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Detection of human cytomegalovirus in medulloblastomas reveals a potential therapeutic target
Ninib Baryawno, … , John Inge Johnsen, Cecilia Söderberg-Nauclér
Ninib Baryawno, … , John Inge Johnsen, Cecilia Söderberg-Nauclér
Published September 26, 2011
Citation Information: J Clin Invest. 2011;121(10):4043-4055. https://doi.org/10.1172/JCI57147.
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Research Article

Detection of human cytomegalovirus in medulloblastomas reveals a potential therapeutic target

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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.

Authors

Ninib Baryawno, Afsar Rahbar, Nina Wolmer-Solberg, Chato Taher, Jenny Odeberg, Anna Darabi, Zahidul Khan, Baldur Sveinbjörnsson, O.-M. FuskevÅg, Lova Segerström, Magnus Nordenskjöld, Peter Siesjö, Per Kogner, John Inge Johnsen, Cecilia Söderberg-Nauclér

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Figure 1

Detection of HCMV DNA and proteins in a majority of primary medulloblastoma tissue samples.

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Detection of HCMV DNA and proteins in a majority of primary medulloblast...
(A–F) Immunohistochemical assessment of HCMV IE (A and D) and late (B and E) proteins in primary medulloblastomas; α-actin served as an isotype control antibody (C and F). Original magnification, ×20 (A–C) and ×40 (D–F). (G–I) Confirmation of immunohistochemical findings by in situ hybridization. (G) HCMV DNA. (H) Negative control. (I) Positive control (Alu). Original magnification, ×40, inset, ×100 (G); ×40 (H); ×20 (I). (J–L) Indirect immunofluorescence staining for HCMV IE (J) and late (K) antigens in frozen sections of a primary medulloblastoma, and isotype control for immunofluorescence (L). Original magnification, ×20 (J–L). (M) Quantification of HCMV expression in medulloblastomas positive for HCMV IE and late proteins. (N) HCMV expression graded 1–4 according to the percentage of HCMV-positive cells in 37 primary medulloblastoma tissue samples (see Methods for details). L, late. (O) Flow cytometric analysis of HCMV UL83 expression in two primary medulloblastomas (M2 and M3). Isotype antibodies served as a negative control.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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