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Michele Carbone

Publications and source records attributed to Michele Carbone.

35 records · Page 2Linked to original sources
PubMed2004

Pathogenesis of malignant mesothelioma.

Malignant mesothelioma (MM) is a very aggressive tumor that is caused by environmental, biologic, and genetic factors. Among these factors, asbestos plays a major role. The link between asbestos and MM has been firmly established through numerous epidemiologic studies conducted during the past 40 years. However, the causal role of chrysotile asbestos compared with crocidolite asbestos in MM, the method of correctly establishing asbestos exposure, the amount of asbestos necessary to cause MM, and the mechanisms of asbestos tumorigenicity are still being debated. Along with asbestos, Simian virus 40 (SV40), a DNA monkey virus, has recently been implicated in the etiology of MM. Simian virus 40 large T antigen (Tag) and small t antigen (tag) are largely responsible for the carcinogenicity of the virus, and it is possible that SV40 and asbestos are cocarcinogens. Finally, a genetic factor identified in 3 villages in Cappadocia, Turkey, where 50% of individuals die of MM, appears to be the cause of a high incidence of the disease. In these villages, genetic predisposition for MM works together with erionite, a nonasbestos fiber found in the stones used in construction of houses. The diagnosis of MM is made histologically and confirmed through electron microscopy and immunohistochemistry. Currently available therapies for MM prolong survival by a few months at most. An SV40 vaccine is being developed for human use and it is hoped that it may reduce the incidence of MM in asbestos workers.

Animals↗
PubMed2003

High throughput testing of the SV40 Large T antigen binding to cellular p53 identifies putative drugs for the treatment of SV40-related cancers.

SV40 has been linked to some human malignancies, and the evidence that this virus plays a causative role in mesothelioma and brain tumors is mounting. The major SV40 oncoprotein is the Large tumor antigen (Tag). A key Tag transforming activity is connected to its capability to bind and inactivate cellular p53. In this study we developed an effective, high throughput, ELISA-based method to study Tag-p53 interaction in vitro. This assay allowed us to screen a chemical library and to identify a chemical inhibitor of the Tag binding to p53. We propose that our in vitro assay is a useful method to identify molecules that may be used as therapeutic agents for the treatment of SV40-related human cancers.

Antigens, Polyomavirus Transforming↗
PubMed2003

Different susceptibility of human mesothelial cells to polyomavirus infection and malignant transformation.

SV40 has been associated with mesothelioma development. The possible role of the closely related human polyomaviruses JC virus (JCV) and BK virus (BKV) in mesothelioma remained unclear. We found that JCV did not infect human mesothelial cells. BKV and SV40 infected mesothelial cells, expressed viral oncoproteins, and caused similar alterations of key cell regulatory genes. BKV replicated faster than SV40 and caused mesothelial cell lysis, not cellular transformation. SV40 did not lyse mesothelial cells and caused a high rate of transformation. These findings provide a rationale for the observation that SV40 is found in mesothelioma, rather than the ubiquitous human JCV and BKV.

Animals↗
PubMed2003

Notch-1 induction, a novel activity of SV40 required for growth of SV40-transformed human mesothelial cells.

We show that SV40 infection of human mesothelial cells directly causes overexpression of Notch-1, a key cell regulatory gene. Notch-1 induction is achieved at the transcriptional level and requires both the SV40 large T-antigen and the small t-antigen. Notch-1 upregulation is maintained in SV40-transformed human mesothelial clones and in SV40-positive mesotheliomas and derived cell lines. Activation of Notch-1 promotes cell cycle progression and it is required for the growth of SV40-transformed mesothelial cells. Our finding is relevant to the process of SV40-mediated human cell transformation, an effect that cannot be accounted for solely by SV40-Tag inhibition of Rb and p53.

Cell Line, Transformed↗
PubMed2003

Molecular pathogenesis of malignant mesothelioma and its relationship to simian virus 40.

