Transcript 4. Tumor Viruses

4.
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(Tumor Viruses)
ว ัตถุประสงค์
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สามารถยกต ัวอย่างไวร ัสทีก
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้ งอกของไวร ัสได้
สามารถอธิบายกลไกในการก่อให้เกิดเนือ
Content
4.1 Tumor Viruses
4.2 How Tumor Viruses Cause Cancer
4.1 Tumor Viruses
Tumor viruses can force host cells to proliferate uncontrollably.
-----> can create cancer
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4.1.1 Cancer viruses were initially discovered in animal
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Peyton Rous (1911) discovered that sarcomas could be transmitted
between chickens by injection of filtered tumor extracts.
-----> Rous Sarcoma Virus (RSV)
Weinberg, R.A. The Biology of Cancer. 2007. Garland Science, Taylor & Francis Group, LLC, New York. p.59.
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Richard Shope (1933) showed that he could transmit skin cancer
between rabbits using tumor extracts containing no intact cells.
-----> Shope papillomavirus
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Dozens of additional oncogenic DNA and RNA viruses were discovered.
DNA Tumor Viruses
Kleinsmith LJ. Principles of cancer biology. Pearson Internatonal Edition.
Benjamin Cummings, San Francisco. 2006. p.121.
RNA Tumor Viruses
Kleinsmith LJ. Principles of cancer biology. Pearson Internatonal Edition.
Benjamin Cummings, San Francisco. 2006. p.121.
4.1.2 Epstein-Barr viruses (EBV)
- EBV is associated with Burkitt’s Lymphoma and several other proliferative
disorders of lymphocytes.
- EBV is a member of the DNA-containing
Herpesvirus group, discovered by two
virologists, Michael Anthony Epstein and
Yvonne Barr.
http://www.nasa.gov/mission_pages/station/science/
experiments/Epstein-Barr.html
http://www.beliefnet.com/healthandhealing/images/
si2073_ma.jpg
- Denis Burkitt, British surgeon, observed
large numbers of children came to
Burkitt’s clinic in Africa with massive
swellings of the jaw.
http://www.nationaljewish.org
/imgs/ewebeditor/burkitts.jpg
http://www.frtomskids.org/images/burkitts1.jpg
Several lines of evidence support the idea that EBV causes Burkitt’s
lymphoma.
1) DNA sequences and proteins encoded by EBV have been found in
tumor cells obtained from patients with Burkitt’s lymphoma but not in
normal cells from the same individuals.
2) Adding EBV to cultures of normal human lymphocytes stimulates cell
proliferation and causes the lymphocytes to acquire some of the traits of
cancer cells.
3) Injecting EBV into monkeys triggers the development of lymphomas.
Why is Burkitt’s lymphoma prevalent in central Africa?
----> Malaria can depress immune function and thereby allows
EBV infections to proceed unchecked by an effective immune response.
Half of the patients with Hodgkin’s disease,
a lymphoma characterized by the presence
of Reed-Sternberg cells, have EBV DNA
sequences in their tumor cells.
www.jamesline.com/.../CDR0000576466_full.jpg
EBV infection can also trigger a nonmalignant proliferation of
lymphocytes known as infectious mononucleosis.
EBV infection is also associated with Nasopharyngeal carcinoma and a few
other epithelial cancers.
Nasopharyngeal carcinoma is a tumor of the nasal passages and
throat that is frequent in Southeast Asia. ----> heredity or dietary factors
http://info.cancerresearchuk.org/images/gpimages/cs_inf_f4.2
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A small percentage of individuals with stomach or breast cancer do have
EBV DNA sequences in their cancer cells, but the precise role played by
EBV in such cases is not clear.
---> EBV protein binds to Nm23-H1, a metastasis suppressor.
4.1.3 Human Papillomavirus (HPV)
HPV = a DNA virus implicated in the cancer of the uterine cervix (cervical
cancer) and in several other cancers of the anal and genital area,
including cancer of the penis.
 High-risk types: HPV 16, HPV 18, HPV 45, HPV 31
-------> cervical cancer
 Low-risk types: HPV 6, HPV 11
-------> genital warts (nonmalignant conditions)
http://kirstyne.files.wordpress.com/
2008/02/hpv_small.jpg
~ 90% of all cancers of the uterine
cervix involve infection with at least
one of the high-risk types.
HPV 16 is the most common form
of HPV to be detected in cervical
cancer.
4.1.4 Hepatitis B and Hepatitis C viruses
----> are responsible for most liver cancers.
Hepatitis = inflammation of the liver
------> toxic effects of alcohol or drug consumption
------> Viruses
At least 6 hepatitis viruses are known to exist.
------> two of them are strongly linked to the development of liver cancer
------> Hepatitis B virus (HBV) and Hepatitis C virus (HCV)
Hepatitis B virus = DNA virus transmitted by exchange of bodily fluids
------> responsible for more than 75% of the world’s cases of liver cancer
------> prevalent in Southeast Asia, China, Africa, Alaska, Northern Canada,
Amazon river basin of South America
Hepatitis C virus = RNA virus transmitted by direct contact with contaminated
blood
------> HCV is more difficult to transmit than HBV but triggers long-term, chronic
infections.
------> prevalent in the US (1.8 % of the population)
------> ~5% of the people with chronic HCV infections eventually develop liver
cancer, although it usually requires several decades to appear
4.1.5 The HTLV-I Retrovirus
---> HTLV-I is associated with adult T-cell Leukemia and Lymphoma.
