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Medicine » Infectious Diseases » "Manifestations of Cytomegalovirus Infection", book edited by Patricia Price, Nandini Makwana and Samantha Brunt, ISBN 978-953-51-1116-0, Published: May 29, 2013 under CC BY 3.0 license. © The Author(s).

Chapter 6

The Oncogenicity of Human Cytomegalovirus

By Prakash Vishnu and David M. Aboulafia
DOI: 10.5772/55051

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Pathway linking chronic inflammation and oncogenesis. (Adapted from Schetter et. al. [13])
Figure 1. Pathway linking chronic inflammation and oncogenesis. (Adapted from Schetter et. al. [13])
Concept of Oncomodulation. (Adapted from Michaelis et. al. [99])
Figure 2. Concept of Oncomodulation. (Adapted from Michaelis et. al. [99])
Major signaling pathways activated by hCMV that contribute to oncomodulation by hCMV. (Adapted from from Michaelis et. al. [100])
Figure 3. Major signaling pathways activated by hCMV that contribute to oncomodulation by hCMV. (Adapted from from Michaelis et. al. [100])

The Oncogenicity of Human Cytomegalovirus

Prakash Vishnu1 and David M. Aboulafia1, 2

1. Introduction

The potential role of Human cytomegalovirus (hCM) infection in promoting neoplasia is an active area of scientific research. [1] Although still controversial, there is a growing body of evidence that links hCMV infection to a variety of malignancies, including those of the breast, prostate, colon, lung and brain (gliomas). [2-7] hCMV induces alterations in regulatory proteins and non-coding RNA that are associated with a malignant phenotype. These changes promote tumour survival by effecting cellular proliferation, invasion, immune evasion, and production of angiogenic factors [8] Constant immune surveillance governs the destruction of the majority of cancer cells and precancerous conditions in the human body. However, the most pathogenic of malignant tumors acquire immune evasion strategies which render them less vulnerable to destruction by immune cells.

The characteristic hallmarks of a malignant cell include:

  1. sustaining proliferative signaling and evading growth suppressors,

  2. resisting cell death and enabling replicative immortality,

  3. inducing angiogenesis, activating invasion and metastasis. [9]

In cancers which are not attributable to infectious agents, chronic inflammation may also play a critical role in the transition from a precancerous condition to invasive malignancy. Inflammation is the seventh hallmark of neoplasia (Table 1). [10] During chronic inflammation, certain “promoters,” such as hepatitis C virus and Epstein-Barr virus (EBV), may facilitate the transformation of a pre-malignant condition to neoplasia. [11,12] Cancer “promoters” are agents that, by themselves, may not have a significant oncogenic impact on normal cells but can drive precancerous cells towards neoplasia.

1. Sustaining proliferative signaling
2. Evading growth suppressors
3. Resisting cell death
4. Inducing angiogenesis
5. Activating invasion and metastasis
6. Enabling replicative immortality
7. Tumor-promoting inflammation

Table 1.

The “seven” hallmarks of cancer

2. Chronic inflammation and oncogenesis

Associations linking chronic infection, chronic inflammation and malignancy have been well chronicled. [13] As many as 25% of all cancers can be traced to chronic infection or other types of chronic inflammation. [14] Infectious agents that cause chronic inflammation promote oncogenesis by complex pathways, and are depicted in Figure 1. Key mediators of inflammation-induced oncogenesis include generation of mutagenic chemical mediators such as reactive oxygen and nitrogen species, genetic variations in inflammatory cytokines [15], and creation of a micro-environment with features of chronic inflammation such as nuclear factor kappa B (NF-κB). [16,17] In such conditions, tumor-associated macrophages (TAMs) play a pivotal role in mediating inflammatory (M1) responses, as well as immunosuppressive and growth (M2) responses. [18]


Figure 1.

Pathway linking chronic inflammation and oncogenesis. (Adapted from Schetter et. al. [13])

M2-polarized TAMs and the related myeloid-derived suppressor cells are key components of smoldering inflammation that drives neoplastic progression. The M2 responses, while important for wound healing, can promote neoplastic transformation. TAMs respond to cytokines such as Interleukin (IL)-10 and Transforming Growth Factor (TGF)-β, acquiring M2 properties that promote immune suppression by blocking dendritic cell (DC) maturation and attracting regulatory T-cells (T-regs). [19,20] T-regs are potent inhibitors of the T-cell anti-tumor response. [21]

Activation of NF-κB pathway mediated by COX-2 and IL-6 via STAT-3 transcriptional activation also promotes malignant transformation. [22] NF-κB is a transcription factor that mediates an inflammatory cascade leading to generation of COX-2, an inducible isoform of nitric oxide synthase (iNOS) and the inflammatory cytokines IL-1β, IL-6, and Tumor Necrosis Factor (TNF) -α. These cytokines, in conjunction with nitric oxide produced by TAMs and tumor cells, are present in high concentration in the tumor microenvironment and are important promoters of inflammation-driven oncogenesis and immunosuppression. [23-25]

