Detection of human cytomegalovirus in medulloblastomas reveals a potential therapeutic target
Open Access
- 3 October 2011
- journal article
- research article
- Published by American Society for Clinical Investigation in JCI Insight
- Vol. 121 (10), 4043-4055
- https://doi.org/10.1172/jci57147
Abstract
Medulloblastomas are the most common malignant brain tumors in children. They express high levels of COX-2 and produce PGE2, which stimulates tumor cell proliferation. Human cytomegalovirus (HCMV) is prevalent in the human population and encodes proteins that provide immune evasion strategies and promote oncogenic transformation and oncomodulation. In particular, HCMV induces COX-2 expression; STAT3 phosphorylation; production of PGE2, vascular endothelial growth factor, and IL-6; and tumor formation in vivo. Here, we show that a large proportion of primary medulloblastomas and medulloblastoma cell lines are infected with HCMV and that COX-2 expression, along with PGE2 levels, in tumors is directly modulated by the virus. Our analysis indicated that both HCMV immediate-early proteins and late proteins are expressed in the majority of primary medulloblastomas. Remarkably, all of the human medulloblastoma cell lines that we analyzed contained HCMV DNA and RNA and expressed HCMV proteins at various levels in vitro. When engrafted into immunocompromised mice, human medulloblastoma cells induced expression of HCMV proteins. HCMV and COX-2 expression correlated in primary tumors, cell lines, and medulloblastoma xenografts. The antiviral drug valganciclovir and the specific COX-2 inhibitor celecoxib prevented HCMV replication in vitro and inhibited PGE2 production and reduced medulloblastoma tumor cell growth both in vitro and in vivo. Ganciclovir did not affect the growth of HCMV-negative tumor cell lines. These findings imply an important role for HCMV in medulloblastoma and suggest HCMV as a novel therapeutic target for this tumor.This publication has 48 references indexed in Scilit:
- The Genetic Landscape of the Childhood Cancer MedulloblastomaScience, 2011
- Effect of daily aspirin on long-term risk of death due to cancer: analysis of individual patient data from randomised trialsThe Lancet, 2010
- Is HCMV a tumor promoter?Virus Research, 2010
- Eicosanoids and cancerNature Reviews Cancer, 2010
- Aspirin and non-steroidal anti-inflammatory drugs for cancer prevention: an international consensus statementThe Lancet Oncology, 2009
- Aspirin, salicylates, and cancerThe Lancet, 2009
- Identification of CD15 as a Marker for Tumor-Propagating Cells in a Mouse Model of MedulloblastomaCancer Cell, 2009
- Human CMV infection induces 5-lipoxygenase expression and leukotriene B4 production in vascular smooth muscle cellsThe Journal of Experimental Medicine, 2008
- Human Cytomegalovirus Inhibits Neuronal Differentiation and Induces Apoptosis in Human Neural Precursor CellsJournal of Virology, 2006
- Human cytomegalovirus-encoded chemokine receptor US28 promotes tumorigenesisProceedings of the National Academy of Sciences, 2006