Retrovirus = RNA virus with reverse transcriptase to synthesize a DNA copy
Human T-cell Lymphotropic Virus-I (HTLV-I) is the only one retrovirus
that causes cancer in human (adult T-cell leukemia/lymphoma).
------> transmitted mainly through sexual contact, through blood products, and
from mother to child during breast-feeding
Adult T-cell leukemia/lymphoma is prevalent in Japan, Africa, and the
Caribbean.
Cancer develops in only a few percent of infected individuals; it usually
arises many decades after initial infection.
4.1.6 Kaposi’s Sarcoma-associated herpesvirus
Kaposi’s sarcoma arises from blood vessels in the skin.
Kaposi’s sarcoma-associated herpesvirus (KSHV) was discovered in
specimens of Kaposi’s sarcoma tissue.
HIV-infected individuals are at increased risk for Kaposi’s Sarcoma and
several other viral cancers.
HIV represents an indirect cancer risk because of its destructive effects on
the immune system.
Relative incidence = the rate for each type of cancer in HIV infected individuals divided by the rate in the
general population
4.1.7 SV40 =Simian virus 40 (monkey virus)
SV40 is an animal cancer virus that contaminated early batches of Polio
Vaccine.
SV40 DNA sequences are sometimes detectable in the cancer cells of
individuals with non-Hodgkin’s lymphoma, mesothelioma, brain cancer, or
bone cancer.
However, we do not know how much (if any) cancer risk was created by
the inadvertent exposure of humans to SV40.
4.2 How Tumor Viruses Cause Cancer
4.2.1 Chronic infections trigger the development of
cancer through indirect as well as direct mechanisms.
The 3 broad mechanisms :
1) Increase cancer risk indirectly by interfering with immune function
----> HIV
2) Create tissue destruction and chronic inflammation
----> HBV, HCV
3) Directly stimulate the proliferation of infected cells
4.2.2 DNA and RNA
viruses employ
different
mechanisms for
latently infecting
Cells.
Infection by a latent
DNA virus
Infection by a latent
RNA virus
4.2.3 Retroviral oncogenes are altered versions of normal cellular
genes
Genes like v-src, which trigger the development of cancer, are referred to
as oncogenes.
DNA sequences that are very similar to the Rous v-src gene have been
detected in the normal cellular DNA of a wide variety of organisms,
including salmon, mice, cows, birds, and humans.
Model for the proposed origin of retroviral oncogenes
4.2.4 Retroviral Oncogenes code for proteins that function in growth
factor signaling pathways
Protein kinases play roles in various signaling pathways for controlling
cell proliferation and survival.
V-Src protein kinase -----> tyrosine kinase
V-Src tyrosine kinase is constitutively active and persistently catalyze the
phosphorylation of target proteins that activate cell proliferation.
V-Src tyrosine kinase is the first example of an oncoprotein (protein that
contributes to the development of cancer).
Oncoproteins produced by dozens of viral oncogenes have been identified.
-----> tyrosine kinases, growth factor, growth receptors, or other proteins
involved in growth signaling pathways
4.2.5 Insertional mutagenesis allows viruses with no oncogenes to
cause cancer by activating cellular proto-oncogenes
Oncogenic retroviruses can be subdivided into two classes based on how
quickly and efficiently they trigger cancer in animals.
1) Acutely transforming retroviruses
--cause animals to develop tumors rapidly, often within days of
injection. -----> RSV
--possess oncogenes
2) Slow-acting retroviruses
--require months or years to induce cancer
--do not possess oncogene
Slow-acting viruses lack oncogenes
--alter the expression of normal cellular genes
--insertional mutagenesis
--Avian leukosis virus (ALV) ----> Chicken retrovirus
--ALV can insert its proviral DNA at a variety of different locations in the
host chromosomal DNA.
-----> Cancer only arises when ALV inserts itself near a cellular gene
called the MYC gene.
MYC gene is a proto-oncogene and thus has the potential to be converted
into an oncogne.
The long terminal repeats
(LTRs) of the proviral DNA
contain sequences that
promote transcription.
Myc protein stimulates the transcription of genes required for cell
proliferation.
4.2.6 Abnormalities involving the Myc protein arise through several
mechanisms in viral cancers
1) Insertion of viral DNA in the vicinity of MYC gene
(Avian leukosis virus)
3) Chromosomal translocation
(EBV : Burkitt’s lymphoma)
2) Insertion of viral v-myc oncogene
(Avian myelocymatosis virus)
4.2.7 Several oncogenic DNA viruses produce oncoproteins that
interfere with p53 and Rb function
HPV contains
oncogenes called
E6 and E7, which
produce proteins
that disrupt the
activity of p53
protein and Rb
protein.
High-Risk strains of HPV integrate their viral DNA into a host chromosome,
thereby placing the viral genes in an environment that causes them to
produce larger amounts of the E6 and E7 oncoproteins.
4.2.8 The ability of viruses to cause cancer has created problems for
the field of gene therapy
One type of gene therapy uses specially modified viruses to transfer
copies of normal genes into cells possessing defective genes.
SCID (severe combined immunodeficiency) patients are extremely
vulnerable to infectious diseases. (Retroviral vector causes cancer.)
“Boy in the bubble syndrome”