3. Concept of oncomodulation

Tumor cells have aberrations in cell cycle signaling, RNA transcription and the production of tumor-suppression proteins. The concept of “oncomodulation” suggests that a virus may modulate cellular pathways [26] through changes to viral regulatory proteins and noncoding RNA which eludes to tumor cell properties (cell proliferation, survival, invasion, production of angiogenic factors, and immune evasion). hCMV not only promotes oncogenesis but also contributes to a more malignant tumor cell phenotype (Figure 2). While investigators have long postulated a role for hCMV in human neoplasia, many of the early studies were not reproducible and lacked clear in situ histopathological correlations with the proposed diseases. [27,28] The concept of “hit-and-run” oncogenesis holds that infection with hCMV takes place during an earlier time frame to tumour development. hCMV infection sets into motion processes resulting in malignancy, but the virus is no longer detectable by the time cancer occurs. [29] Several of the more important cellular pathways that could lead to cancer and which are modulated by hCMV are reviewed below.


Figure 2.

Concept of Oncomodulation. (Adapted from Michaelis et. al. [99])

3.1. Resistance to apoptosis

Resistance to apoptosis is a common feature of cancer cells. [9,30,31] Early research on hCMV infection revealed that hCMV protects the fibroblasts it infects from apoptosis. hCMV immediate early (IE) proteins (e.g., IE2-86 & IE2-72) [32] are able to prevent adenovirus E1A protein-induced apoptosis-by both p53-dependent and independent mechanisms- of hCMV infected fibroblasts. Direct anti-apoptotic activity of hCMV proteins is related to defined transcripts encoded by the hCMV UL36-UL37 genes. [33,34] The product of the UL36 gene is an inhibitor of caspase activation which binds to the pro-domain of caspase-8 and inhibits Fas-mediated apoptosis. [35] Similarly, the UL37 gene product, UL37 exon 1, is a mitochondrial inhibitor of apoptosis and inhibits the recruitment of the pro-apoptotic proteins Bax and Bak to mitochondria, resulting in their functional inactivation. [36] hCMV further protects tumor cells from apoptosis by the induction of cellular proteins, including AKT, Bcl-2, and ΔNp73α. [37] Induction of the anti-apoptotic protein Bcl-2 by hCMV, results in acquired resistance to cytotoxic drugs such as cisplatin and etoposide. This resistance can be reversed after treatment with the anti-hCMV drug, ganciclovir. [37] Engagement of platelet derived growth factor receptor (PDGFR) α or virus co-receptors (including integrins and Toll-like receptor-2) by hCMV glycoproteins can also lead to activation of mitogen-activated protein kinase (MAPK) and/or phosphatidyl-inositol 3-kinase (PI3-K) pathways that can alter apoptotic responses (Figure 3). [38-40]


Figure 3.

Major signaling pathways activated by hCMV that contribute to oncomodulation by hCMV. (Adapted from from Michaelis et. al. [100])

3.2. Cancer cell adhesion, migration and invasion

Adhesion of cancer cells to endothelium is critical in promoting metastases. [41-43] hCMV can facilitate this process by promoting activation of integrins (e.g., β1α5 and B1) on the tumor cell surface, and by increasing adhesion of tumor cells to the neighboring endothelium. Tumor cell adhesion to endothelium is also facilitated by activation of integrin-linked kinases (e.g., phosphorylation of focal adhesion kinase Tyr397). [4,,44] Down regulation of adhesion molecule receptors by hCMV (e.g., neural cell adhesion molecule, CD56), causes a focal disruption of endothelial cells facilitating tumor cell transmigration. [1,45] The net effects of hCMV on adhesion molecules account for decreased binding of cancer cells to each other and increased binding to endothelium, which is an important early process in formation of metastasis.

3.3. Angiogenesis

Angiogenesis is the growth of the new blood vessels and is essential for growth of malignant tumors. [9,46] Through the technique of secretome analysis researchers have shown that proteins secreted from hCMV-infected cells contain increased levels of pro-angiogenic molecules, and increased pro-angiogenic activity in cell-free supernatants. [47] US28 is a hCMV protein seen in high concentrations in the supernatant. This particular protein alters adhesion properties of epithelial cells inducing a pro-angiogenic and transformed phenotype through up-regulation of vascular endothelial growth factor (VEGF). [48] Additional supernatant proteins, including IE1-72 and IE2-86, increase vascular smooth muscle cell migration, proliferation, and expression of PDGF-β receptor. Furthermore, IE2-86 promotes endothelial proliferation by binding and inactivating the tumor oncogene p53 in endothelial cells. [49,50] Expression of IL-8, another well-recognized promoter of tumor angiogenesis, is increased by hCMV via transactivation of IL-8 promoter through the cellular transcription factors NF-κB and AP-1. [51] Binding of hCMV to and signaling through integrin β1, integrin β3, and epidermal growth factor receptor can also promote angiogenesis. [47,52]

