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Sera from Patients with Malignant Pleural Mesothelioma Tested Positive for IgG Antibodies against SV40 Large T Antigen: The Viral Oncoprotein

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  • Sera from Patients with Malignant Pleural Mesothelioma Tested Positive for IgG Antibodies against SV40 Large T Antigen: The Viral Oncoprotein

    https://www.hindawi.com/journals/jo/2022/7249912/#B27
    Elisa Mazzoni, Ilaria Bononi, John Charles Rotondo, Chiara Mazziotta, Roberta Libener, Roberto Guaschino, Roberta Gafà, Giovanni Lanza, Fernanda Martini, Mauro Tognon, "Sera from Patients with Malignant Pleural Mesothelioma Tested Positive for IgG Antibodies against SV40 Large T Antigen: The Viral Oncoprotein", Journal of Oncology, vol. 2022, Article ID 7249912, 9 pages, 2022. https://doi.org/10.1155/2022/7249912

    Abstract


    Malignant pleural mesothelioma (MPM), a fatal tumor, is mainly linked to the asbestos exposure. It has been reported that together with the inhalation of asbestos fibers, other factors are involved in the MPM onset, including simian virus 40 (SV40). SV40, a polyomavirus with oncogenic potential, induces (i) in vitro the mesenchymal cell transformation, whereas (ii) in vivo the MPM onset in experimental animals. The association between MPM and SV40 in humans remains to be elucidated. Sera (n = 415) from MPM-affected patients (MPM cohort 1; n = 152) and healthy subjects (HSs, n = 263) were investigated for their immunoglobulin G (IgG) against simian virus 40 large tumor antigen (Tag), which is the transforming protein. Sera were investigated with an indirect enzyme-linked immunosorbent assay (ELISA) using two synthetic peptides from SV40 Tag protein. SV40 Tag protein was evaluated by immunohistochemical (IHC) staining on MPM samples (MPM cohort 2; n = 20). Formalin-fixed and paraffin-embedded (FFPE) samples were obtained from MPM patients unrelated to MPM serum donors. The proportion of sera, from MPM patients, showing antibodies against SV40 Tag (34%) was significantly higher compared to HSs (20%) (odds ratio 2.049, CI 95% 1.32–3.224;

    ). Immunohistochemical staining (IHS) assays showed SV40 Tag expression in 8/20, 40% of MPM specimens. These results indicate that SV40 is linked to a large fraction of MPM. It is worth noting that the prevalence of SV40 Tag antibodies detected in sera from cohort 1 of MPM patients is similar to the prevalence of SV40 Tag found to be expressed in FFPE tissues from MPM cohort 2.
    1. Introduction


    Malignant pleural mesothelioma (MPM) is a highly aggressive tumor arising from the mesothelium of the pleural surface [1]. MPM is responsible for 4% of cancer deaths [2]. This malignancy is considered a rare cancer, but in recent years, MPM cases have increased significantly. Indeed, MPM accounts approximately 40,000 deaths/year worldwide [3]. MPM is linked to asbestos, which was employed as different tumorigenic natural mineral fibers [4]. The incidence of MPM is variable among different countries, whereas it has been estimated that this cancer will increase its incidence worldwide in the subsequent 20 years [4, 5]. Currently, MPM causes approximately 5,000 and 3,000 deaths/year in western Europe and the USA, respectively [4,5].

    The MPM onset is predominant in males, whereas 80% of cases result from the asbestos exposure in the workplace. However, 20% of MPM arises in patients not exposed to asbestos fibers [6]. Many investigations support a clear link between asbestos fiber exposure and the subsequent MPM onset [7]. Indeed, asbestos fibers have been established to be the cause of the MPM onset/progression, which may occur up to 50 years after the asbestos exposure [4,5]. In this context, it is worth recalling that asbestos is a general term employed for regulatory purposes to identify six out of about 400 mineral fibers commercially distributed. It has been estimated that several millions of individuals have been contaminated with asbestos fibers worldwide [8]. MPM incidence is increasing because this carcinogenic mineral was massively employed for decades [3]. Many reports and clinical evidence have confirmed the asbestos carcinogenic properties [4,5]. It has been reported that MPM arises in ex-exposed asbestos workers with a prevalence, depending on the studies, in the range of 1–10% [1]. However, 20% of MPM arises in patients not exposed to asbestos fibers [6].

    MPM is becoming a significant health problem due to its increasing incidence [9] and the absence of efficient therapies/treatments. Among MPM peculiarities, the poor prognosis and median survival, less than 1 year from the time of diagnosis, can be accounted [9]. In addition, in the early step of the MPM onset, the tumor appears asymptomatic or the clinical symptoms are not specific. Consequently, MPM is often recognized at advanced stages for an appropriate treatment [10]. Altogether, these considerations indicate the need of novel strategies for diagnosis, prognostication, and effective treatments.

    Together with asbestos fibers, there is a need to verify whether additional factors, such as the presence of asbestos fibers in the environment, other mineral fibers, ionizing radiation, or infections by oncogenic viruses, are associated with the onset of this fatal cancer. Together with the environmental factors, the genetic background of the host seems to predispose to the MPM onset [3,4].

    Among oncogenic viruses [11], the transforming polyomavirus simian virus 40 (SV40) was associated with MPM, as an additional risk factor. Indeed, SV40 was proposed as a potential cofactor in the MPM onset/progression [12,13].

    SV40 sequences and expression of its Tag viral oncoprotein were revealed by several groups in MPM tumor tissues, whereas other investigators reported negative data [12,14–19]. Indeed, SV40 DNA has been detected in mesotheliomas and other human tumors of different histotypes. [17,20,21] In addition, it has been reported that mesothelioma cells/MPM tissues tested positive for SV40 Tag expression [22–25].

    SV40-contaminated antipolio vaccines, which were administered in different amounts in distinct countries, are considered the main source of SV40 infection in humans [17, 26]. However, new data suggest that SV40 circulates at present in some populations independently from contaminated vaccines [27]...
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