title: Detection of human cytomegalovirus in medulloblastomas reveals a potential therapeutic target.
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.affiliation: Karolinska Institutet, Department of Women's and Children's Health, Childhood Cancer Research Unit, Stockholm, Sweden.
authors.forename: Ninib
authors.initials: N
authors.lastname: Baryawno
authors.forename: Afsar
authors.initials: A
authors.lastname: Rahbar
authors.forename: Nina
authors.initials: N
authors.lastname: Wolmer-Solberg
authors.forename: Chato
authors.initials: C
authors.lastname: Taher
authors.forename: Jenny
authors.initials: J
authors.lastname: Odeberg
authors.forename: Anna
authors.initials: A
authors.lastname: Darabi
authors.forename: Zahidul
authors.initials: Z
authors.lastname: Khan
authors.forename: Baldur
authors.initials: B
authors.lastname: Sveinbjörnsson
authors.forename: O-M
authors.initials: OM
authors.lastname: FuskevÅg
authors.forename: Lova
authors.initials: L
authors.lastname: Segerström
authors.forename: Magnus
authors.initials: M
authors.lastname: Nordenskjöld
authors.forename: Peter
authors.initials: P
authors.lastname: Siesjö
authors.forename: Per
authors.initials: P
authors.lastname: Kogner
authors.forename: John Inge
authors.initials: JI
authors.lastname: Johnsen
authors.forename: Cecilia
authors.initials: C
authors.lastname: Söderberg-Nauclér
mesh_terms: D000328:Adult; D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology; D001932:Brain Neoplasms / Q000188:drug therapy / Q000821:virology*; D000068579:Celecoxib; D045744:Cell Line, Tumor; D002648:Child; D002675:Child, Preschool; D052246:Cyclooxygenase 2 Inhibitors / Q000494:pharmacology; D003587:Cytomegalovirus / Q000187:drug effects / Q000302:isolation & purification* / Q000472:pathogenicity / Q000502:physiology; D015232:Dinoprostone / Q000096:biosynthesis; D005260:Female; D015774:Ganciclovir / Q000031:analogs & derivatives / Q000494:pharmacology; D006801:Humans; D007223:Infant; D008297:Male; D008527:Medulloblastoma / Q000188:drug therapy / Q000821:virology*; D051379:Mice; D008819:Mice, Nude; D008875:Middle Aged; D011720:Pyrazoles / Q000494:pharmacology; D013449:Sulfonamides / Q000494:pharmacology; D000077562:Valganciclovir; D014779:Virus Replication / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays; D055815:Young Adult
chemical_list: D000998:Antiviral Agents; D052246:Cyclooxygenase 2 Inhibitors; D011720:Pyrazoles; D013449:Sulfonamides; D000077562:Valganciclovir; D000068579:Celecoxib; D015232:Dinoprostone; D015774:Ganciclovir