Expression of thrombospondin (TSP-1), a potent inhibitor of angiogenesis, is suppressed in several hCMV-infected cancer cell lines, suggesting yet another mechanism by which hCMV can promote increased angiogenesis and a more malignant phenotype. [53,54] hCMV -mediated activation of COX-2 may also promote angiogenesis in tumor cells by inducing expression of Fibroblast Growth Factor (FGF), VEGF, PDGF, iNOS, and TGF-α, and by promoting capillary endothelial cell migration and tube formation (Figure 3). [55]

3.4. Impact of hCMV on cell cycle

In hCMV-infected host cells, viral regulatory proteins induce cell cycle arrest and prevent cellular DNA replication, whilst replication of viral DNA remains enabled. [8,56] While some hCMV regulatory proteins can induce cell cycle arrest, others can promote cell cycle progression. [57,58] hCMV IE2-86 induces cell cycle arrest by activating ataxia telangiectasia mutated (ATM) gene-dependent phosphorylation of p53, leading to p53- and p21-dependent inhibition of cell cycle progression. [59] In contrast, the hCMV regulatory proteins IE1-72, IE2-86, and the tegument proteins pp71 and UL97 interact with and deactivate proteins of the Rb family, promoting entry into S-phase of the cell cycle. [60]

The cell cycle of neoplastic cells is inherently dysfunctional. [9,31] In precancerous or transformed cells, the function of virus regulatory proteins may depend on the replicative status of the cell. [61,62] The hCMV protein US28 promotes cell cycle progression and cyclin D1 expression in cells with a neoplastic phenotype; whereas, it induces apoptosis in non-neoplastic cells. [48] Persistent hCMV infection of tumor cells may lead to a selection of virus variants with changes in virus regulatory proteins that have lost their ability to induce cell cycle arrest. [63,64]

4. Escape of immune surveillance by cancer cells: Role of hCMV

Immunological tolerance is a process by which the immune system no longer recognizes an aberrant antigen as “foreign.” [67] Through “natural” or “self-tolerance” the body does not mount an immune response to self-antigens. “Induced tolerance” to external antigens can be created by manipulating the immune system. Mechanisms of tolerance that exist to prevent autoimmune disease may also preclude the development of an adequate antitumor response. [65-67] This concept of “immune tolerance” may be particularly important in malignancies whose etiology is associated with inflammation. [68] Expression of hCMV proteins by infected tumor cells may induce ‘immune tolerance’ to tumor cells. Also, several tumor-derived factors contribute to the emergence of complex local and regional immunosuppressive networks, including VEGF, IL-10, TGF-β, and prostaglandin E-2 (PGE2). [66,69]

hCMV has evolved multiple strategies for immune evasion resulting in persistent viral infection in the host [70-74] Several hCMV proteins, including those expressed with IE genes, block the host cell MHC class I antigen expression, which is essential for activation of CD8+ T-lymphocyte anti-tumor cytotoxicity. hCMV UL83 protein (pp65) blocks antigen presentation of hCMV epitopes to CD8+ T-cells, and expression of hCMV UL18, a MHC class I homologue, disrupts “natural killer” (NK) cell recognition of hCMV-infected cells. [75] Disruption of hCMV antigen presentation by infected cells is mediated by hCMV protein US3, which sequesters MHC class I complexes in the endoplasmic reticulum, and hCMV protein US11 which causes dislocation of the MHC class I heavy chain from the cytoplasm. [76-78] hCMV-encoded IL-10 homologue impairs tumor antigen presentation by inhibiting maturation, normal differentiation and cytokine production of dendritic cells and macrophages.. [79-81] hCMV induces integrin αvβ6 expression in endothelial cells of blood vessels in different tissues, causing activation of TGF-β1, resulting in interference of host immune responses against tumor cells by blocking the activation of lymphocytes and monocyte derived phagocytes. [82] These direct immune-modulatory effects of hCMV on myeloid cells within the tumor microenvironment, along with expression of immunosuppressive cytokines provide a virtually impassable environment for the host anti-tumor immune system.

5. Influence of CMV on tumor microenvironment

Persistent hCMV infection of non-neoplastic cells in the tumor microenvironment leads to a paracrine secretion of inflammatory molecules that promote malignancy. [83] The secretome of hCMV-infected fibroblasts contains exceedingly high levels of growth factors, matrix remodeling proteins such as matrix metalloproteinases (MMPs), and angiogenic factors that signal through the TGF-β pathway. [47,84] These paracrine-secreted factors are also able to activate latent growth factors. PDGFs acts as strong mitogens and their overexpression is important in the pathogenesis of multiple malignancies. [85-87] In addition to growth factors, high levels of many ECM modifiers such as MMPs, tissue inhibitors of metalloproteinases (TIMPs) and urokinase receptor (uPAR) secreted by hCMV infected cells aiding, tumor invasion and metastasis. [84]

