Modulatory Effects of Human Cytomegalovirus Infection on Malignant Properties of Cancer Cells

Abstract

Although there is no definitive evidence of the association of human cytomegalovirus (HCMV) infection with human cancers, the oncogenic potential of HCMV has been well established by in vitro studies demonstrating the ability of UV-irradiated or infectious virus to transform a variety of cells. After prolonged passaging the transformed cell type was maintained while HCMV DNA sequences were no more detectable. Three morphological transforming regions (mtr) of HCMV have been identified. The effects of HCMV on cellular functions which may be associated with the malignant phenotype include the expression of oncogenes and transcriptional activation of growth factors and interleukin synthesis. In infected cells, HCMV induces cytoskeletal alterations and changes in expression of cell surface receptors for extracellular matrix proteins which could result in increased motility and dissemination of cancer cells. Several human neuroblastoma cell lines undergo maturation in different neural crest derived cell types upon treatment with oncogenic potential agents, i. e. retinoic acid. The persistent HCMV infection of neuroblastoma cells (>1 year) is accompanied by the increased expression of oncoproteins (i.e. N-myc) and decreased expression of tyrosine hydroxylase and dopamine-β-hydroxylase. The activation of the cellular metabolism is due to HCMV binding to cellular receptors (prior to virus gene expression) and to the activity of HCMV immediate early (IE) gene products. IE proteins act directly as transcriptional activators or their activity is mediated by a variety of cellular transcription factors. HCMV infection may result in activation of promoters of cellular genes coding for cytokines, replication enzymes, protooncogenes and viral promoters. Recently it has been demonstrated that HCMV IE proteins block apoptosis probably by suppressing the ability of the antioncogene p53 to activate a reporter gene. The interactions of HCMV with tumor suppressor proteins such as p53 or retinoblastoma (pRb) susceptibility protein are reminiscent of those mediated by the oncoproteins of DNA tumor viruses. The acquisition of a fully malignant phenotype by normal cells is thought to require several mutations in a number of cellular genes. In this connection, HCMV may play the role of a nonobligate either direct or indirect cofactor for tumor genesis, e.g. by blocking apoptosis, which may be an essential requirement for tumor progression. Due to the stimulation of growth factors and/or inhibition of antioncogenes by its gene products, HCMV may modulate the malignant potential of tumor cells.

Lack of association of cytomegalovirus with human brain tumors

“…[14][15][16][17] In addition, CMV infection has been shown to stimulate nucleic acid and protein synthesis, activate transcription of protooncogenes, and modulate expression of proteins involved in cellular regulatory and apoptotic pathways. [14][15][16][17][24][25][26][27] CMV has been associated with several specific human malignancies including carcinomas of the cervix, [28][29][30][31][32] prostate, [33][34][35][36] and colon. [37][38][39] However, a number of conflicting reports have either failed to show evidence of an association with CMV or have questioned the significance of the presence of CMV in these particular tumors.…”

Viral epigenomes in human tumorigenesis

“…Although HCMV is not considered to be oncogenic, its infection has been implicated in carcinogenesis by different pathways, and the concept of 'oncomodulation' emerged to explain the role of this virus in tumor progression (Cinatl et al, 1996(Cinatl et al, , 2004Michaelis et al, 2009).…”

Human Cytomegalovirus Infection Decreases Expression of Thrombospondin-1 Independent of the Tumor Suppressor Protein p53

“…by immunoperoxidase staining using monoclonal antibodies (MAbs; DuPont, Bad Homburg, Germany) di-rected against 72-kd immediate-early antigen (IEA) and 67-kd late antigen (LA), respectively (described in detail elsewhere). 3,4 …”

“…These changes result in disturbance of normal tissue homeostasis, which indirectly may promote tumor growth. [2][3][4][5][6] In particular, in vitro studies have shown that HCMV gene products such as immediate-early (IE) proteins or morphological transforming region II oncoprotein bind wild-type p53 tumor suppressor protein and thereby down-regulate p53-activated transcription. [7][8][9][10][11] The development of new blood vessels (angiogenesis) is necessary to sustain the growth, invasion, and metastasis of tumors.…”