Abstract
The human cytomegalovirus (HCMV) is suspected to increase tumour malignancy by infection of cancer and/or stroma cells (oncomodulation). So far, oncomodulatory mechanisms have been attributed to the presence of HCMV and direct action of its gene products on cancer cells. Here, we investigated whether the prolonged presence of HCMV can result in the irreversible selection of a cancer cell population with increased malignancy. The neuroblastoma cell line UKF-NB-4 was long-term (200 passages) infected with the HCMV strain Hi91 (UKF-NB-4Hi) before virus eradication using ganciclovir (UKF-NB-4HiGCV). Global gene expression profiling of UKF-NB-4, UKF-NB-4Hi and UKF-NB-4HiGCV cells and subsequent bioinformatic signal transduction pathway analysis revealed clear differences between UKF-NB-4 and UKF-NB-4Hi, as well as between UKF-NB-4 and UKF-NB-4HiGCV cells, but only minor differences between UKF-NB-4Hi and UKF-NB-4HiGCV cells. Investigation of the expression of a subset of five genes in different chronically HCMV-infected cell lines before and after virus eradication suggested that long-term HCMV infection reproducibly causes specific changes. Array comparative genomic hybridisation showed virtually the same genomic differences for the comparisons UKF-NB-4Hi/UKF-NB-4 and UKF-NB-4HiGCV/UKF-NB-4. UKF-NB-4Hi cells are characterised by an increased invasive potential compared with UKF-NB-4 cells. This phenotype was completely retained in UKF-NB-4HiGCV cells. Moreover, there was a substantial overlap in the signal transduction pathways that differed significantly between UKF-NB-4Hi/UKF-NB-4HiGCV and UKF-NB-4 cells and those differentially regulated between tumour tissues from neuroblastoma patients with favourable or poor outcome. In conclusion, we present the first experimental evidence that long-term HCMV infection can result in the selection of tumour cell populations with enhanced malignancy.
Highlights
Human cytomegalovirus (HCMV), a ubiquitous herpes virus, infection leads to a life-long persistence after primary infection
With our studies about the influence of HCMV on cancer cells,[5,6,7] we introduced the concept of oncomodulation, meaning that HCMV may infect cancer cells and/or stromal cells in established tumours and increase tumour malignancy in the absence of transformation potential.[1,2,3,6,8,9]
HCMV-induced oncomodulatory effects were attributed to the presence of HCMV and direct action of its gene products, 2,3,10,24 antigen expression remained detectable in UKF-NB-4Hi cells, resulting in about 30–60% infected cells (Figure 1)
Summary
Human cytomegalovirus (HCMV), a ubiquitous herpes virus, infection leads (in immunocompetent individuals usually symptomless) to a life-long persistence after primary infection. HCMV-induced oncomodulatory effects were attributed to the presence of HCMV and direct action of its gene products, 2,3,10,24 antigen expression remained detectable in UKF-NB-4Hi cells, resulting in about 30–60% infected cells (Figure 1). (a concentration that did not affect the viability of UKF-NB-4 or UKF-NB-4Hi cells) for six passages until no HCMV gene expression was detected anymore (UKF-NB-4HiGCV; Figure 1). Further cultivation of UKF-NB-4HiGCV cells for 10 passages did not result in These data indicate that the long-term presence of HCMV can recurrence of HCMV gene expression (Figure 1). The absence of result in the irreversible selection of a cancer cell population with HCMV from UKF-NB-4HiGCV cells was confirmed by virus yield assay increased malignancy. Investigation of the expression of a subset and quantitative PCR detecting HCMV genome (Supplementary of five genes in additional long-term HCMV-infected Figure 2). Comparison of global gene expression in UKF-NB-4, UKF-NB-4Hi and UKF-NB-4HiGCV cells
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