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Tumor Viruses
Viruses can cause benign tumor or malignant tumors in many species
of animals . Only a few viruses are associated with human tumors.
Tumor viruses has no characteristic size , shape , or chemical
composition . Some are large ,and some are small ; some are
enveloped, and others are naked ; some have DNA as their genetic
material , and others have RNA .The factor that unites all of them is
A
***Role of Tumor Viruses in Malignant Transformation
Malignant transformation is a permanent change in the behavior of the
cell.
The use of temperature –sensitive mutant of rouse sarcoma virus
which has an altered transforming gene that is functional at the low,
permissive temperature (35ºc) but not at the high, restrictive
temperature( 39ºc). When chicken cell were infected at35ºc they
transformed as expected , but when incubated at 39ºc they regained
their normal morphology and behavior within few hours . Days or
weeks later , when these cells were returned to 35ºc they recovered
their transformed phenotype, thus continued production of some
functional virus - encoded protein is required for the transformed
state.
Provirus and Oncogenes
Viral tumor genesis occurs are expressed in the terms provirus and
oncogene.
1- In the provirus model the genes inter the cell at the time of
infection by tumor virus.
2- In the oncogene model, the gene for malignancy are already
present in all cells of the body by virtue of being present in the
initial sperm and egg.
These oncogenes encoded proteins that encourage cell growth , example
fibroblast growth factor .
In oncogene model , carcinogen such as chemicals , radiation, and tumor
viruses activate cellular oncogenes to overproduce these growth factors.
This initiates inappropriate cell growth and malignant transformation .
****Evidence for the provirus mode consist of finding copies of viral
DNA integrated in cell DNA only in cell that have been infected with the
tumor virus . The corresponding uninfected cell have no copies of the
viral DNA.
The first direct evidence that oncogenes exist in normal cell was based on
results of experiments in which the DNA copy of the onc-gene of the
chicken retroviruses , rouse sarcoma virus was used as a probe DNA in
normal embryonic cell hybridized to the probe indicating that the cells
contain a , gene homologous to the viral gene .
It is hypothesized that cellular oncogenes ( proto-oncogenes) may be
the3 precursor of viral oncogenes.
****Although cellular oncogenes and viral oncogenes are similar they
are not identical .They differ in base sequence at various points and
cellular oncogenes have exons and introns, where as viral oncogenes do
not have.
*/* It seems likely that viral oncogen were acquired by incorporation of
cellular oncogenes into retrovirus lacking these gene . Retroviruses can
be though of as transducing agents , carrying oncogenes from one cell to
another .
### A marked diversity of viral oncogene function has been found
…..some encode a protein kinase that specifically phosphorylates the
amino acid tyrosine . The cellular protein(s) phosphorylated by this
kinase are unknown in contras to the commonly found protein kinase of
cells, which preferentially phosphorylate serine.
@@@ Other oncogenes have a base sequence almost identical to that of
the gene for certain cellular growth factors. Several proteins encoded by
oncogenes have their effect at the cell membrane (e.g., the ras oncogen
encode a G protein ) ,where as some act in the nucleus by binding to
DNA ( e.g., the myc oncogene encodes a transcription factor ).
These observation suggest that growth control is a multistep process and
that carcinogenesis can be induced by affecting one or more of several
steps.
1- on the basis of the known categories of oncogenes the following model
of growth control can be constructed after a growth factor binds to its
receptor on the cell membrane , membrane –associated G – proteins and
tyrosine kinases are activated . These, in turn , interact with cytoplasmic
proteins or produce second messengers, which are transported to the
nucleus and interact with nucleus factors ----DNA synthesis is activated ,
and cell division occurs .
****#### Over production or inappropriate expression of any of the
above factors in bold face type can result in malignant transformation
+++++ Not all tumor viruses of the retrovirus family contain onc genes
How do these viruses cause malignant transformation ?.
It appear that the DNA copy of the viral RNA integrates near a cellular
oncogenes , causing a marked increase in its expression --------,overexpression of the cellular oncogenes may play a key role in
malignant transformation by these viruses.
Although it has been demonstrated that viral oncogenes can cause
malignant transformation , it has not been directly shown that
cellular oncogenes can do so. However the following incidence
suggest that they do:
1-DNA containing cellular oncogen isolated from certain tumor cells can
transform normal cells in culture .When the base sequence of these
transforming cellular oncogenes was analyzed , it was found to have a
single base change from the normal cellular oncogenes, i.e., it had
mutated . In several tumor isolates , the altered sites in the gene are the
same.
2-In certain tumors ,characteristic transformations of chromosomal
segment can be seen.
In Burkitt′s lymphoma cells, a translocation occurs that moves a cellular
oncogenes ( c-myc ) from its normal site on chromosome 8 to a new site
adjacent to an immunoglobulin heavy chain gene on chromosome 14
This shift enhances expression of the c-myc gene.
3- Some tumors have multiple copies of the cellularoncogenes, either on
the same chromosome or on multiple tiny chromosomes . The
amplification of these genes result in over expression of their m RNA and
proteins.
4-Insertion of the DNA copy of the retroviral RNA (Proviral DNA) near a
cellular oncogene stimulate expression of the c-onc gene.
5- Certain cellular oncogenes isolated from normal cell can cause
malignant transformation if they have been modified to be overexpressed
within the recipient cell.
Sumry
In summery, two different mechanisms, mutation and increased
expression …..appear to be able to activate the quiescent ((protooncogene)) into a functioning oncogene capabile of transforming a
cell.
