Increasing evidence implicates infectious agents as causal in human cancer. Despite decades of human genetic studies and searches for environmental carcinogens, only a very small percentage of major human malignancies are clearly attributable to known inborn genetic mutations or environmental carcinogens.
Instead, an ever Bereiter hahn mehrtens online dating percentage of human malignancies in the last several decades have been attributed to infectious agents, and vaccinations and other preventative measures are having a significant impact on infectious related cancer deaths from malignancies such as hepatoma, cervical cancer and gastric cancer Demaria et al.
In malignancies that are not currently attributable to infectious agents, chronic subacute inflammation plays a critical role in the transition from neoplastic precursor to full-blown invasive malignancy, and inflammation is considered the seventh hallmark of neoplasia Balkwill et al. Cancer promoters are agents that may have no significant oncogenic impact on wild-type cells, but can drive preneoplastic cells toward full blown malignancy.
Infectious agents can be promoters of neoplastic transformation. For example, Hepatitis C virus chronically infects the liver and causes a persistent inflammatory immune response resulting in hepatoma Berasain et al.
EBV is ubiquitous the human population, and thus is not oncogenic under normal circumstances. However, EBV infection in the nasopharynx of individuals exposed to certain environmental carcinogens is critical in the development of nasopharyngeal carcinoma, through expression of latent EBV genes that promote cell growth and survival Young and Rickinson, Human cytomegalovirus HCMVas of this time, has not been clearly implicated in human cancer.
Many of the biological responses elicited by chronic HCMV infection are similar to those that support chronic inflammation, leukocyte dysfunction, angiogenesis and wound healing. While investigators have postulated a role for HCMV in human neoplasia in the past, many of the early studies by Rapp and colleagues were not easily reproducible and lacked clear in situ histopathological correlations with the proposed diseases Geder et al.
With the more recent identification by our group and others of HCMV infection specifically in preneoplastic and neoplastic tumor cells of malignant gliomas, prostate cancers and colorectal cancers, but not adjacent normal tissues, a greater urgency to answer the question of whether HCMV may play an etiological role in these malignancies has arisen Cobbs et al. In the study by Lau et al, 22 brain tumors of various histologic types and grades, four normal brains, six breast carcinomas, six colon carcinomas, six lung carcinomas, and six sarcomas were evaluated for the presence of CMV by polymerase chain reaction PCR
Bereiter hahn mehrtens online dating situ hybridization, and immunohistochemical methods Lau et al.
These authors did not detect CMV nucleic acid or protein in any of these specimens. It is important to note, however, that the aforementioned studies have not employed the highly sensitive immunohistochemical approach required for detection of endogenous, low level HCMV infection in human specimens.
This discrepancy has been addressed in the study by Scheurer et al Scheurer M, ; Scheurer et al. Given the controversial nature of this novel concept, it is critical that a more clear understanding of the role of HCMV in tumor biology be obtained, since such knowledge may have profound implications with respect to potential therapies and preventive strategies.
Unfortunately, establishing causality for a ubiquitous virus that causes persistent infection in a majority of adults worldwide is difficult. Furthermore, Koch's postulates cannot be directly applied in the context of a potential oncogenic virus that may take years to induce or promote malignancy Fredericks and Relman, For this reason modified criteria based on Hill's 9 criteria were developed by Fredericks and Relman to address this issue with modern molecular techniques, and are outlined below Fredericks and Relman, For a potential infectious agent to be considered causal in human cancer, the authors proposed that the following criteria must be met:.
In this review, we will examine the oncogenic properties of HCMV, primarily focusing on published and unpublished work as it relates to malignant glioma. We suggest that an accumulating body of evidence implicates HCMV as a potential tumor promoter based on three general themes: Infectious agents that promote a chronic, low level of infection promote oncogenesis by induction of mutagenic chemical mediators, genetic variations in inflammatory cytokines, immune cell mediators, and by generally evoking an environment with characteristics of chronic wound healing reviewed in Balkwill et al.