6. DNA mutations, impaired DNA repair mechanisms and epigenetic changes by hCMV that leads to genomic instability

hCMV infection can drive neoplastic transformation by causing chromosome damage and genetic instability in infected cells, particularly in vulnerable adult stem cells. [88-90] hCMV in combination with cytotoxic chemotherapy agents synergistically increases genotoxic effects. [91,92] The virus can induce specific chromosome 1 strand breaks at positions 1q42 and 1q21 in a replication-independent fashion, both of which are associated with DNA repair and replication genes. [89,93,94] hCMV IE1-72 and IE2-86 proteins when in conjunction with other viral oncogenic proteins (e.g., adenovirus E1A protein) that disrupt cell cycle can induce oncogenic transformation. [29]

hCMV can contribute to genomic instability through a variety of different pathways. In brief, the virus may induce chromosomal aberrations (e.g., production of micronuclei, misaligned chromosomes, chromosomal lagging and bridging) by hCMV UL76 protein. [95,96] The virus can also disrupt DNA repair pathways, including the activity of ATM and ATM-Rad3 (ATR). [97] More recently, hCMV has been shown to modulate oncogenesis through the telomerase pathway by activating human telomerase reverse transcriptase (hTERT) in fibroblasts and malignant cells. [98]

7. Conclusions

Significant advances have been made in understanding the roles of chronic inflammation, tumor microenvironment, cancer stem cells, tumor immunology, and infectious agents in the pathobiology of cancer. Several clinical and experimental findings suggest that hCMV may play a role in promoting certain cancers. In cells that are persistently infected with hCMV, the expression of viral proteins may prevent the immune system from identifying or removing these cells, thereby offsetting immune detection of transformed cells. The effects of hCMV in promoting tumor cell immune evasion may prove important in development of cancer immunotherapies, particularly if the hCMV-infected cells are resistant to the action of cytolytic peptides released by activated NK and cytotoxic T-cells. Also, if viral proteins that inhibit apoptosis are expressed by hCMV infected tumour cells, the cancer cells may be less susceptible conventional chemotherapeutic agents. Whether hCMV is ultimately established as an oncogenic virus will require additional research in the areas of virology, epidemiology and molecular oncology, and systematic refinement of the concept of “oncomodulation.” Insights into the role of hCMV in oncogenesis may increase understanding of cancer biology and promote development of novel therapeutic strategies.


