The Role of the JC Virus in Central Nervous System Tumorigenesis

Abstract

Cancer is the second leading cause of mortality worldwide. The study of DNA tumor-inducing viruses and their oncoproteins as a causative agent in cancer initiation and tumor progression has greatly enhanced our understanding of cancer cell biology. The initiation of oncogenesis is a complex process. Specific gene mutations cause functional changes in the cell that ultimately result in the inability to regulate cell differentiation and proliferation effectively. The human neurotropic Polyomavirus JC (JCV) belongs to the family Polyomaviridae and it is the causative agent of progressive multifocal leukoencephalopathy (PML), which is a fatal neurodegenerative disease in an immunosuppressed state. Sero-epidemiological studies have indicated JCV infection is prevalent in the population (85%) and that initial infection usually occurs during childhood. The JC virus has small circular, double-stranded DNA that includes coding sequences for viral early and late proteins. Persistence of the virus in the brain and other tissues, as well as its potential to transform cells, has made it a subject of study for its role in brain tumor development. Earlier observation of malignant astrocytes and oligodendrocytes in PML, as well as glioblastoma formation in non-human primates inoculated with JCV, led to the hypothesis that JCV plays a role in central nervous system (CNS) tumorigenesis. Some studies have reported the presence of both JC viral DNA and its proteins in several primary brain tumor specimens. The discovery of new Polyomaviruses such as the Merkel cell Polyomavirus, which is associated with Merkel cell carcinomas in humans, ignited our interest in the role of the JC virus in CNS tumors. The current evidence known about JCV and its effects, which are sufficient to produce tumors in animal models, suggest it can be a causative factor in central nervous system tumorigenesis. However, there is no clear association between JCV presence in CNS and its ability to initiate CNS cancer and tumor formation in humans. In this review, we will discuss the correlation between JCV and tumorigenesis of CNS in animal models, and we will give an overview of the current evidence for the JC virus’s role in brain tumor formation.

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“…Initially reported in animal models, JVC can induce tumors of glial origin. In humans, JCV seems to be especially associated with medulloblastomas among other primary brain tumors, e.g., glioblastoma multiforme and primary CNS lymphomas, as reviewed by Ahye et al (10).…”

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 ). Furthermore, detection of JCV in renal tubules and tonsil lymphocytes indicated JCV persistence in a quiescent state of these cells during latency and infection of other cells upon immune suppression ( Zheng et al, 2007b ).…”

“…The late region encodes the capsid structural proteins VP1, VP2 and, VP3 and agnoprotein ( Reiss and Khalili, 2003 ; Saxena et al, 2021 ). Serologically, there is asymptomatic JCV infection in 80–90% of the adult population ( Ahye et al, 2020 ). JCV enters the human body through both digestive and respiratory tracts and persists quiescent in the kidney and lymphoid tissues ( White and Khalili, 2005 ; Delbue et al, 2017 ; Dwyer et al, 2021 ).…”

“…JCV enters the human body through both digestive and respiratory tracts and persists quiescent in the kidney and lymphoid tissues ( White and Khalili, 2005 ; Delbue et al, 2017 ; Dwyer et al, 2021 ). However, it may be activated under immunosuppressive conditions, resulting in progressive multifocal leukoencephalopathy (PML) ( Reiss and Khalili, 2003 ; Delbue et al, 2017 ; Ahye et al, 2020 ; Dwyer et al, 2021 ; Saxena et al, 2021 ). During permissive infection, replication of viral DNA can cause lytic infection, but in non-permissive cells, either abortive infection or cell transformation is the outcome ( Delbue et al, 2017 ; Ahye et al, 2020 ; Saxena et al, 2021 ).…”

“…However, it may be activated under immunosuppressive conditions, resulting in progressive multifocal leukoencephalopathy (PML) ( Reiss and Khalili, 2003 ; Delbue et al, 2017 ; Ahye et al, 2020 ; Dwyer et al, 2021 ; Saxena et al, 2021 ). During permissive infection, replication of viral DNA can cause lytic infection, but in non-permissive cells, either abortive infection or cell transformation is the outcome ( Delbue et al, 2017 ; Ahye et al, 2020 ; Saxena et al, 2021 ). JCV can transform cells, which display rapid growth and division, prolongation of lifespan, anchorage-dependent growth, chromosomal instability, and dense foci formation in culture ( Eash et al, 2004 ; White and Khalili, 2005 ).…”