liver cancer than
  uninfected human
• F. 7-4
• HCV RNA virus
• Transmitted by blood
• HCV has a greater tendency to trigger long-term,
  chronic infections than HBV

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Infectious Agents in Human Cancers
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The HTLV-1 retrovirus is associated with adult
T-cell leukemia and lymphoma

• Retrovirus
• Only one retrovirus has been shown to cause
  cancer in human
• Human T-cell lymphotropic virus-I (HTLV-I)
• adult T-cell leukemia and lymphoma
• Major by sexual contact or breast-feeding

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HIV-infected individuals are at increased risk
for Kaposis sarcoma and several other viral
cancers

• Retrovirus HIV (human immunodeficiency virus) is
  a indirect cancer risk
• AIDS (acquired immunodeficiency syndrome)
• Fig. 7-5
• Kaposis sarcoma (100X in AIDS)
• In 1944, KSHV was discovered
• Need immume deficiency
• For treatment of AIDS with HAART improving
  immune function, and Kaposis sarcoma disappears
• Several cancers arise in people with HIV/AIDS

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Infectious Agents in Human Cancers
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SV40 is an animal cancer virus that contaminated
early batches of polio vaccine

• In 1955-1963, the polio vaccine were contaminated
  with monkey virus---SV 40 (simian virus 40)
• SV 40 In monkey kidney cells
• SV 40 triggers several types human cancers
  development
• Epidemiological studies have failed to reveal the
  cancers and contaminated polio vaccine

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Infection with the bacterium Helicobacter pylori
is linked to stomach cancer

• Helicobacter pylori (H. pylori)
• In 1982, Barry Marshall
• gastritis
• Stomach ulcers
• Stomach cancer
• H. pylori can secret toxins and cause
  inflammation
• Cell proliferation and DNA damage
• Antibiotics
• F. 7-6
• Only a few percent develop stomach cancer in H.
  pylori-infected people
• Strains
• Blood types (O type is prefer)
• Diet (high-salt diet) enhance H. pylori activity

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Infectious Agents in Human Cancers
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Flatworm infections can lead to cancers of the
bladder and bile ducts

• Table-7-2
• Blood flukes schistosomiasis
• Infected by snail
• Schistosomiasis kidney and liver failure
• Chronic inflammation bladder cancer
• Liver fluke
• Infected by eating raw or undercooked fisk
• Bile duct cancer

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Infectious Agents in Human Cancers
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How infections cause cancer
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Chronic infections trigger the development of
cancer through indirect as well as direct
mechanisms

• Mechanisms
• Immune system HIV
• Tissue destruction and chronic inflammation HBV,
  HCV, H. pylori
• Directly Stimulating cell proliferation of
  infected cells
• H. pylori inject CagA protein into epithelial
  cells
• CagA bind with specific protein to accelerate
  proliferation

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DNA and RNA viruses employ different mechanisms
for latently infecting cells

• Fig. 7-7
• Fig. 7-8

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How Infections Cause Cancer
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How Infections Cause Cancer
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Retroviral oncogenes are altered versions of
normal cellular genes

• Rous sarcoma gene (fig. 7-9)
• v-src oncogene gene
• The similar DNA sequence with v-src has also
  found in normal cells
• Salmon, mice, cows, birds, human.
• SRC gene (c-SRC) a protooncogene
• F. 7-10

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How Infections Cause Cancer
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How Infections Cause Cancer
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Retroviral oncogenes code for proteins that
function in growth factor signaling pathways

• v-src codes a protein called v-Src (Table 7-3)
• v-Src is a constutively active protein kinase

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How Infections Cause Cancer
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Insertional mutagenesis allows viruses with no
oncogenes to cause cancer by activating cellular
proto-oncogenes

• Oncogenic retroviruses can be subdivided into
• Acutely transforming retroviruses (often several
  days) have oncogene
• Slow-acting retroviruses (months or years) have
  no oncogene
• Slow-acting retroviruses by insertional
  mutagenesis
• avain leukosis virus (ALV) in chicken
• F. 7-11 (MYC gene a proto-oncogene)
• Long terminal repeat (LTR) in retrovirus
• Each LTR is bounded at both ends by short
  repeated sequences for inseration into the host
  chromosomal DNA
• LTR contain sequences for promoting transcription

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How Infections Cause Cancer
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Abnormalities involving the Myc protein arise
through several mechanisms in viral cancers

• By two different ways
• Virus integrate proviral DNA to leading
  overproduction of Myc protein
• Virus introduce its own v-myc oncogene to produce
  abnormal protein
• Burkitts lymphoma
• EBV immune dysfunction
• Chromosomal translocation
• Chromosome 8 (contain MYC gene) is translocated
  to chromosome 14 (Fig. 7-12)

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How Infections Cause Cancer
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Several oncogenic DNA viruses produce
oncoproteins that interfere with p53 and Rb
function

• HPV Fig. 7-13
• HPV ? E6 and E7 protein ? only some form of
  cancer?
• How do these oncoproteins express?
• Fig. 7-14

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How Infections Cause Cancer
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The ability of viruses to cause cancer has
created problems for the field of gene therapy

• Gene therapy
• In 2000, the first apparent successes of gene
  therapy is SCID (severe combined
  immunodeficiency)
• SCID
• Immune system does not develop in baby
• Bubble babies
• Therapy by infection with artificial retrovirus