Cytomegalovirus in der Prostata

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Although human cytomegalovirus HCMV is generally not regarded to be an oncogenic virus, HCMV infection has been implicated Cytomegalovirus in der Prostata malignant diseases from different cancer entities.

Oncomodulation means that HCMV infects tumor cells and increases their malignancy. By this concept, HCMV was proposed to be a therapeutic target in a fraction of cancer patients. However, the clinical relevance of HCMV-induced oncomodulation remains to be clarified. One central question that has to be definitively answered is if HCMV establishes persistent virus replication in tumor cells or not. In our eyes, recent clinical findings from different groups in glioblastoma patients and especially the detection of a correlation between the numbers of HCMV-infected glioblastoma cells and tumor stage malignancy strongly increase the evidence that HCMV may exert oncomodulatory effects.

Here, we summarize the currently available knowledge about the molecular mechanisms that may contribute to oncomodulation by HCMV as well as the clinical findings that suggest that a fraction of tumors from different entities is indeed infected with HCMV. Human cytomegalovirus HCMV is a ubiquitous herpes virus that leads to a life-long persistence.

Human cytomegalovirus causes severe and often fatal disease in immunocompromised individuals including recipients of organ transplants and AIDS patients. It routinely reactivates in healthy virus carriers, but this is usually controlled by the host immune response [ 1—3 ]. Monocytes may be an important reservoir for latent HCMV; however, the primary reservoir may be a more primitive cell from the myeloid lineage. Reactivation may result from cellular differentiation or inflammation [ 1—3 ].

The possible relationship between HCMV infection and cancer has been investigated for decades for review see, e. Although the transformed cell lines exhibited enhanced tumorigenicity in nude mice, the expression of HCMV-specific antigens in the transformed and tumor-derived lines decreased with increasing passage Cytomegalovirus in der Prostata 6 ]. In later studies using normal rodent cells, HCMV infectious virus or virus DNA was shown to induce mutations in Cytomegalovirus in der Prostata that are critical for malignant transformation [ 7—10 ].

However, viral DNA was not detected in most transformants. However, this scenario is difficult to prove because it supposes that virus nucleic acids are not retained in transformed cells.

In fact, up to now, there is no conclusive evidence for the transformation of normal cells after HCMV infection in humans, Cytomegalovirus in der Prostata the mechanism by which HCMV might contribute to oncogenesis remains obscure.

Today, it is generally accepted that infection of normal permissive cells with HCMV does not result in malignant transformation cells actively expressing virus no longer divide and eventually dieso that the virus is not considered to be oncogenic. Twelve years ago, we proposed the concept of oncomodulation in which HCMV may favor tumor progression without being an oncogenic virus to explain the frequent presence of HCMV in tumor tissues [ 11 ]. Oncomodulation means that HCMV may infect tumor cells and modulate their malignant properties, in a fashion not involving direct transformation.

We postulated that tumor cells provide a genetic environment, characterized by disturbances in intracellular signaling pathways, transcription factors, and tumor suppressor proteins, that enables HCMV to exert its oncomodulatory potential, although it cannot be manifested in normal cells. To study these effects, we established persistently HCMV-infected cancer cell lines see, e. Studies in these cell lines demonstrated that long-term persistent HCMV infection is necessary to fully express oncomodulatory effects.

Subcutaneous injection of persistently HCMV-infected neuroblastoma cells resulted in increased malignant behavior as indicated by enhanced tumor growth and metastasis formation compared to noninfected cells [ 11 ]. Human cytomegalovirus—induced oncomodulation may result from the activity of virus regulatory proteins and noncoding RNA, which influence properties of tumor cells including cell proliferation, survival, invasion, production of angiogenic factors, and immunogenicity.

As a result, HCMV infection may lead to a shift to a more malignant phenotype of tumor cells and tumor progression [ 1,14 ]. The Cytomegalovirus in der Prostata relevance of these experimental findings remains a matter of debate. We will first briefly summarize the molecular mechanisms that may underlie HCMV-induced oncomodulation before we discuss the current evidence concerning its clinical relevance.