Malignant mesothelioma is a relatively rare tumor, but the incidence of the disease appears to be increasing. Unique molecular changes are associated with the disease that distinguish it from lung cancers. Smoking is not an etiologic factor; the major causative agent is asbestos exposure, usually many years or decades before the development of the tumor. Recently, a simian virus, SV40, has been associated with malignant mesotheliomas and is a probable cofactor in tumor development. The molecular changes caused by each of these major etiologic factors and their interrelationships are the focus of this review.

Asbestos↗
PubMed2002

Progressive aberrant methylation of the RASSF1A gene in simian virus 40 infected human mesothelial cells.

Mesotheliomas are tumors arising from mesothelial cells and are associated with asbestos exposure and approximately 50% contain simian virus 40 (SV40) DNA sequences. SV40 infection of human mesothelial cells (HM) causes early cellular immortalization and late transformation. Aberrant methylation is a major mech-anism for loss of function of tumor suppressor genes (TSGs). We recently reported that of seven genes frequently methylated in epithelial tumors, only RASSF1A gene was frequently methylated in mesotheliomas, and its methylation was correlated with loss of RASSF1A expression and the presence of SV40. We studied whether SV40 infection of normal HM induces aberrant methylation of the genes previously studied in mesotheliomas. Of six infected foci examined at early passages (passages 8-30) there was no methylation of the seven genes examined. Of two foci examined at late passages (passages 51-86) after the appearance of morphological changes suggestive of transformation, methylation and loss of expression of RASSF1A was detected. Sequencing of the CpG dense region around the transcription start site and semi-quantitative real-time methylation specific PCR (MSP) assay for RASSF1A methylation demonstrated progressive methylation during late passages. Exposure to the demethylating agent 5-aza-2'-deoxycytidine restored RASSF1A expression, while exposure to the histone deacetylation inhibitor trichostatin A had no effect. These data, together with our previous findings, support a causal relationship between SV40 infection, progressive RASSF1A methylation and its silencing, and the pathogenesis of mesothelioma.

Alleles↗
PubMed2002

Lung diseases due to environmental exposures to erionite and asbestos in Turkey.

Asbestos deposits have been used locally by the rural inhabitants of Central and Southeastern Anatolia for domestic purposes for many years. Mineralogical analysis revealed that tremolite is the most prominent asbestos type found in the region. There is in addition another mineral fiber found particularly in three villages located in the Cappadocian region of Central Anatolia (zeolite villages). This is a non-asbestos mineral, which has been identified as the fibrous zeolite, erionite. This fiber is present in the volcanic tuffs, which are used as building stone. Hence, exposure to erionite fibers is always possible in the houses, annexes, and streets of the villages. It has been demonstrated that both asbestos and erionite cause a variety of benign and malignant chest diseases. Among the diseases, calcified pleural plaques (CPP) are the most frequently seen and may be used as an indicator of mineral fiber exposure. Asbestos and erionite exposure are the main causes of malignant mesotheliomas in Turkey. In zeolite villages malignant mesothelioma is responsible for more than 50% of the total deaths. A recent study showed that simian virus 40 is not a cofactor in the pathogenesis of environmental malignant mesothelioma in Turkey. An additional recent genetic-epidemiological study showed that there are some families, which are genetically predisposed to mesothelioma.

Asbestos↗
PubMed2002

SV40 infection induces telomerase activity in human mesothelial cells.

