Limits...
Chronic viral infection and primary central nervous system malignancy.

Saddawi-Konefka R, Crawford JR - J Neuroimmune Pharmacol (2010)

Bottom Line: Primary central nervous system (CNS) tumors cause significant morbidity and mortality in both adults and children.In primary CNS malignancies, two families of viruses, namely polyomavirus and herpesvirus, have been detected with varied frequencies in a number of pediatric and adult histological tumor subtypes.While direct evidence of a role of viruses in neuro-oncogenesis in humans is lacking, a more plausible hypothesis of neuro-oncomodulation has been proposed.

View Article: PubMed Central - PubMed

Affiliation: School of Medicine, University of California, San Diego, CA, USA.

ABSTRACT
Primary central nervous system (CNS) tumors cause significant morbidity and mortality in both adults and children. While some of the genetic and molecular mechanisms of neuro-oncogenesis are known, much less is known about possible epigenetic contributions to disease pathophysiology. Over the last several decades, chronic viral infections have been associated with a number of human malignancies. In primary CNS malignancies, two families of viruses, namely polyomavirus and herpesvirus, have been detected with varied frequencies in a number of pediatric and adult histological tumor subtypes. However, establishing a link between chronic viral infection and primary CNS malignancy has been an area of considerable controversy, due in part to variations in detection frequencies and methodologies used among researchers. Since a latent viral neurotropism can be seen with a variety of viruses and a widespread seropositivity exists among the population, it has been difficult to establish an association between viral infection and CNS malignancy based on epidemiology alone. While direct evidence of a role of viruses in neuro-oncogenesis in humans is lacking, a more plausible hypothesis of neuro-oncomodulation has been proposed. The overall goals of this review are to summarize the many human investigations that have studied viral infection in primary CNS tumors, discuss potential neuro-oncomodulatory mechanisms of viral-associated CNS disease and propose future research directions to establish a more firm association between chronic viral infections and primary CNS malignancies.

Show MeSH

Related in: MedlinePlus

Molecular mechanisms of CNS neuro-oncomodulation. The known proliferative molecular mechanisms of herpesvirus and polyomavirus infections on promoting gene expression, inhibition of apoptosis, and enhancing cell motility are shown (black arrows). In general, five major signaling pathways converge to promote oncogenesis for both families of viruses (green arrows), namely NOTCH/WNT, receptor tyrosine kinase RTK (EGFR/PDGFR), telomerase (Tel), retinoblastoma protein-E2F, and P53 pathways as described in the text
© Copyright Policy
Related In: Results  -  Collection


getmorefigures.php?uid=PMC2914282&req=5

Fig1: Molecular mechanisms of CNS neuro-oncomodulation. The known proliferative molecular mechanisms of herpesvirus and polyomavirus infections on promoting gene expression, inhibition of apoptosis, and enhancing cell motility are shown (black arrows). In general, five major signaling pathways converge to promote oncogenesis for both families of viruses (green arrows), namely NOTCH/WNT, receptor tyrosine kinase RTK (EGFR/PDGFR), telomerase (Tel), retinoblastoma protein-E2F, and P53 pathways as described in the text

Mentions: While few studies have been performed to investigate the prevalence of the alpha herpesviruses (HSV-1/2, VZV) in primary CNS tumors, aside from serological studies, this family of herpesviruses has been shown to interact with and regulate the retinoblastoma (Rb) tumor suppressor pathway; a well-characterized pathway involved oncogenesis (Hayward et al. 2006; Hume and Kalejta 2009). As illustrated in Fig. 1, Rb is a transcriptional co-repressor (along with p107, p130) that regulates cellular proliferation and differentiation. During cellular senescence, the active hyperphosphorylated form of Rb binds to transcription factor E2F to repress transcriptional activity. In HSV-infected cells, Rb is held in its inactive hypophosphorylated state, possibly due to low cyclin-dependent kinase (CdK) activity. HSV-1, in particular, prevents Rb phosphorylation and through mislocalization, keeps CdK inactive. In the case of VZV, Rb and p107 remain unphosphorylated, in spite of normal CdK activity. One report demonstrated that HSV-2-infected cells induced Rb phosphorylation (Hossain et al. 1997). However, since many of the in vitro studies of HSV-induced hypophosphorylation of Rb was performed in cycling cells, little is known about the effects of latent infection on cellular growth and differentiation in either CNS tumor cell lines or actual disease.Fig. 1


Chronic viral infection and primary central nervous system malignancy.