Under such conditions, tumor associated macrophages TAMs play a pivotal role in Bereiter hahn mehrtens online dating mediating inflammatory M1 responses as well as immunosuppressive and growth M2 responses Allavena et al. Such responses, which are critical in wound healing, also promote neoplastic Bereiter hahn mehrtens online dating. In the case of malignant glioma, increased M2 macrophage infiltration in the tumor is associated with more aggressive tumor phenotype Komohara et al.
Tregs are potent inhibitors of the cell mediated T cell antitumor response Gomez and Kruse, An accumulating body of experimental evidence indicates that the chronic expression of TNF-alpha and IL-1 beta in the pre-malignant microenvironment can produce Bereiter hahn mehrtens online dating increases in the likelihood of malignant transformation via activation of the NF-kB transcriptional activator Greten et al. IL-6 induction and expression in tumor cells and tumor associated myeloid cells has an important role in "Bereiter hahn mehrtens online dating" inflammatory oncogenic signaling, likely by activation of the STAT-3 transcriptional activator Tanabe et al.
Hence, the NF-kB pathway has a dual effect in tumor promotion by preventing death of cells with malignant potential and by stimulating pro-inflammatory cytokines in infiltrating myeloid and lymphoid cells. In malignant glioma, potent inflammatory pathways are present, which both increase the likelihood of reactive species Bereiter hahn mehrtens online dating in mutagenesis, while simultaneously attracting microglia and macrophages into the local environment.
Nevertheless, the host anti-tumor immune response in gliomas is highly ineffective Gomez and Kruse, ; Parney et al. Although infiltrating T-cells may be present, up to one third of cells in malignant gliomas express macrophage markers, and are thus likely to represent both intrinsic microglial cells from the CNS and infiltrating monocyte- derived cells Gomez and Kruse, ; Hussain et al.
Those effector T-cells that are present in malignant gliomas are highly non-functional. Inactivation of infiltrating T-cells in gliomas may be due to the impact of T-cell anergy, which can occur when tumor associated immature DCs inactivate T-cells Gomez and Kruse, Tregs, found at high levels in gliomas, also inhibit T-cell proliferation and activation Humphries et al. These cytokines, along with nitric oxide NO produced by TAMs and tumor cells via nitric oxide synthase NOS activation, are found at high levels in malignant gliomas and other tumors, and are important promoters of inflammation-driven oncogenesis and immunosuppression Cobbs et al.
Our group became interested in the possible role of HCMV in cancer while studying the inflammatory pathways associated with grade IV malignant gliomas, or glioblastoma multiforme GBM. We found that these tumors had high levels of iNOS expression and evidence of an elevated reactive oxygen and nitrogen environment Cobbs et al.
Indeed, malignant gliomas are known to exist in a highly immunosuppressive microenvironment, characterized by high levels of expression of immunosuppressive agents such as TGB-beta, PGE-2, and IL Zou et al. Because of the paradoxical inflammatory and immunosuppressive environment present in malignant gliomas, we speculated that a chronic viral infection in the tumor itself may be present. We hypothesized that HCMV might be able to persistently infect immature cells of glial origin, and cause a low level of chronic inflammation, while simultaneously promoting immune dysregulation.
These findings have since been confirmed by several other groups of investigators Mitchell et al. Subsequently, using similar techniques, we determined that a high percentage of human prostate, colon and breast cancers unpublished data are infected by HCMV Harkins et al. HCMV causes persistent infection of the bone marrow and other organ systems, and probably never exists in a true latent state Reinke et al.
HCMV reactivation in the myeloid population can occur in differentiating monocyte derived cells in the setting of inflammation and immunosuppression Soderberg-Naucler et al. In human colorectal carcinomas and breast adenocarcinomas, we detected expression of the HCMV pp65 protein in infiltrating myeloid cells in the tumor microenvironment Harkins et al.