Cellular oncogene provide a rational for a carcinogenesis by chemical
and radiation , example ,a chemical carcenogene might act by
enhancing the expression of of cellular oncogene . Furthermore ,
DNA isolated from cell treated with a chemical carcenogene can
malignant transform other normal cell .
The resulting tumor cell contain cellular oncogenes from the
chemically treated cell, and these genes are expressed with high
efficiency.
There is another mechanism of carcinogenesis involving celluler
genes , namely, mutation of a tumor suppressor gene .A well
documented example is the retinoblastoma susceptibility gene which
normally acts as a suppressor of retinoblastoma formation when both
alleles of this anti- oncogene are mutated ( made functional)--retinoblastoma occurs.
Human papilloma virus and SV40 virus produce a protein that bind
the protein induce by the retinoblastoma gene.
Human papilloma virus also produces a protein that inactivates the
protein encoded by the protein P53 gene , another tumor suppressor
gene in human cells. The P53 gene encodes a transcription factor that
activates the synthesis of a second protein which blocks the cyclindependent kinases required for the cell division to occur .
The P53 protein also promotes apoptosis of cell that have sustained
DNA damage or contain activated cellular oncogen .
Apoptosis – educed death of these cells has a tumor –suppressive
effect by killing those cells distained to become cancerous.
Inactivation of tumor suppressor genes appears likely to be an
important general mechanism of viral oncogenesis. Tumor
suppressor genes are involved in the formation of other cancers as
well, example , brest and colon carcinoma and varcomas. For
example , in many colon carcinomas , two genes are involved and
inactivated, the P53 gene and the DCC (deleted in colon carcinoma)
gene. More than half of human cancers have a mutated P53 gene in
the DNA of malignant cells.
Evidence For Human Tumor Viruses.
At present , only two viruses , Human T-cell lymphotropic virus and
Human papilloma virus , are considered to be human tumor viruses.
However, several other candidate viruses are implicated by
epidemiologic correlation , by serologic relationship , or by recovery
of the virus from tumor cell.
Human T-cell lymphotropic virus : There are tow Human T-cell
Lymphotropic virus (HTLV)isolated so far , HTLV-1 and HTLV-2
both of which are associated with leukemias and lymphomas. HTLV
-1 was isolated 1981 from the cell of patient with cutaneous T-cell
lymphoma. It was induced from tumor cell by exposure to iodo –
deoxy uridin . Its RNA and proteins are different from those of all
other retroviruses.
IN addition to cancer, HTLV is the cause of tropical spastic Para
paresis and autoimmune disease in which progressive weakness of
the leg occurs. HTLV – 1 may cause cancer by a mechanism
different from that of other retroviruses. It has no viral oncogen .
Rather it has two special genes ( in addition to the standard
retroviral genes gag , pol , and env ) called tax and rex they play a
role in oncogenesis by regulating mRNA transcription and translation.
The tax protein has two activities :
1- It acts on the viral long terminal repeat (LTR) sequences to stimulate
viral mRNA synthesis.
2- It induces NF-KB which stimulate the production of interleukin – 2
(IL- 2)and the IL- 2 receptor.
The increase in the levels of IL – 2 and its receptors stimulates the Tcells to continue growing , thus increasing the likelihood that the cells
will become malignant.
The Rex protein determines which viral mRNA s can exit the nucleus
and inter the cytoplasm to be translated.
Examples of other viruses causing human cancer :
Human papilloma virus ( HPV )>>>>This virus definitely known to
progress to form carcinomas , especially in an immunocompromised
person . Papilloma virus are members of the family Papilloma viridae (
formerly Papovaviridae ). Carcinogenesis.by Human Papilloma Virus
(HPV) involve two proteins encoded by this virus(HPV) gene E6 and E7
that interfere with the activity of proteins encoded by two tumor
suppressor genes , P53 and Rb (retinoblastoma).
In most papilloma tumor cell , the viral DNA is integrated into the
cellular DNA and the E6 and E7 protein are produced.
******Epstein – Barr virus ( EBV)
EbV is herpes virus that was isolated from the cells of an East African
individual with burkitt's lymphoma. EBV , the cause of infectious
mononucleosis , transform B lymphocytes in culture and causes
lymphomas in marmoset monkeys . It also associated with
nasopharyngeal carcinoma , a tumor that occure primarly in china and
with thymic carcinoma and B – cell lymphoma in United state .
**** only a small fraction of the many copies of EBV DNA is integrated
, most viral DNA is in the form of closed circle in the cytoplasm .
#@* Hepatitis B Virus cause hepatocellular carcinoma ( hepatoma) , a
chronic hepatitis B infection commonly cause cirrhosis of liver.
<<< … >>> Hepatitis - C virus (HCV ): chronic infection with HCV ,
like HBV , also predispose hepatocellular carcinoma. HCV is RNA
VIRUS THAT HAVE NO ONCOGEN AND FORM NO DNA
intermediate mediate during replication ,,,,,it cause chronic hepatitis
which seem likely to be the main predisposing events.
Human Herpes virus – 8 (HHV- 8) , also known as kaposi’s sarcoma –
associated herpes virus, may cause kaposi’s sarcoma. The DNA of the
virus has been detected in the sarcomas cell . but the role of the virus in
oncogenesis remained to be determined.
Transmission of Human Viruses
1- vertical transmission :
a- by sperm or ova , example HIV …..high incidence of tumor
b- through placenta, example Rubella and Measles
c-Brest milk example , HIV and CMV …… high incidence of tumor
2- Horizontal transmission …..Probably does not occur in human.