1 - Cinatl J, Scholz M, Kotchetkov R, Vogel JU, Doerr HW. Molecular mechanisms of the modulatory effects of HCMV infection in tumor cell biology. Trends in molecular medicine. Jan 2004;10(1):19-23.
2 - Harkins LE, Matlaf LA, Soroceanu L, et al. Detection of human cytomegalovirus in normal and neoplastic breast epithelium. Herpesviridae. 2010;1(1):8.
3 - Cobbs CS, Harkins L, Samanta M, et al. Human cytomegalovirus infection and expression in human malignant glioma. Cancer research. Jun 15 2002;62(12):3347-3350.
4 - Cobbs CS, Soroceanu L, Denham S, et al. Human cytomegalovirus induces cellular tyrosine kinase signaling and promotes glioma cell invasiveness. Journal of neuro-oncology. Dec 2007;85(3):271-280.
5 - Giuliani L, Jaxmar T, Casadio C, et al. Detection of oncogenic viruses SV40, BKV, JCV, HCMV, HPV and p53 codon 72 polymorphism in lung carcinoma. Lung Cancer. Sep 2007;57(3):273-281.
6 - Harkins L, Volk AL, Samanta M, et al. Specific localisation of human cytomegalovirus nucleic acids and proteins in human colorectal cancer. Lancet. Nov 16 2002;360(9345):1557-1563.
7 - Scheurer ME, Bondy ML, Aldape KD, Albrecht T, El-Zein R. Detection of human cytomegalovirus in different histological types of gliomas. Acta neuropathologica. Jul 2008;116(1):79-86.
8 - Castillo JP, Kowalik TF. HCMV infection: modulating the cell cycle and cell death. International reviews of immunology. Jan-Apr 2004;23(1-2):113-139.
9 - Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell. Mar 4 2011;144(5):646-674.
10 - Colotta F, Allavena P, Sica A, Garlanda C, Mantovani A. Cancer-related inflammation, the seventh hallmark of cancer: links to genetic instability. Carcinogenesis. Jul 2009;30(7):1073-1081.
11 - Berasain C, Castillo J, Perugorria MJ, Latasa MU, Prieto J, Avila MA. Inflammation and liver cancer: new molecular links. Annals of the New York Academy of Sciences. Feb 2009;1155:206-221.
12 - Young LS, Rickinson AB. Epstein-Barr virus: 40 years on. Nature reviews. Cancer. Oct 2004;4(10):757-768.
13 - Schetter AJ, Heegaard NH, Harris CC. Inflammation and cancer: interweaving microRNA, free radical, cytokine and p53 pathways. Carcinogenesis. Jan 2010;31(1):37-49.
14 - Hussain SP, Harris CC. Inflammation and cancer: an ancient link with novel potentials. International journal of cancer. Journal international du cancer. Dec 1 2007;121(11):2373-2380.
15 - de Visser KE, Eichten A, Coussens LM. Paradoxical roles of the immune system during cancer development. Nature reviews. Cancer. Jan 2006;6(1):24-37.
16 - Grivennikov SI, Greten FR, Karin M. Immunity, inflammation, and cancer. Cell. Mar 19 2010;140(6):883-899.
17 - Balkwill F, Charles KA, Mantovani A. Smoldering and polarized inflammation in the initiation and promotion of malignant disease. Cancer cell. Mar 2005;7(3):211-217.
18 - Allavena P, Sica A, Garlanda C, Mantovani A. The Yin-Yang of tumor-associated macrophages in neoplastic progression and immune surveillance. Immunological reviews. Apr 2008;222:155-161.
19 - Zamarron BF, Chen W. Dual roles of immune cells and their factors in cancer development and progression. International journal of biological sciences. 2011;7(5):651-658.
20 - Gomez GG, Kruse CA. Mechanisms of malignant glioma immune resistance and sources of immunosuppression. Gene therapy & molecular biology. 2006;10(A):133-146.
21 - Wolf AM, Wolf D, Steurer M, Gastl G, Gunsilius E, Grubeck-Loebenstein B. Increase of regulatory T cells in the peripheral blood of cancer patients. Clinical cancer research : an official journal of the American Association for Cancer Research. Feb 2003;9(2):606-612.
22 - Greten FR, Eckmann L, Greten TF, et al. IKKbeta links inflammation and tumorigenesis in a mouse model of colitis-associated cancer. Cell. Aug 6 2004;118(3):285-296.
23 - Cobbs CS, Brenman JE, Aldape KD, Bredt DS, Israel MA. Expression of nitric oxide synthase in human central nervous system tumors. Cancer research. Feb 15 1995;55(4):727-730.
24 - Hara A, Okayasu I. Cyclooxygenase-2 and inducible nitric oxide synthase expression in human astrocytic gliomas: correlation with angiogenesis and prognostic significance. Acta neuropathologica. Jul 2004;108(1):43-48.
25 - Jia W, Jackson-Cook C, Graf MR. Tumor-infiltrating, myeloid-derived suppressor cells inhibit T cell activity by nitric oxide production in an intracranial rat glioma + vaccination model. Journal of neuroimmunology. Jun 2010;223(1-2):20-30.
26 - Cinatl J, Jr., Cinatl J, Vogel JU, Rabenau H, Kornhuber B, Doerr HW. Modulatory effects of human cytomegalovirus infection on malignant properties of cancer cells. Intervirology. 1996;39(4):259-269.
27 - Geder L, Sanford EJ, Rohner TJ, Rapp F. Cytomegalovirus and cancer of the prostate: in vitro transformation of human cells. Cancer treatment reports. Mar-Apr 1977;61(2):139-146.