Mesotheliomas are malignant tumors of the pleural and peritoneal membranes which are often associated with asbestos exposure and with Simian virus 40 (SV40) infection. Telomerase activity is repressed in somatic cells and tissues but is activated in immortal and malignant cells. We evaluated telomerase activity in seven primary malignant mesothelioma biopsies and matched lung specimens and 20 mesothelioma cell lines and eight corresponding primary tumor cultures. All the tumor biopsies, and nearly all primary cell mesothelioma cultures and cell lines were telomerase positive. The findings in cell lines paralleled those observed in primary cultures in cases where paired samples were available. Next, we found that SV40, a DNA tumor virus present in approximately 50% of mesothelioma biopsies in the USA, induced telomerase activity in primary human mesothelial cells, but not in primary fibroblasts. Telomerase activity became detectable as early as 72 h following wild-type (strain 776) SV40 infection, and a clear DNA ladder was detectable 1 week after infection. The amount of telomerase activity increased during passage in cell culture and appeared to parallel increases in the cellular amounts of the SV40 large T-antigen. Thus, SV40 infection leads to telomerase activity before the infected mesothelial cells become transformed and immortalized. SV40 infection of human fibroblasts did not cause detectable telomerase activity. We also determined that the SV40 small t-antigen (tag) plays an important role in inducing telomerase activity because this activity was undetectable or minimal in mesothelial cells infected and/or transformed by SV40 tag mutants. Asbestos alone did not induce telomerase activity, and asbestos did not influence telomerase activity in mesothelial cells infected with SV40. Induction of telomerase activity by SV40 may be related to the very high rate of mesothelial cell immortalization that is characteristically associated with SV40 infection of mesothelial cells.

Blotting, Southern↗
PubMed2002

SV40 and human tumours: myth, association or causality?

An increasing number of scientific reports have described evidence for a polyomavirus, simian virus 40, in a highly select group of human tumours. How did a simian virus infect humans and is the virus a passenger in tumours or is it important in their pathogenesis?

Animals↗
PubMed2002

The pathogenesis of mesothelioma.

About 80% of malignant mesotheliomas (MM) in the Western World develop in individuals with higher than background exposure to asbestos. Only a fraction of those exposed to asbestos develop mesothelioma, indicating that additional factors play a role. Simian virus 40 (SV40), a DNA tumor virus that preferentially causes mesothelioma in hamsters, has been detected in several human mesotheliomas. The expression of the SV40 large tumor antigen in mesothelioma cells, and not in nearby stromal cells, and the capacity of antisense T-antigen treatment to arrest mesothelioma cell growth in vitro suggest that SV40 contributes to tumor development. The capacity of T-antigen to bind and inhibit cellular p53 and retinoblastoma (Rb)-family proteins in mesothelioma, together with the very high susceptibility of human mesothelial cells to SV40-mediated transformation in vitro, supports a causative role of SV40 in the pathogenesis of mesothelioma. Asbestos appears to increase SV40-mediated transformation of human mesothelial cells in vitro, suggesting that asbestos and SV40 may be cocarcinogens. p53 mutations are rarely found in mesothelioma; p16, p14ARF, and NF2 mutations/losses are frequent. Recent studies revealed the existence of a genetic factor that predisposes affected individuals to mesothelioma in the villages of Karain and Tuzkoy, in Anatolia, Turkey. Erionite, a type of zeolite, may be a cofactor in these same villages, where 50% of deaths are caused by mesothelioma. Mesothelioma appears to have a complex etiology in which environmental carcinogens (asbestos and erionite), ionizing radiation, viruses, and genetic factors act alone or in concert to cause malignancy.

Animals↗
PubMedDate not supplied

The role of environmental carcinogens, viruses and genetic predisposition in the pathogenesis of mesothelioma.

Mesothelioma is one of the most aggressive human cancers and kills approximately 2500 people per year in the US. This cancer was almost unknown until the second half of the 20th century, and its rapid increase has been linked to the widespread use of asbestos. In spite of an enormous research effort, the mechanisms of asbestos carcinogenicity have remained an enigma. Why only a fraction of individuals exposed to high levels of asbestos develop mesothelioma while individuals with low to no asbestos exposure also develop this cancer remains unknown. Recently, simian virus 40, a DNA tumor virus known to preferentially cause mesotheliomas in hamsters, and genetic factors have been linked to mesothelioma development. Therefore, a new research front has been opened in mesothelioma, a cancer that appears to be caused by the environmental carcinogens asbestos and erionite, viruses, and genetic predisposition. The challenge for future research is to establish how these apparently very different factors interact to cause mesotheliomas.