In normal permissive cells, HCMV-encoded regulatory proteins induce cell cycle arrest and prevent cellular DNA replication but maintain an active state that enables replication of viral DNA [ 15,16 ]. In HCMV-infected cells, the expression of the cyclins D1 and A Cytomegalovirus in der Prostata inhibited, although hallmarks of S-phase, including pRB hyperphosphorylation, cyclin E and cyclin A kinase activation, and expression of many S-phase genes are present.

Several HCMV regulatory proteins such as the kDa immediate early-1 IEkDa IE, and the tegument protein pp71 were shown to interact and inactivate proteins of the Rb family pRb, p, and p promoting Cytomegalovirus in der Prostata into S phase of the cell cycle. Moreover, the UL97 protein Cytomegalovirus in der Prostata shown to exert cyclin-dependent kinase activity resulting in phosphorylation and inactivation of pRb [ 17 ]. Conversely, HCMV IE may induce cell cycle arrest by activating an ataxia telangiectasia mutated gene—dependent phosphorylation of p53 at Ser These events result in p53 accumulation and activation, leading to a p and pdependent inhibition of cell cycle progression [ 18 ].

In tumor cells, cell cycle is commonly deregulated [ 19,20 ]. In cells with disrupted cell cycle control mechanisms such as tumor cellsthe function of virus regulatory proteins may depend on the internal context of tumor cells [ 14 ] Figure 1. In Cytomegalovirus in der Prostata fibroblasts expressing wild-type p53, HCMV IE protein cannot drive cells out of quiescence, whereas IE can induce S phase and delay cell cycle exit in pdeficient cells.

In T89G glioblastoma cells with disrupted p53 signaling, persistent HCMV infection did not induce cell cycle arrest and virus antigen-positive cells continued to divide Cytomegalovirus in der Prostata 21 ]. In experiments using a panel of human glioblastoma cell lines, a stable expression of IE was shown to differentially affect cell growth, resulting either in cell proliferation or in arrest.

In U87 and U glioblastoma cells, IE—induced proliferation was paralleled by reduction in steady state expression levels of pRb and p53 family including p53, p63, or p73 members. In contrast, IE expression in LN and U glioblastoma cells was associated with increased expression of p53 family proteins, accompanied by growth arrest [ 22 ].

The HCMV protein US28 promoted cell cycle progression and cyclin D1 expression in cells with a tumorigenic phenotype, whereas it induced apoptosis in nontumorigenic cells [ 23 ]. It has also been shown that persistent HCMV infection of tumor cells may lead to a selection of novel virus variants characterized by changes in coding sequences for virus regulatory proteins that have lost their ability to induce cell cycle arrest.

Human cytomegalovirus Cytomegalovirus in der Prostata infection of tumor cells including glioblastoma and osteosarcoma results in the development of mutated virus variants, which grow slowly and yield lower amounts of progeny virus compared to wild-type virus strains originally used for infection [ 24,25 ].

Moreover, stable expression of HCMV IE protein in retrovirus-transduced fibroblasts did not abrogate the G 1 checkpoint owing to a mutation within a critical carboxyl-terminal domain of IE protein, thus making it unable to halt cell cycle progression [ 26 ]. These findings demonstrate that the effects of HCMV on cell cycle and cell proliferation may depend both on the context of the internal cellular environment and on the properties of virus regulatory proteins.

Resistance to apoptosis is a common feature of Cytomegalovirus in der Prostata cells and represents a relevant chemoresistance mechanism [ 19,20,28—30 ]. The authors speculated that HCMV exerts its antiapoptotic effects through IE proteins by both pindependent and pdependent mechanisms.