28 - Sanford EJ, Geder L, Laychock A, Rohner TJ, Jr., Rapp F. Evidence for the association of cytomegalovirus with carcinoma of the prostate. The Journal of urology. Nov 1977;118(5):789-792.
29 - Shen Y, Zhu H, Shenk T. Human cytomagalovirus IE1 and IE2 proteins are mutagenic and mediate "hit-and-run" oncogenic transformation in cooperation with the adenovirus E1A proteins. Proceedings of the National Academy of Sciences of the United States of America. Apr 1 1997;94(7):3341-3345.
30 - Plati J, Bucur O, Khosravi-Far R. Dysregulation of apoptotic signaling in cancer: molecular mechanisms and therapeutic opportunities. Journal of cellular biochemistry. Jul 1 2008;104(4):1124-1149.
31 - Pucci B, Kasten M, Giordano A. Cell cycle and apoptosis. Neoplasia. Jul-Aug 2000;2(4):291-299.
32 - Zhu H, Shen Y, Shenk T. Human cytomegalovirus IE1 and IE2 proteins block apoptosis. Journal of virology. Dec 1995;69(12):7960-7970.
33 - McCormick AL. Control of apoptosis by human cytomegalovirus. Current topics in microbiology and immunology. 2008;325:281-295.
34 - Michaelis M, Kotchetkov R, Vogel JU, Doerr HW, Cinatl J, Jr. Cytomegalovirus infection blocks apoptosis in cancer cells. Cellular and molecular life sciences : CMLS. Jun 2004;61(11):1307-1316.
35 - Skaletskaya A, Bartle LM, Chittenden T, McCormick AL, Mocarski ES, Goldmacher VS. A cytomegalovirus-encoded inhibitor of apoptosis that suppresses caspase-8 activation. Proceedings of the National Academy of Sciences of the United States of America. Jul 3 2001;98(14):7829-7834.
36 - Goldmacher VS, Bartle LM, Skaletskaya A, et al. A cytomegalovirus-encoded mitochondria-localized inhibitor of apoptosis structurally unrelated to Bcl-2. Proceedings of the National Academy of Sciences of the United States of America. Oct 26 1999;96(22):12536-12541.
37 - Cinatl J, Jr., Cinatl J, Vogel JU, et al. Persistent human cytomegalovirus infection induces drug resistance and alteration of programmed cell death in human neuroblastoma cells. Cancer research. Jan 15 1998;58(2):367-372.
38 - Soroceanu L, Akhavan A, Cobbs CS. Platelet-derived growth factor-alpha receptor activation is required for human cytomegalovirus infection. Nature. Sep 18 2008;455(7211):391-395.
39 - Johnson RA, Wang X, Ma XL, Huong SM, Huang ES. Human cytomegalovirus up-regulates the phosphatidylinositol 3-kinase (PI3-K) pathway: inhibition of PI3-K activity inhibits viral replication and virus-induced signaling. Journal of virology. Jul 2001;75(13):6022-6032.
40 - Johnson RA, Huong SM, Huang ES. Activation of the mitogen-activated protein kinase p38 by human cytomegalovirus infection through two distinct pathways: a novel mechanism for activation of p38. Journal of virology. Feb 2000;74(3):1158-1167.
41 - Kopfstein L, Christofori G. Metastasis: cell-autonomous mechanisms versus contributions by the tumor microenvironment. Cellular and molecular life sciences : CMLS. Feb 2006;63(4):449-468.
42 - Cruz-Monserrate Z, O'Connor KL. Integrin alpha 6 beta 4 promotes migration, invasion through Tiam1 upregulation, and subsequent Rac activation. Neoplasia. May 2008;10(5):408-417.
43 - Hall CL, Dubyk CW, Riesenberger TA, Shein D, Keller ET, van Golen KL. Type I collagen receptor (alpha2beta1) signaling promotes prostate cancer invasion through RhoC GTPase. Neoplasia. Aug 2008;10(8):797-803.
44 - Blaheta RA, Weich E, Marian D, et al. Human cytomegalovirus infection alters PC3 prostate carcinoma cell adhesion to endothelial cells and extracellular matrix. Neoplasia. Oct 2006;8(10):807-816.
45 - Blaheta RA, Beecken WD, Engl T, et al. Human cytomegalovirus infection of tumor cells downregulates NCAM (CD56): a novel mechanism for virus-induced tumor invasiveness. Neoplasia. Jul-Aug 2004;6(4):323-331.
46 - Goon PK, Lip GY, Boos CJ, Stonelake PS, Blann AD. Circulating endothelial cells, endothelial progenitor cells, and endothelial microparticles in cancer. Neoplasia. Feb 2006;8(2):79-88.
47 - Dumortier J, Streblow DN, Moses AV, et al. Human cytomegalovirus secretome contains factors that induce angiogenesis and wound healing. Journal of virology. Jul 2008;82(13):6524-6535.
48 - Maussang D, Verzijl D, van Walsum M, et al. Human cytomegalovirus-encoded chemokine receptor US28 promotes tumorigenesis. Proceedings of the National Academy of Sciences of the United States of America. Aug 29 2006;103(35):13068-13073.
49 - Reinhardt B, Mertens T, Mayr-Beyrle U, et al. HCMV infection of human vascular smooth muscle cells leads to enhanced expression of functionally intact PDGF beta-receptor. Cardiovascular research. Jul 1 2005;67(1):151-160.
50 - Kovacs A, Weber ML, Burns LJ, Jacob HS, Vercellotti GM. Cytoplasmic sequestration of p53 in cytomegalovirus-infected human endothelial cells. The American journal of pathology. Nov 1996;149(5):1531-1539.
51 - Murayama T, Mukaida N, Sadanari H, et al. The immediate early gene 1 product of human cytomegalovirus is sufficient for up-regulation of interleukin-8 gene expression. Biochemical and biophysical research communications. Dec 9 2000;279(1):298-304.
