Summary: Progressive multifocal leukoencephalopathy (PML) is a debilitating and frequently fatal central nervous system (CNS) demyelinating disease caused by JC virus (JCV), for which there is currently no effective treatment. Lytic infection of oligodendrocytes in the brain leads to their eventual destruction and progressive demyelination, resulting in multiple foci of lesions in the white matter of the brain. Before the mid-1980s, PML was a relatively rare disease, reported to occur primarily in those with underlying neoplastic conditions affecting immune function and, more rarely, in allograft recipients receiving immunosuppressive drugs. However, with the onset of the AIDS pandemic, the incidence of PML has increased dramatically. Approximately 3 to 5% of HIV-infected individuals will develop PML, which is classified as an AIDS-defining illness. In addition, the recent advent of humanized monoclonal antibody therapy for the treatment of autoimmune inflammatory diseases such as multiple sclerosis (MS) and Crohn's disease has also led to an increased risk of PML as a side effect of immunotherapy. Thus, the study of JCV and the elucidation of the underlying causes of PML are important and active areas of research that may lead to new insights into immune function and host antiviral defense, as well as to potential new therapies.

Molecular biology, epidemiology, and pathogenesis of progressive multifocal leukoencephalopathy, the JC virus-induced demyelinating disease of the human brain.

Medulloblastoma is the most common malignant tumor of central nervous system in children. Patients affected by medulloblastoma may be categorized as high-risk and standard-risk patients, based on the clinical criteria and histologic features of the disease. Currently, multimodality treatment, including surgery, radiotherapy, and chemotherapy is considered as the most effective strategy against these malignant cerebellar tumors of the childhood. Despite the potential poor outcomes of these lesions, the 5-year survival stands, at present, at 70% to 80% for standard-risk patients, whereas high-risk patients have a 5-year survival of 55% to 76%. Attempts to further reduce the morbidity and mortality associated with medulloblastoma have been restricted by the toxicity of conventional treatments and the infiltrative nature of the disease. Over the past decade, new discoveries in molecular biology have revealed new insights in signaling pathways regulating medulloblastoma tumor formation. Recent advances in the molecular biology of medulloblastoma indicate that the classification of these embryonal tumors, solely based on histology and clinical criteria, may not be adequate enough. Better understanding of the growth control mechanisms involved in the development and progression of medulloblastoma will allow a better classification, leading to the improvement of the existing therapies, as well as to the development of new therapeutic approaches.

https://clincancerres.aacrjournals.org/content/clincanres/14/4/971.full.pdf

Medulloblastoma: from molecular pathology to therapy.

JC Virus: An oncogenic virus in animals and humans?

Human polyomaviruses and brain tumors

The struggle to understand the origins of human cancers has captured the imagination of many investigators. The epidemiology of human cancers and the availability of many laboratory models of cancer could give the casual observer the impression that all cancers are a result of exposures to chemical carcinogens in the environment. This is only part of the story, and in most instances environmental exposures are very different in scale from what is required in laboratory animals to induce tumours. Actually, most laboratory models have been carefully developed to match the carcinogen with the host. For example, several alkylating agents can induce intestinal cancers in rodents.1 However, the distribution of the neoplasms throughout the gut varies from one mouse strain to another, and in some instances the carcinogens induce tumours only outside the gut. Lower doses—perhaps those more relevant for human cancers—may be tolerated, and not induce cancer at all. The mechanisms for tumour development in the human gastrointestinal tract appear to be a much more complicated issue.

This review of recent advances in basic science will focus on newly discovered mechanisms involved in the development of colorectal cancer (CRC). This is potentially a very broad topic, and therefore we have selected two novel mechanisms for emphasis. Firstly, a virus carried by most healthy individuals has been implicated as a possible cause for chromosomal instability (CIN), the process that leads to aneuploidy. Chromosomal aberrations and this form of genomic instability play a major role in the development and progression of multistep carcinogenesis, such as occurs in CRC.2 Secondly, it is abundantly clear that inflammation is carcinogenic, and furthermore, endogenous processes that can modify the ability of the host to cope with inflammation appear to modify the risk of cancer to the host. There is growing evidence that this may …

https://gut.bmj.com/content/gutjnl/54/9/1321.full.pdf

Infection, inflammation, and gastrointestinal cancer

Aims —Although the aetiology of medulloblastoma remains elusive, several lines of evidence suggest an association with the human neurotropic polyomavirus JC and its oncoprotein T antigen. The tumour forming properties of JC virus T antigen are the result, at least in part, of its ability to bind and inactivate tumour suppressor/cell cycle regulatory proteins, such as p53 and the retinoblastoma family of proteins. Methods —To examine potential relations between these factors, immunohistochemistry was used to determine associations between the T antigen and the expression of p53 and the retinoblastoma proteins pRb, p107, and Rb2/p130 in eight medulloblastomas. Results —Only the three medulloblastomas with T antigen expression also showed nuclear positivity with antibodies to p53. Although immunohistochemistry detected nuclear labelling for pRb in five of the cases, the three that were positive for T antigen showed the highest pRb labelling. The retinoblastoma related proteins p107 and Rb2/p130 were also immunopositive in most T antigen positive medulloblastomas. Double label immunohistochemistry also demonstrated p53 and pRb positivity in the same cells that were T antigen positive. Conclusions —These correlations suggest that associations between T antigen and p53 and/or T antigen and pRb occur in some of these tumours. These data provide indirect evidence that JC virus, acting through T antigen, might be involved in the formation and progression of medulloblastoma.

https://mp.bmj.com/content/molpath/54/5/331.full.pdf

Expression of a human polyomavirus oncoprotein and tumour suppressor proteins in medulloblastomas.

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Expression of a human polyomavirus oncoprotein and tumour suppressor proteins in medulloblastomas.