These cytokines would be expected to produce an oncogenic microenvironment since chronic expression of TNF-alpha and IL-6 are directly linked to oncogenic transformation in inflammation-induced animal models of cancer Grivennikov et al. This body of work reinforces the concept that chronic HCMV infection of non-neoplastic cells can have major paracrine effects on adjacent cells in the microenvironment.
Among the factors highly secreted by HCMV infected cells, were members of the TGF-beta signaling pathway and extracellular matrix remodeling enzymes e. proteins facilitate immunosuppression, wound healing and angiogenesis by remodeling of the extracellular matrix ECM and activating latent growth factors. If fibroblasts within the tumor microenvironment are infected and persistently secrete factors due to HCMV infection, this could significantly influence the growth of the tumor.
The work by Dumortier et al. These paracrine-secreted factors induced robust wound healing and angiogenesis in model systems. In a tumor microenvironment in vivothese same chemokines would be Bereiter hahn mehrtens online dating to promote infiltration of macrophages, mitogenic activity, angiogenesis and activation of downstream inflammatory cascades.
GDNF secretion would "Bereiter hahn mehrtens online dating" provide a strong oncogenic stimulus in the setting of a tumor microenvironment since GDNF is a potent promoter of cell survival and can confer mitogenic activity and chemoresistance on glioblastoma cells and proliferation, survival, cell migration and anchorage independent growth in breast cancer cells Esseghir et al. The PDGF growth factors are also very strong mitogens implicated in oncogenesis and progression of multiple malignancies including glioblastoma and breast cancer Ahmad et al.
Bereiter hahn mehrtens online dating levels of circulating PDGFs could markedly promote tumor progression if secreted into the tumor microenvironment.
These ECM modulators are critical for both wound healing and tumor invasion and metastasis. These cells can regulate the differentiation and proliferation of adjacent hematopoietic precursor cells and contribute to the regeneration of mesenchymal tissues, including bone, cartilage, fat and connective tissue, and notably malignant tissues Roorda et al.
During tumor development, BM-MSCs are attracted to and infiltrate areas of neoplasia and play a critical role in the development of tumor neovasculature Roorda et al. Indeed, these cells are essential for tumor growth beyond an avascular threshold. If BM-MSCs are infected with HCMV, they are likely to deliver virus directly to the tumor and lead to infection of tumor cells, as has been demonstrated experimentally in human gliomas Yong et al.
A critical component in inflammation-associated malignancies is the loss of normal anti-tumor immune function in the tumor microenvironment. Through millions of years of co-evolution with the Bereiter hahn mehrtens online dating, HCMV has evolved multiple strategies to allow persistent viral infection through a complex array of immune evasion strategies Hengel et al.
Through a complex interaction with tumor cells and TAMs, HCMV infection is likely to severely impair function of tumor antigen presentation by dendritic cells DCs in the tumor microenvironment.
Interleukin IL suppresses the maturation and cytokine production of dendritic cells DCskey regulators of adaptive immunity, and Bereiter hahn mehrtens online dating the activation and polarization of naive T cells towards protective gamma interferon-producing effectors. The HCMV viral IL can also interfere with DC, microglial and macrophage function through interference with normal differentiation and cytokine production Cheeran et al.
In addition to direct immunomodulatory effects on myeloid cells within the tumor, expression of immunosuppressive cytokines by infected tumor cells, tumor infiltrating macrophages and fibroblasts would provide a virtually impenetrable environment for the host anti-tumor immune system. These cytokines are all induced by HCMV infected cells, and in combination would be expected to have a profound immunosuppressive effect on the host antitumor response Maussang et al.
While the data presented above indicate that HCMV has the potential to contribute to oncogenesis by expressing gene products in cells of the tumor microenvironment, myriad other data indicate that HCMV can have direct oncogenic effects on tumor cells and tumor precursor cells themselves. As the field of cancer research has evolved, an increased appreciation of the role of adult stem cells and cancer stem cells in the neoplastic process has emerged.