Animals↗
PubMedDate not supplied

Molecular analyses, morphology and immunohistochemistry together differentiate pleural synovial sarcomas from mesotheliomas: clinical implications.

BACKGROUND: Only recently pleural synovial sarcomas (SS) have been definitively identified because of the presence of a characteristic X;18 translocation. SS are sarcomatoid or biphasic malignancies morphologically almost indistinguishable from sarcomatoid or biphasic malignant mesotheliomas (MM). PATIENT AND METHODS: We demonstrated a primary pleural biphasic SS in a patient referred to us has having a biphasic MM. RESULTS: Histology showed a spindle cell tumor with focal epithelioid differentiation, microcalcifications, and a hemangiopericytomatous vascular pattern. Ultrastructurally, the epithelioid tumor cells had few blunt microvilli and occasional intercellular junctions. Immunohistochemically the tumor cells were positive for BCL-2, CD99, CD56, and focally for BerEp4, Pancytokeratin and cytokeratin 5/6. These findings suggested the possibility of SS rather than MM. Detection of the t(X:18) translocation using RT-PCR, Southern blot, and DNA sequencing definitively confirmed the diagnosis of SS. CONCLUSION: The differential between pleural SS and MM requires a high degree of suspicion and molecular analyses because morphology (histology, immunohistochemistry and electron microscopy) is insufficient to definitively distinguish between these two malignancies. This differential is critical because patients with pleural SS can be susceptible to chemotherapy, and accordingly are treated, while patients with sarcomatoid MM are resistant to chemotherapy and accordingly are not treated.

Aged↗
PubMedDate not supplied

A cytokeratin- and calretinin-negative staining sarcomatoid malignant mesothelioma.

Malignant Mesothelioma, or mesothelioma, is a mesothelial-based malignancy that may occur in the pleura, pericardium and peritoneum. Mesothelioma is a very aggressive cancer with limited treatment, and a median survival of about 1 year. At times, the diagnosis of mesothelioma may be problematic. The final diagnosis of mesothelioma relies on histology and often is dependent upon immunohistochemistry. It is generally assumed that mesotheliomas must stain positive for cytokeratin and calretinin and negative staining for these markers would rule out the diagnosis. We encountered a patient with a pleural-based, cytokeratin- and calretinin-negative sarcomatoid malignancy. These negative stainings would rule out the diagnosis of mesothelioma but, after careful consideration of the patient's clinical records, and additional histological and immunohistochemical studies, we conclude that this patient suffered from mesothelioma of the sarcomatoid type.

Aged↗
PubMedDate not supplied

Development of malignant mesothelioma during treatment for prolymphocytic leukemia: is asbestos or simian virus 40 a link?

A patient with a history of heavy asbestos exposure presented with B-prolymphocytic leukemia/lymphoma (B-PLL). Soon after, he developed rapidly progressing malignant peritoneal mesothelioma. The concurrent development of both relatively uncommon diseases raised the possibility that a common causative factor might exist. Since asbestos, simian virus 40 (SV40), or both have been associated with lymphoproliferative disease and mesothelioma, we investigated both possible links in our patient. Imaging studies provided evidence for asbestos exposure because bilateral pleural plaques were identified. Tissues from bone marrow (involved with B-PLL) and from a peritoneal nodule (involved with mesothelioma) were examined for SV40 DNA using polymerase chain reaction (PCR): no SV40 DNA was detected. We conclude that asbestos remains the sole possible connection to both malignancies in this patient. It seems possible that fludarabine, an immunosuppressive chemotherapy, accelerated the occurrence and progression of malignant mesothelioma during the therapy for his B-PLL.

Aged↗