In fact, other investigators revealed that, in some cells, HCMV IE binds to p53, inhibits its transactivating function, and protects from pmediated apoptosis under conditions that would otherwise induce the pathway [ 32—36 ] Figure 1. IE inhibited doxorubicin-induced apoptosis in smooth muscle cells, indicating that IE can suppress pmediated apoptosis after DNA damage [ 35 Cytomegalovirus in der Prostata.

Furthermore, ts13 cells with a temperature-sensitive mutation in TAF II do not undergo pdependent apoptosis when IE is expressed and the cells are grown at the nonpermissive temperature [ 36 ]. The product of UL36, a viral inhibitor of caspase activation, binds to the prodomain of caspase-8, thus inhibiting Fas-mediated apoptosis [ 39,40 Cytomegalovirus in der Prostata. The UL37 gene product, UL37 exon 1 UL37x1a viral mitochondrial inhibitor of apoptosis, inhibits the recruitment of the proapoptotic endogenous Bcl-2 family member Bax and Bak Cytomegalovirus in der Prostata mitochondria, resulting in their functional neutralization [ 41,42 ].

Notably, cervix carcinoma HeLa cells expressing the viral mitochondrial inhibitor of apoptosis were resistant to apoptosis triggered by doxorubicin. The HCMV UL38 gene encodes a protein that protects infected cells from apoptosis induced by a mutant adenovirus lacking Cytomegalovirus in der Prostata antiapoptotic E1BK protein or by thapsigargin, which disrupts calcium homeostasis in the endoplasmic reticulum [ 43 ].

In cells infected with wild type virus, pUL38 was shown to interact with tuberous sclerosis tumor suppressor protein complex resulting in a failure to regulate the mammalian target of rapamycin complex 1 [ 44 ]. Viral 2. Human cytomegalovirus binding to its cellular receptors such as integrins initiates activation of AKT through the phosphatidylinositol 3-kinase PI3K pathway. Moreover, stable expression of the IE protein was sufficient to sustain increased Cytomegalovirus in der Prostata activity in glioblastoma cells independently of virus receptor signaling [ 22 ].

Furthermore, HCMV activated AKT by selective phosphorylation of the upstream nonreceptor cellular kinase focal adhesion kinase FAK at Tyr, in glioblastoma and prostate carcinoma cell lines [ 47,48 ]. These complex events may result in gene transcription, which alters apoptotic responses and other malignant properties of tumor cells Figure 2.

Increased expression of the antiapoptotic protein Bcl-2 and decreased sensitivity to chemotherapeutic agents were reported in HCMV-infected neuroblastoma and colon carcinoma cell lines [ 13,49 ]. In persistently infected neuroblastoma cells, HCMV decreased the expression Cytomegalovirus in der Prostata p73 with a concomitant increase in N- myc expression, suggesting that HCMV could also enable neuroblastoma cells to escape the apoptotic properties of p73 through N- myc -dependent pathway [ 50 ].

Cancer cell invasion, migration, and adhesion to the endothelium play important roles during formation of metastases [ 52—54 ]. Neuroblastoma cells persistently infected Cytomegalovirus in der Prostata HCMV expressed increased motility and adhesion to human endothelial cells [ 1 ]. Moreover, HCMV downregulated neural cell adhesion molecule NCAM; CD56 receptors in persistently infected neuroblastoma cells contributing to augmented tumor cell adhesion and transendothelial penetration [ 51 ].

The effects of HCMV on NCAM also account for decreased adhesion of cancer cells to each other, which is presumably one of the first steps in metastasis. In human prostate cancer PC-3 cells, HCMV infection upregulated tumor cell adhesion to the endothelium and to extracellular matrix proteins.

In human malignant Cytomegalovirus in der Prostata cells, HCMV infection also increased extracellular matrix—dependent migration and invasion in dependence on FAK phosphorylation at Tyr [ 48 ]. These effects were not observed in normal astroglial cells, suggesting that HCMV can selectively augment glioma invasiveness. US28 protein, a G protein—coupled chemokine receptor encoded by HCMV, induces arterial smooth muscle cell migration by a ligand-dependent process [ 55 ].

