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Viruses and human brain tumors: cytomegalovirus enters the fray
Cynthia Hawkins1 and Sidney Croul2
1Division of Pathology, The Hospital for Sick Children, and 2Division of Pathology, University Health Network, Toronto, Ontario, Canada.
Address correspondence to: Cynthia Hawkins, Department of Paediatric Laboratory Medicine, The Hospital for Sick Children, 555 University Avenue, Toronto, Ontario M5G 1X8, Canada. Phone: 416.813.5938; Fax: 416.813.5974; E-mail: cynthia.hawkins@sickkids.ca.
Find articles by Hawkins, C. in: PubMed | Google Scholar
1Division of Pathology, The Hospital for Sick Children, and 2Division of Pathology, University Health Network, Toronto, Ontario, Canada.
Address correspondence to: Cynthia Hawkins, Department of Paediatric Laboratory Medicine, The Hospital for Sick Children, 555 University Avenue, Toronto, Ontario M5G 1X8, Canada. Phone: 416.813.5938; Fax: 416.813.5974; E-mail: cynthia.hawkins@sickkids.ca.
Find articles by Croul, S. in: PubMed | Google Scholar
Published September 26, 2011 - More info
J Clin Invest. 2011;121(10):3831–3833. https://doi.org/10.1172/JCI60005.
© 2011 The American Society for Clinical Investigation
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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
Brain tumors account for 20% of all neoplasms in children and are the largest group of solid tumors that develop in childhood (1). Medulloblastoma is the most common malignant pediatric brain tumor, constituting 20%–25% of pediatric central nervous system neoplasms (2, 3). Its incidence is estimated at 2–6 cases per million children per year, with approximately 540 new cases diagnosed annually in the United States (2, 4). Medulloblastoma typically arises in the midline cerebellum, in the region of the mid- and inferior vermis. Current treatment includes surgery, craniospinal irradiation, and chemotherapy. Overall survival for all medulloblastoma patients is roughly 50%–60% in population-based studies (5). However, as we have gained a better understanding of clinical risk factors, the incorporation of patient stratification in larger, multi-institutional studies has resulted in improved survival. Currently, there are three major treatment strategies for medulloblastoma patients based on their clinical status. For patients younger than 3–5 years, treatments are aimed at maximizing survival while avoiding radiation (6, 7). Older patients are stratified by the extent of resection and metastatic status. Patients with metastatic disease or a less-than-optimal resection are classified as high-risk and are treated with high doses of craniospinal irradiation (36–39 Gy) and aggressive chemotherapy. Patients with totally, or near-totally, resected, non-disseminated disease are designated average-risk. This is the most prevalent group, and these patients are treated with a combination of lower-dose irradiation and chemotherapy. This clinical stratification has resulted in higher cure rates for all groups, with 80% of average-risk patients reaching progression-free survival at 5 years (8, 9). Despite the improved survival, there still remains a substantial amount of mortality associated with medulloblastoma, and survivors often experience neurological, endocrinological, and social sequelae as a result of treatment. Thus, many researchers are seeking to develop new, more targeted and less toxic therapeutic strategies. In this issue of the JCI, Baryawno et al. describe a potential novel therapeutic strategy for medulloblastoma that takes advantage of their finding that human cytomegalovirus (HCMV) is frequently expressed in such tumors (10).
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Can the presence of virus be used to target brain tumors therapeutically?
HCMV DNA and proteins have been found in tumors of different origins, including 90%–100% of high-grade glial brain tumors (24). Unlike polyomaviruses, CMV is not considered to be oncogenic itself and has likewise not been used as an oncolytic virus. In this issue of the JCI, Baryawno et al. report their work examining the prevalence of HCMV in medulloblastomas and whether the presence of the virus can be used to target medulloblastoma therapeutically (10). Of the 37 primary medulloblastomas examined by Baryawno et al. for the presence of HCMV, 92% expressed HCMV immediate early proteins and 73% expressed late proteins. Similarly, HCMV proteins were detected in all 8 medulloblastoma cell lines tested, including within the CD133+ putative tumor-initiating cell population.
Baryawno and colleagues then went on to test whether either ganciclovir, which targets the DNA polymerase during HCMV replication, or the COX-2 inhibitor celecoxib, which prevents HCMV replication by decreasing PGE2 levels, affected medulloblastoma growth (10). They found that ganciclovir decreased the clonogenic capacity of HCMV-positive cell lines but had no effect on HCMV-negative lines. This effect was augmented by the addition of celecoxib. While this study did not address these questions, it will be important to test what effect the drugs have on cell growth in vitro, and whether the effects are cytotoxic or cytostatic.
In a flank xenograft model, Baryawno et al. found that medulloblastoma tumor volume could be reduced by approximately 40% in mice treated with either valganciclovir or celecoxib alone, and by 72% with a combined drug regimen (10). Similar to the in vitro data, HCMV-negative xenografts were not affected by the drug treatment, supporting the hypothesis that the effect was specific to HCMV-positive tumor cells. Future preclinical studies looking at whether this drug treatment can extend the survival of mice in an orthotopic xenograft model and whether these drugs can be effectively combined with other chemotherapeutic agents and/or radiotherapy will be key.
The data presented by Baryawno et al. demonstrating in vivo reduction of tumor size following treatment with valganciclovir and celecoxib (ref. 10 and Figure 1) are intriguing, as they raise a new potential route through which viruses may be exploited to treat brain tumors. The relatively low toxicity and good blood brain barrier penetration of these agents make them attractive for clinical use, eliminating many of the barriers that still face oncolytic viral therapies. However, the claim of Baryawno and colleagues that their observations suggest a pathogenic role for HCMV in medulloblastoma (10) is less well substantiated. As for polyomavirus, a causal role for HCMV in medulloblastoma development has yet to be shown.
Figure 1Effect of valganciclovir and celecoxib on medulloblastoma cell lines expressing HCMV proteins as observed by Baryawno and colleagues (10). Injection of medulloblastoma cell lines expressing HCMV proteins into the flanks of nude mice results in tumors (Control), which are reduced in size following treatment with either valganciclovir, which targets the DNA polymerase during HCMV replication, or the COX-2 inhibitor celecoxib, which prevents HCMV replication by decreasing PGE2 levels. Treatment with a combination of celecoxib and valganciclovir causes a greater reduction in tumor size than either drug alone. LP, HCMV late protein; IE, HCMV immediate early protein.
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