52 - Bentz GL, Yurochko AD. Human CMV infection of endothelial cells induces an angiogenic response through viral binding to EGF receptor and beta1 and beta3 integrins. Proceedings of the National Academy of Sciences of the United States of America. Apr 8 2008;105(14):5531-5536.
53 - Hsu SC, Volpert OV, Steck PA, et al. Inhibition of angiogenesis in human glioblastomas by chromosome 10 induction of thrombospondin-1. Cancer research. Dec 15 1996;56(24):5684-5691.
54 - Tenan M, Fulci G, Albertoni M, et al. Thrombospondin-1 is downregulated by anoxia and suppresses tumorigenicity of human glioblastoma cells. The Journal of experimental medicine. May 15 2000;191(10):1789-1798.
55 - Tsujii M, Kawano S, Tsuji S, Sawaoka H, Hori M, DuBois RN. Cyclooxygenase regulates angiogenesis induced by colon cancer cells. Cell. May 29 1998;93(5):705-716.
56 - Sanchez V, Spector DH. Subversion of cell cycle regulatory pathways. Current topics in microbiology and immunology. 2008;325:243-262.
57 - Jault FM, Jault JM, Ruchti F, et al. Cytomegalovirus infection induces high levels of cyclins, phosphorylated Rb, and p53, leading to cell cycle arrest. Journal of virology. Nov 1995;69(11):6697-6704.
58 - Salvant BS, Fortunato EA, Spector DH. Cell cycle dysregulation by human cytomegalovirus: influence of the cell cycle phase at the time of infection and effects on cyclin transcription. Journal of virology. May 1998;72(5):3729-3741.
59 - Song YJ, Stinski MF. Inhibition of cell division by the human cytomegalovirus IE86 protein: role of the p53 pathway or cyclin-dependent kinase 1/cyclin B1. Journal of virology. Feb 2005;79(4):2597-2603.
60 - Hume AJ, Finkel JS, Kamil JP, Coen DM, Culbertson MR, Kalejta RF. Phosphorylation of retinoblastoma protein by viral protein with cyclin-dependent kinase function. Science. May 9 2008;320(5877):797-799.
61 - Hwang ES, Zhang Z, Cai H, et al. Human cytomegalovirus IE1-72 protein interacts with p53 and inhibits p53-dependent transactivation by a mechanism different from that of IE2-86 protein. Journal of virology. Dec 2009;83(23):12388-12398.
62 - Luo MH, Fortunato EA. Long-term infection and shedding of human cytomegalovirus in T98G glioblastoma cells. Journal of virology. Oct 2007;81(19):10424-10436.
63 - Furukawa T. A variant of human cytomegalovirus derived from a persistently infected culture. Virology. Aug 1984;137(1):191-194.
64 - Ogura T, Tanaka J, Kamiya S, Sato H, Ogura H, Hatano M. Human cytomegalovirus persistent infection in a human central nervous system cell line: production of a variant virus with different growth characteristics. The Journal of general virology. Dec 1986;67 ( Pt 12):2605-2616.
65 - Dunn GP, Bruce AT, Ikeda H, Old LJ, Schreiber RD. Cancer immunoediting: from immunosurveillance to tumor escape. Nature immunology. Nov 2002;3(11):991-998.
66 - Kim R, Emi M, Tanabe K. Cancer immunosuppression and autoimmune disease: beyond immunosuppressive networks for tumour immunity. Immunology. Oct 2006;119(2):254-264.
67 - Drake CG, Jaffee E, Pardoll DM. Mechanisms of immune evasion by tumors. Advances in immunology. 2006;90:51-81.
68 - Kamp DW, Shacter E, Weitzman SA. Chronic inflammation and cancer: the role of the mitochondria. Oncology (Williston Park). Apr 30 2011;25(5):400-410, 413.
69 - Kim R, Emi M, Tanabe K, Arihiro K. Tumor-driven evolution of immunosuppressive networks during malignant progression. Cancer research. Jun 1 2006;66(11):5527-5536.
70 - Hengel H, Brune W, Koszinowski UH. Immune evasion by cytomegalovirus--survival strategies of a highly adapted opportunist. Trends in microbiology. May 1998;6(5):190-197.
71 - Loenen WA, Bruggeman CA, Wiertz EJ. Immune evasion by human cytomegalovirus: lessons in immunology and cell biology. Seminars in immunology. Feb 2001;13(1):41-49.
72 - Michelson S. Human cytomegalovirus escape from immune detection. Intervirology. 1999;42(5-6):301-307.
73 - Scholz M, Doerr HW, Cinatl J. Human cytomegalovirus retinitis: pathogenicity, immune evasion and persistence. Trends in microbiology. Apr 2003;11(4):171-178.
74 - Wiertz E, Hill A, Tortorella D, Ploegh H. Cytomegaloviruses use multiple mechanisms to elude the host immune response. Immunology letters. Jun 1 1997;57(1-3):213-216.
75 - Farrell HE, Vally H, Lynch DM, et al. Inhibition of natural killer cells by a cytomegalovirus MHC class I homologue in vivo. Nature. Apr 3 1997;386(6624):510-514.
76 - Greijer AE, Verschuuren EA, Dekkers CA, et al. Expression dynamics of human cytomegalovirus immune evasion genes US3, US6, and US11 in the blood of lung transplant recipients. The Journal of infectious diseases. Aug 1 2001;184(3):247-255.
77 - Benz C, Hengel H. MHC class I-subversive gene functions of cytomegalovirus and their regulation by interferons-an intricate balance. Virus genes. 2000;21(1-2):39-47.
