Feb. 20, 2002 PHILADELPHIA -- An association between a common virus and brain tumors has been established by a group of researchers from Temple University, suggesting a possible role for it in the development of the most frequent type of malignant brain tumor in children.
Their study, “Expression of human polyomavirus JCV late gene product agnoprotein in human medulloblastoma,” appears in the Feb. 20 issue of the Journal of the National Cancer Institute.
Luis Del Valle, M.D., and Kamel Khalili, Ph.D., of Temple’s Center for Neurovirology and Cancer Biology, and their co-investigators found the viral genome and viral proteins T antigen and agnoprotein in samples of pediatric brain tumors, which may play a role in the development of these tumors.
“There is a virus, the JC Virus (JCV), which infects greater than 70 percent of the human population worldwide during early childhood,” says Khalili, director and professor of Temple’s Center for Neurovirology and Cancer Biology and one of the study’s lead researchers.
“What we have shown in this study is that medulloblastoma tumors that we see in pediatrics, have in some portions, the genome of the JC Virus,” says Khalili. “This genome expresses the viral proteins T antigen, which has oncogenic potential, and an agnoprotein, whose function is unknown.”
T antigen may cause brain tumors in part by blocking tumor suppressor proteins such as p53 and pRb. The role of agnoprotein in the development of brain tumors is unknown. Recent studies suggest, however, that the interaction of T antigen with agnoprotein may affect T antigen's ability to control cell growth.
“We know that the agnoprotein has the capacity to associate with the T antigen,” adds Khalili. “So it seems that the communication between these two viral proteins may impact the ability of the virus to induce brain tumors.”
In the current study, the authors found the gene that produces agnoprotein in 69 percent of 16 medulloblastoma samples, and the gene that produces T antigen in 65 percent of 20 medulloblastoma samples. The researchers also found agnoprotein and T antigen in about 50 percent of the samples, with some samples containing only agnoprotein. They conclude that “the finding of agnoprotein expression in the absence of T-antigen expression suggests a potential role for agnoprotein in pathways that control the development of JCV-associated medulloblastomas.”
According to Khalili, the JC Virus most likely infects humans through the upper respiratory tract and remains in a latent stage in most people throughout their lives, and, in some cases, causes very minor sub-clinical problems. However, in people whose immune systems go down, either through kidney transplantation or an illness such as AIDS, the JCV can become active and lead to the fatal demyelinating disease Progressive Multifocal Leukoencephalopathy (PML).
“What we are trying to show in this study is that the JC virus has the ability to do more than just cause PML,” says Khalili, who has been studying the molecular biology of the JC Virus for nearly two decades. “We have a virus in our body which may have the potential to cause tumors.”
Khalili says that the questions now facing researchers are whether or not the JC virus actually causes tumors; whether the tumors formed because of other elements and the virus helped as a co-factor; or whether something else causes the tumors and the presence of the virus is a mere chance association.
“We’re not saying every single brain tumor is being induced by the JC Virus,” Khalili cautions. “What we are saying is that the virus can be detected in a good number of the human brain tumors we sampled, and the product of the virus, the viral protein T antigen, which has oncogenic potential, can be detected in those tumor cells.”
Khalili says that since scientists aren’t sure what causes brain tumors, the discovery of the association between JCV and brain tumors is important for therapeutic and treatment reasons. “We can start developing strategies and vaccines against the JC Virus, which will hopefully lead to the prevention of the brain tumors it induces,” he says.
### News Media Contact: Preston Moretz, Science Writer Temple University Office of News and Media Relations, (215) 204-7476, firstname.lastname@example.org
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About Temple’s Center for Neurovirology and Cancer Biology:
The Center for Neurovirology and Cancer Biology is a state-of-the-art multidisciplinary research and education facility in Temple University’s College of Science and Technology. The goals and objectives of the Center are to perform cutting edge research on the molecular biology, genetics and biochemistry of viral and non-viral induced neurological disorders in order to facilitate development of molecular therapeutics strategies against relevant diseases; and train first-rate scientists/educators in the field of modern biology who will successfully develop new ideas and technologies to further the field of biomedical life sciences and medical research.
Definition of Terms:
JC Virus: A human retrovirus similar to polyoma virus, but which has not been associated with any human cancer. Member of the Papovaviridae.
Medulloblastoma: A primary brain cancer that is a tumor in which cancerous cells begin to grow in the tissues of the brain. Medulloblastoma is an infratentorial tumor (located below the tentorium cerebelli in the brain). Medulloblastoma is usually found only in children or young adults. It can spread from the brain to the spine or to other parts of the body.
Oncogene: Mutated and/or overexpressed version of a normal gene of animal cells (the proto-oncogene) that in a dominant fashion can release the cell from normal restraints on growth, and thus alone, or in concert with other changes, convert a cell into a tumor cell.
p53: A 393 residue (in humans) phosphoprotein that is a common tumor antigen, expressed in many transformed cells. However, it is believed to be the product of a tumor suppressor gene, rather than an oncogene, as it is frequently inactivated or mutated in tumors.
pRb: Tumor suppressor gene encoding a nuclear protein that, if inactivated, enormously raises the chances of development of cancer, classically retinoblastoma, but also other sarcomas and carcinomas.
Progressive Multifocal Leukoencephalopathy (PML): A rapidly debilitating opportunistic infection caused by the JC Virus that infects brain tissue and causes damage to the brain and the spinal cord. Symptoms vary from patient to patient but include loss of muscle control, paralysis, blindness, problems with speech, and an altered mental state. PML can lead to coma and death.
T-antigen: Proteins coded by viral genes that are expressed early in the replication cycle of papovaviruses such as SV40 and polyoma. Essential for normal viral replication, they are also expressed in non-permissive cells transformed by these viruses. Originally detected as Tumor-antigens by immunofluorescence with antisera from tumor-bearing animals. SV40 has two, large T and small t; polyoma has three, large, middle and small. Appear to be collectively responsible for transformation by these viruses.
Tumor suppressor: A gene that encodes a product that normally negatively regulates the cell cycle, and that must be mutated or otherwise inactivated before a cell can proceed to rapid division. Examples: p53, RB (retinoblastoma), WT-1 (Wilms&’ tumor), DCC (deleted in colonic carcinoma), NF-1 (neurofibrosarcoma) and APC (adenomatous polyposis coli).
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