Induction of Brain Tumors by the Archetype Strain of Human Neurotropic JCPyV in a Transgenic Mouse Model

Abstract

JC Virus (JCPyV), a member of the Polyomaviridiæ family, is a human neurotropic virus with world-wide distribution. JCPyV is the established opportunistic infectious agent of progressive multifocal leukoencephalopathy, a fatal demyelinating disease, which results from the cytolytic infection of oligodendrocytes. Mutations in the regulatory region of JCPyV determine the different viral strains. Mad-1 the strain associated with PML contains two 98 base pair repeats, whereas the archetype strain (CY), which is the transmissible form of JCPyV, contains only one 98 tandem with two insertions of 62 and 23 base pairs respectively. The oncogenicity of JCPyV has been suspected since direct inoculation into the brain of rodents and primates resulted in the development of brain tumors and has been attributed to the viral protein, T-Antigen. To further understand the oncogenicity of JCPyV, a transgenic mouse colony containing the early region of the archetype strain (CY), under the regulation of its own promoter was generated. These transgenic animals developed tumors of neural crest origin, including: primitive neuroectodermal tumors, medulloblastomas, adrenal neuroblastomas, pituitary tumors, malignant peripheral nerve sheath tumors, and glioblastomas. Neoplastic cells from all different phenotypes express T-Antigen. The close parallels between the tumors developed by these transgenic animals and human CNS tumors make this animal model an excellent tool for the study of viral oncogenesis.

The Oncogenic Roles of JC Virus T Antigen in Breast Carcinogenesis

“…Cellular malignant transformation needs a series of genetic or epigenetic accumulation, including oncogene activation or overexpression ( Del Valle and Khalili, 2021 ). Although JCV is a highly neurotropic virus and induces brain tumors, JCV DNA was discovered in the respiratory and the upper and lower gastrointestinal tracts ( Ahye et al, 2020 ).…”

“…Intravenous or intracranial inoculation of JCV has been found to cause astrocytomas, glioblastomas, neuroblastomas, and medulloblastomas ( Miller et al, 1984 ; Hayashi et al, 2001 ). In addition, transgenic mice expressing T antigen developed pituitary adenomas or malignant peripheral nerve sheath tumors ( London et al, 1978 ; Del Valle and Khalili, 2021 ). In previous studies, we established transgenic mice and found that T antigen induced lens tumors and lung cancer ( Gou et al, 2015 ; Noguchi et al, 2013 ).…”

Functional Domains of the Early Proteins and Experimental and Epidemiological Studies Suggest a Role for the Novel Human Polyomaviruses in Cancer

“…Cell culture studies with temperature sensitive mutants demonstrated that the oncogenic potential of SV40 primarily depends on its LT-ag and this was later confirmed by animal studies (Noonan and Butel, 1978;Sáenz Robles and Pipas, 2009;Hudson and Colvin, 2016). LT-ag of BKPyV and JCPyV are also strongly oncogenic in heterologous animal models (Small et al, 1986a,b;Dalrymple and Beemon, 1990;Noguchi et al, 2013;Del Valle and Khalili, 2021). SV40 LT-ag interferes with DNA repair, apoptosis, cellular transcription, protein degradation, telomerase activity, immune and inflammatory responses, and stimulate cell proliferation, angiogenesis, and cell migration.…”

The oncogenic roles of JC polyomavirus in cancer

“…The spontaneous tumors in the transgenic mice of JCV T antigen can provide direct evidences for the oncogenic role of JCPyV as shown in Table 1. The transgenic mouse with the early encoding region of the archetype strain was generated using its own promoter and developed neural crest tumors, such as primitive neuroectodermal tumors, adrenal neuroblastomas, medulloblastomas, pituitary tumors, glioblastomas, and malignant peripheral nerve sheath tumors (114). Krynska et al (115) established the same transgenic mice and observed primitive tumors originating from the cerebellum and adjacent brain stem that were grossly and histologically similar to human medulloblastoma and primitive neuroectodermal tumors.…”