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Detection of human cytomegalovirus in medulloblastomas reveals a potential therapeutic target

Baryawno, Ninib; Rahbar, Afsar; Wolmer-Solberg, Nina; Taher, Chato; Odeberg, Jenny; Darabi, Anna LU ; Khan, Zahidul; Sveinbjornsson, Baldur; Fuskevag, O. -M. and Segerstrom, Lova, et al. (2011) In Journal of Clinical Investigation 121(10). p.4043-4055
Abstract
Medulloblastomas are the most common malignant brain tumors in children. They express high levels of COX-2 and produce PGE(2), 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... (More)
Medulloblastomas are the most common malignant brain tumors in children. They express high levels of COX-2 and produce PGE(2), 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 riot 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. (Less)
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Journal of Clinical Investigation
volume
121
issue
10
pages
4043 - 4055
publisher
The Journal of Clinical Investigation
external identifiers
  • wos:000295601000031
  • scopus:80053390591
ISSN
0021-9738
DOI
10.1172/JCI57147
language
English
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yes
id
0599b10d-23cd-40a1-830d-09a018c9f162 (old id 2212733)
date added to LUP
2011-12-01 08:34:09
date last changed
2017-11-19 03:41:24
@article{0599b10d-23cd-40a1-830d-09a018c9f162,
  abstract     = {Medulloblastomas are the most common malignant brain tumors in children. They express high levels of COX-2 and produce PGE(2), 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 riot 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.},
  author       = {Baryawno, Ninib and Rahbar, Afsar and Wolmer-Solberg, Nina and Taher, Chato and Odeberg, Jenny and Darabi, Anna and Khan, Zahidul and Sveinbjornsson, Baldur and Fuskevag, O. -M. and Segerstrom, Lova and Nordenskjold, Magnus and Siesjö, Peter and Kogner, Per and Johnsen, John Inge and Soderberg-Naucler, Cecilia},
  issn         = {0021-9738},
  language     = {eng},
  number       = {10},
  pages        = {4043--4055},
  publisher    = {The Journal of Clinical Investigation},
  series       = {Journal of Clinical Investigation},
  title        = {Detection of human cytomegalovirus in medulloblastomas reveals a potential therapeutic target},
  url          = {http://dx.doi.org/10.1172/JCI57147},
  volume       = {121},
  year         = {2011},
}