78 - Besold K, Wills M, Plachter B. Immune evasion proteins gpUS2 and gpUS11 of human cytomegalovirus incompletely protect infected cells from CD8 T cell recognition. Virology. Aug 15 2009;391(1):5-19.
79 - Chang WL, Baumgarth N, Yu D, Barry PA. Human cytomegalovirus-encoded interleukin-10 homolog inhibits maturation of dendritic cells and alters their functionality. Journal of virology. Aug 2004;78(16):8720-8731.
80 - Cheeran MC, Hu S, Sheng WS, Peterson PK, Lokensgard JR. CXCL10 production from cytomegalovirus-stimulated microglia is regulated by both human and viral interleukin-10. Journal of virology. Apr 2003;77(8):4502-4515.
81 - Nachtwey J, Spencer JV. HCMV IL-10 suppresses cytokine expression in monocytes through inhibition of nuclear factor-kappaB. Viral immunology. Dec 2008;21(4):477-482.
82 - Tabata T, Kawakatsu H, Maidji E, et al. Induction of an epithelial integrin alphavbeta6 in human cytomegalovirus-infected endothelial cells leads to activation of transforming growth factor-beta1 and increased collagen production. The American journal of pathology. Apr 2008;172(4):1127-1140.
83 - Chan G, Bivins-Smith ER, Smith MS, Smith PM, Yurochko AD. Transcriptome analysis reveals human cytomegalovirus reprograms monocyte differentiation toward an M1 macrophage. J Immunol. Jul 1 2008;181(1):698-711.
84 - Streblow DN, Dumortier J, Moses AV, Orloff SL, Nelson JA. Mechanisms of cytomegalovirus-accelerated vascular disease: induction of paracrine factors that promote angiogenesis and wound healing. Current topics in microbiology and immunology. 2008;325:397-415.
85 - Ahmad A, Wang Z, Kong D, et al. Platelet-derived growth factor-D contributes to aggressiveness of breast cancer cells by up-regulating Notch and NF-kappaB signaling pathways. Breast cancer research and treatment. Feb 2011;126(1):15-25.
86 - Campbell JS, Hughes SD, Gilbertson DG, et al. Platelet-derived growth factor C induces liver fibrosis, steatosis, and hepatocellular carcinoma. Proceedings of the National Academy of Sciences of the United States of America. Mar 1 2005;102(9):3389-3394.
87 - Shih AH, Holland EC. Platelet-derived growth factor (PDGF) and glial tumorigenesis. Cancer letters. Feb 8 2006;232(2):139-147.
88 - Hartmann M, Brunnemann H. Chromosome aberrations in cytomegalovirus-infected human diploid cell culture. Acta virologica. Mar 1972;16(2):176.
89 - Fortunato EA, Spector DH. Viral induction of site-specific chromosome damage. Reviews in medical virology. Jan-Feb 2003;13(1):21-37.
90 - Jefford CE, Irminger-Finger I. Mechanisms of chromosome instability in cancers. Critical reviews in oncology/hematology. Jul 2006;59(1):1-14.
91 - Deng CZ, AbuBakar S, Fons MP, Boldogh I, Albrecht T. Modulation of the frequency of human cytomegalovirus-induced chromosome aberrations by camptothecin. Virology. Jul 1992;189(1):397-401.
92 - Deng CZ, AbuBakar S, Fons MP, et al. Cytomegalovirus-enhanced induction of chromosome aberrations in human peripheral blood lymphocytes treated with potent genotoxic agents. Environmental and molecular mutagenesis. 1992;19(4):304-310.
93 - Fortunato EA, Dell'Aquila ML, Spector DH. Specific chromosome 1 breaks induced by human cytomegalovirus. Proceedings of the National Academy of Sciences of the United States of America. Jan 18 2000;97(2):853-858.
94 - Baumgartner M, Schneider R, Auer B, Herzog H, Schweiger M, Hirsch-Kauffmann M. Fluorescence in situ mapping of the human nuclear NAD+ ADP-ribosyltransferase gene (ADPRT) and two secondary sites to human chromosomal bands 1q42, 13q34, and 14q24. Cytogenetics and cell genetics. 1992;61(3):172-174.
95 - Albrecht T, Deng CZ, Abdel-Rahman SZ, Fons M, Cinciripini P, El-Zein RA. Differential mutagen sensitivity of peripheral blood lymphocytes from smokers and nonsmokers: effect of human cytomegalovirus infection. Environmental and molecular mutagenesis. 2004;43(3):169-178.
96 - Siew VK, Duh CY, Wang SK. Human cytomegalovirus UL76 induces chromosome aberrations. Journal of biomedical science. 2009;16:107.
97 - Luo MH, Rosenke K, Czornak K, Fortunato EA. Human cytomegalovirus disrupts both ataxia telangiectasia mutated protein (ATM)- and ATM-Rad3-related kinase-mediated DNA damage responses during lytic infection. Journal of virology. Feb 2007;81(4):1934-1950.
98 - Straat K, Liu C, Rahbar A, et al. Activation of telomerase by human cytomegalovirus. Journal of the National Cancer Institute. Apr 1 2009;101(7):488-497.
99 - Michaelis M, Baumgarten P, Mittelbronn M, Driever PH, Doerr HW, Cinatl J, Jr. Oncomodulation by human cytomegalovirus: novel clinical findings open new roads. Medical microbiology and immunology. Feb 2011;200(1):1-5.
100 - Michaelis M, Doerr HW, Cinatl J. The story of human cytomegalovirus and cancer: increasing evidence and open questions. Neoplasia. Jan 2009;11(1):1-9.