Oncomodulatory Role of the Human Cytomegalovirus in Glioblastoma

Abstract

The most malignant form of primary CNS tumors, glioblastoma (GBM), is rapidly fatal in most patients despite current therapies. Recently, it has been shown that a “tumor stem cell-like” population (CD133 positive) exists within GBMs, which can drive tumor initiation and may be responsible for tumor recurrence (Singh et al., 2004). Other studies have shown that a platelet-derived growth factor receptor (PDGFR)-alpha positive subset of neural precursor cells (NPCs) in the adult brain may give rise to glioma-like lesions in vivo when PDGFR-alpha (PDGFRα) signaling is activated in these cells and their differentiation is “blocked” (Jackson et al., 2006). These data suggest that a stimulus capable of inducing chronic activation of the PDGFR-α in adult NPCs, blocking their differentiation, and promoting oncogenic signaling would be an ideal candidate for a glioma-inducing agent. Our laboratory was the first to show that human cytomegalovirus (HCMV) nucleic acids and proteins are present in over 90% of human malignant gliomas (Cobbs et al., 2002), and these data were recently confirmed by others (Mitchell et al., 2008). HCMV, a neurotropic beta-herpesvirus, persistently infects over 70% of the adult population worldwide, is the most common cause of congenital CNS disease in humans and can establish a lifelong persistent CNS infection (Britt and Alford, 1996). Mouse models of CMV infection show that the virus can be reactivated from latency specifically in the NPCs of the subventricular zone (SVZ) (Tsutsui et al., 2002). In human embryonic neural precursor stem cells, HCMV gene expression is activated at the onset of differentiation (Odeberg et al., 2006) and can arrest the progression from the NPC state toward terminal neuronal/glial phenotypes. In addition, HCMV gene products (such as the immediate-early-1, IE1, gene) can cause DNA mutations and deregulation of myriad pathways involved in maintaining cell homeostasis (Castillo and Kowalik, 2002). Our unpublished data demonstrate that the HCMV IE1 gene product is preferentially expressed in the CD133+, stem-like subpopulation of glioblastoma-derived primary neurospheres, suggesting that the virus may be selectively reactivated in and modulate the biology of this tumor cell pool (Fig. 19.1). In addition, we recently discovered that HCMV infection potently and selectively activates the PDGFRα tyrosine kinase signaling pathway in human glioma and fibroblast cells (Fig. 19.2) and that the HCMV IE1 and PDGFRα proteins co-localize in human primary GBM in situ (Fig. 19.3). We showed that HCMV infection causes activation of signaling pathways downstream of PDGFRα that promote glioma cell survival, proliferation, and invasion, such as PI3K-Akt, PLC-gamma, and FAK (Cobbs et al., 2007). Using genetic approaches to knock down the receptor, we determined that PDGFRα is required for cellular infection by HCMV (Soroceanu et al., 2008). We also found that sustained expression of the essential IE1 viral gene augments the proliferation rate and cell cycle progression of glioblastoma cells by sustained activation of Akt, down-regulation of p53, and inactivation of the Rb tumor suppressor protein (Cobbs et al., 2008). Taken together, our data suggest that HCMV infection and gene expression in human NPCs, particularly in the PDGFRα positive subpopulation of NPC, could potentially cause oncogenic transformation by blockade of differentiation, by increased proliferation, and by causing increased self-renewal capacity of neural stem cells and accumulation of genetic alterations. Therefore, HCMV is an important marker of brain tumors and a potential target for novel therapies.