Saddawi-Konefka R, Crawford JR - J Neuroimmune Pharmacol (2010)

Molecular mechanisms of CNS neuro-oncomodulation. The known proliferative molecular mechanisms of herpesvirus and polyomavirus infections on promoting gene expression, inhibition of apoptosis, and enhancing cell motility are shown (black arrows). In general, five major signaling pathways converge to promote oncogenesis for both families of viruses (green arrows), namely NOTCH/WNT, receptor tyrosine kinase RTK (EGFR/PDGFR), telomerase (Tel), retinoblastoma protein-E2F, and P53 pathways as described in the text
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2914282&req=5

Fig1: Molecular mechanisms of CNS neuro-oncomodulation. The known proliferative molecular mechanisms of herpesvirus and polyomavirus infections on promoting gene expression, inhibition of apoptosis, and enhancing cell motility are shown (black arrows). In general, five major signaling pathways converge to promote oncogenesis for both families of viruses (green arrows), namely NOTCH/WNT, receptor tyrosine kinase RTK (EGFR/PDGFR), telomerase (Tel), retinoblastoma protein-E2F, and P53 pathways as described in the text
Mentions: While few studies have been performed to investigate the prevalence of the alpha herpesviruses (HSV-1/2, VZV) in primary CNS tumors, aside from serological studies, this family of herpesviruses has been shown to interact with and regulate the retinoblastoma (Rb) tumor suppressor pathway; a well-characterized pathway involved oncogenesis (Hayward et al. 2006; Hume and Kalejta 2009). As illustrated in Fig. 1, Rb is a transcriptional co-repressor (along with p107, p130) that regulates cellular proliferation and differentiation. During cellular senescence, the active hyperphosphorylated form of Rb binds to transcription factor E2F to repress transcriptional activity. In HSV-infected cells, Rb is held in its inactive hypophosphorylated state, possibly due to low cyclin-dependent kinase (CdK) activity. HSV-1, in particular, prevents Rb phosphorylation and through mislocalization, keeps CdK inactive. In the case of VZV, Rb and p107 remain unphosphorylated, in spite of normal CdK activity. One report demonstrated that HSV-2-infected cells induced Rb phosphorylation (Hossain et al. 1997). However, since many of the in vitro studies of HSV-induced hypophosphorylation of Rb was performed in cycling cells, little is known about the effects of latent infection on cellular growth and differentiation in either CNS tumor cell lines or actual disease.Fig. 1

Bottom Line: Primary central nervous system (CNS) tumors cause significant morbidity and mortality in both adults and children.In primary CNS malignancies, two families of viruses, namely polyomavirus and herpesvirus, have been detected with varied frequencies in a number of pediatric and adult histological tumor subtypes.While direct evidence of a role of viruses in neuro-oncogenesis in humans is lacking, a more plausible hypothesis of neuro-oncomodulation has been proposed.

View Article: PubMed Central - PubMed

Affiliation: School of Medicine, University of California, San Diego, CA, USA.

ABSTRACT
Primary central nervous system (CNS) tumors cause significant morbidity and mortality in both adults and children. While some of the genetic and molecular mechanisms of neuro-oncogenesis are known, much less is known about possible epigenetic contributions to disease pathophysiology. Over the last several decades, chronic viral infections have been associated with a number of human malignancies. In primary CNS malignancies, two families of viruses, namely polyomavirus and herpesvirus, have been detected with varied frequencies in a number of pediatric and adult histological tumor subtypes. However, establishing a link between chronic viral infection and primary CNS malignancy has been an area of considerable controversy, due in part to variations in detection frequencies and methodologies used among researchers. Since a latent viral neurotropism can be seen with a variety of viruses and a widespread seropositivity exists among the population, it has been difficult to establish an association between viral infection and CNS malignancy based on epidemiology alone. While direct evidence of a role of viruses in neuro-oncogenesis in humans is lacking, a more plausible hypothesis of neuro-oncomodulation has been proposed. The overall goals of this review are to summarize the many human investigations that have studied viral infection in primary CNS tumors, discuss potential neuro-oncomodulatory mechanisms of viral-associated CNS disease and propose future research directions to establish a more firm association between chronic viral infections and primary CNS malignancies.

Show MeSH
Related in: MedlinePlus