It has been shown that US28 signals through the non—receptor protein tyrosine kinases Src Cytomegalovirus in der Prostata FAK and that this activity is necessary for USmediated smooth muscle cell migration [ 56 ].

Investigation of gene expression in Cytomegalovirus in der Prostata persistently HCMV-infected neuroblastoma cell lines by gene microarray revealed up-regulation of genes that are involved in cancer cell invasion [ 57 ]. Recruitment of tumor vessels is an integral part of cancer initiation and progression [ 19,58,59 ].

US28 protein, a G protein—coupled chemokine receptor encoded by HCMV, induced a proangiogenic and transformed phenotype in mouse fibroblast NIH-3T3 cells through up-regulation of vascular endothelial factor [ 23 ].

USexpressing cells were tumorigenic in nude mice. Expression of a G protein—uncoupled constitutively inactive mutant of US28 delayed and attenuated tumor formation, indicating a role of constitutive receptor activity in the onset of tumor development. Importantly, US28 was also shown to be involved in HCMV-induced angiogenesis in glioblastoma cells infected with a clinical HCMV strain through the induction of vascular endothelial factor production.

Moreover, expression of interleukin 8 IL-8another well-recognized promoter of tumor angiogenesis, was stimulated by HCMV infection in leukemia and glioma cells [ 60,61 ]. In addition, HCMV infection of glioma cells suppressed the expression of angiogenesis inhibitors, such as thrombospondins 1 and 2, through the activity of IE proteins without the involvement of p53 [ Cytomegalovirus in der Prostata ].

Secretome Cytomegalovirus in der Prostata of HCMV-infected cells revealed enhanced levels of proangiogenic molecules as well as increased proangiogenic activity of cell-free supernatants [ 65 ]. By this mechanism, tumor cells themselves as well as nontransformed stroma cells e.

The ability to evade from recognition by the immune system is Cytomegalovirus in der Prostata for cancer cells [ 66,67 ]. The potential contribution of such oncomodulatory mechanisms to tumor progression was shown in a murine cytomegalovirus MCMV model. Expression of the MCMV-encoded class I homolog m protected lymphoma cells from NK cell lysis Cytomegalovirus in der Prostata in increased tumor growth and decreased survival in a syngeneic mouse model [ 72 ]. Immune escape mechanisms mediated by HCMV in tumor cells.

Human cytomegalovirus-infected tumor cells may avoid immune responses also by production of immunosuppressive cytokines. During latent infection, the ULa region transcript undergoes alternative splicing, which results in the expression of latency-associated cmvIL The latency-associated cmvIL retains some, but not all, of the immunosuppressive functions of cmvIL and its expression may enable HCMV to avoid immune recognition and clearance during latency [ 75 ].

This Cytomegalovirus in der Prostata be of relevance for tumor cells with limited permissiveness for HCMV. This may promote virus replication and interfere with host immune responses against tumor cells. Human Cytomegalovirus in der Prostata infection has been demonstrated to induce chromosome damage [ 82 ], and genetic instability is considered to be major driver of cancer progression [ 83,84 ].

Inchromosome damage induced by HCMV infection in human cells was reported for the first time [ 85 ]. Human cytomegalovirus infection in combination with cytotoxic agents synergistically increased genotoxic effects [ 86,87 ]. Most notably, HCMV was shown to induce specific chromosome 1 strand breaks at positions 1q42 and 1q21 Cytomegalovirus in der Prostata a replication-independent manner [ 88 ].

The possible targets residing near 1q42 include the ADPRT locus involved in DNA repair and replication [ 89 ] whose deletion has been connected to the development of glioblastoma [ 90 ]. A breast cancer tumor suppressor gene was proposed to be located Cytomegalovirus in der Prostata 1q [ 91 ], therefore representing a potential target of 1q21 strand breaks. The finding that many of the transformed BRK cell lines contained mutated p53 alleles suggest that mutation of p53 might be one of the mechanisms by which IE proteins contribute to transformation.