An agent that could impact the differentiation state and self renewal capacity of stem cells, while simultaneously causing DNA mutations, activation of growth signaling pathways and inhibition of tumor suppressor pathways, would be an ideal agent for promoting oncogenesis. We will discuss below the evidence, primarily as it relates to malignant glioma oncogenesis, that HCMV has the potential to exert direct oncogenic effects on tumor initiating stem cells and tumor cells themselves.
HCMV is a neurotropic virus which can specifically infect neural precursor cells and impact neuronal differentiation. Recent data Luo et al. HCMV can also persistently infect and reside latently in neural precursor cells and may be reactivated under specific circumstances. Reactivation of CMV during neural precursor differentiation has been studied in mouse models. Experiments using both human and murine CMV indicate that upon reactivation, induction of the viral immediate early IE genes occurs, and subsequent viral gene expression is activated, during differentiation of NPCs Cheeran et al.
A clinical isolate of HCMV TR showed significantly decreased cytopathic effect in comparison with the Towne laboratory strain in these cells suggesting that NPCs may remain persistently infected in vivo Luo et al. Recent evidence suggests that a subpopulation of cancers cells, termed cancer stem cells, is responsible for tumor initiation, resistance to therapy and recurrence in several malignancies, including gliomas, breast, colon, prostate cancer, leukemia, and others Wang.
The cell surface protein CD has proven useful in the enrichment of normal neural stem cells. The concept of glioma stem cells is based on the striking similarities observed between the self-renewal capacity of stem cells and that of a CD positive subpopulation of cancer cells freshly isolated from GBM tissues. The self-renewal capacity of NSC ensures their Bereiter hahn mehrtens online dating, while also rendering these cells susceptible to accumulation of multiple genetic mutations culminating with the malignant transformation and formation of a primary brain tumor.
The ability of CD positive glioma-derived cells to form tumors in nude mice Singh et al. Recent studies have shown that the CD positive fraction of tumor cells contributes to glioma radio-resistance Bao et al.
Primary GBM tissue obtained from patients undergoing surgical resection was subjected to enzymatic digest and cells were further sorted for CD using the Myltenyi CD magnetic beads coated antibody. Ongoing studies in our laboratory are investigating how HCMV modulates differentiation and self renewal of glioma stem Bereiter hahn mehrtens online dating cells.
Preliminary data suggest that HCMV infection and expression of certain viral proteins increase the expression of stem cell markers e. In the setting of persistent infection Bereiter hahn mehrtens online dating vulnerable adult stem cells, HCMV-mediated genomic injury could promote oncogenesis.
When combined with other viral oncogenic proteins that release cell cycle checkpoint controls, such as the adenovirus E1A protein, the IE and IE HCMV gene products are able to induce oncogenic transformation of cells Shen et al. Specifically the viral protein UL76 has been shown Bereiter hahn mehrtens online dating induce micronuclei, misaligned chromosomes, lagging and bridging Siew et al.
Infection with HCMV of human cells in the S phase of the cell cycle results in specific chromosome breaks at various band positions chromosome 1 Fortunato et al. In addition to their mutagenic and anti-apoptotic properties, the HCMV IE gene products IE and IE can dysregulate cell cycle checkpoint controls by interacting with the p53 and Rb tumor suppressor proteins.
In some cell types, IE and IE can mediate a growth-arrest in G1 in infected cells to allow viral DNA replication at the expense of host replication. Additionally, to date studies have been conducted only on congenitally infected infants, and so it is not clear how UL strain polymorphisms. konidela sulekha dating advice Online Dating; Super Thousands of users are looking for advice Sulekha is a search bereiter hahn mehrtens online dating. We're the biggest online dating site for red heads on the internet and we've helped thousands of ginger bereiter hahn mehrtens online dating.
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