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Dissertation
Viral model for tumor pathogenesis in CNS
Doctor of Philosophy (Ph.D.), Medical College of Pennsylvania and Hahnemann University
Jul 1999
DOI:
https://doi.org/10.17918/00008567
Abstract
The human polyomavirus, JCV, is the causative agent of Progressive Multifocal Leukoencephalopathy (PML), a fatal human demyelinating disease. PML results from the cytolytic destruction of oligodendrocytes, the myelin producing cells of the nervous system. JCV has also been shown to be tumorigenic in several animal models. Transgenic mice expressing the JCV early protein, T-antigen, develop poorly differentiated neural crest origin tumors. Intracerebral inoculation of JCV into newborn hamsters induces medulloblastomas, astrocytomas, and primitive neuroectodermal tumors. Further, inoculation of the virus into the brains of non-human primates, owl and squirrel monkeys, results in astrocytomas and glioblastoma multiforme. Several case reports have associated JCV with human CNS tumors in patients with concomitant PML, suggesting a possible role for JCV in the induction of human tumors. In vitro studies on cells generated from a JCV-induced hamster brain tumor have identified individual clonal populations of tumor cells which differ in their growth characteristics, morphology, and level of expression of JCV T-antigen. Hamsters intracerebrally inoculated with these clonal cells were subjected to MRI followed by multispectral tissue segmentation analysis in order to develop a non-invasive model for the imaging of CNS pathology. Further, two distinct lines of transgenic mice containing the coding sequence for JCV T-antigen under its own promoter were generated and characterized histologically. One such line developed inheritable neuroectodermal origin tumors suggestive of neuroblastomas, while the other line developed aggressive pituitary neoplasms. In one of the transgenic lines, an association between the transgene T-antigen, and the tumor suppressor protein, p53 has been demonstrated. Finally, JCV T-antigen was detected within an oligoastrocytoma of an immunocompetent, HIV-1 negative patient. The use of animal models of tumorigenesis induced by JCV to elucidate mechanisms of cellular transformation and to aide in the development of non-invasive diagnostic procedures is discussed. In addition, the potential role of JCV in induction of human tumors is addressed. Further, possible mechanisms by which JCV may exert its oncogenic potential via alteration of cellular growth control pathways in both humans and experimental animals is discussed.
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Details
- Title
- Viral model for tumor pathogenesis in CNS
- Creators
- Jennifer Gordon
- Contributors
- Kamel Khalili (Advisor) - Drexel University, Medical College of Pennsylvania and Hahnemann University (1993-1996, 1998-2002)
- Awarding Institution
- Medical College of Pennsylvania and Hahnemann University
- Degree Awarded
- Doctor of Philosophy (Ph.D.)
- Publisher
- Medical College of Pennsylvania and Hahnemann University; Philadelphia, Pennsylvania
- Number of pages
- xi, 140 pages
- Resource Type
- Dissertation
- Language
- English
- Academic Unit
- School of Medicine (1993-1996, 1998-2002); Medical College of Pennsylvania and Hahnemann University (1993-1996, 1998-2002)
- Other Identifier
- 991021888753504721