Chemokines involved in the early inflammatory response and in pro-tumoral activity in asbestos-exposed workers from an Italian coastal area with territorial clusters of pleural malignant mesothelioma
Introduction
Exposure to asbestos and the nature of the inhaled fibers are associated with a high risk of developing lung and mesothelial diseases including pleural malignant mesothelioma (PMM) [1], [2].
In mesothelial and lung epithelial cells, asbestos fibers initiate signaling and survival pathways which are often up-regulated in PMM and contribute to tumor pathogenesis [3]. Asbestos fibers deposited in the distal regions of the respiratory system cause early and sustained inflammation. The inflammatory process is sustained by interaction of the fibers with epithelial cells and alveolar macrophages which, in turn, may release chemical mediators up-regulating these pathways. The mentioned pathways may be activated by a direct interplay of asbestos fibers with receptors on the cell surface and with integrins or via elaboration of ROS generated catalytically on the fiber surface or after frustrated phagocytosis [4]. In addition, an increase in the expression of genes encoding cytokines/chemokines such as IL-8 and their receptors or ligands such as CXCL2 and CXCL3 is promoted, suggesting that mesothelial cells may orchestrate leukocyte chemotaxis and trafficking and pleural inflammation [5], [6], [7], [8].
Recent research has reported that cancer, including mesothelioma, subvert the normal pathway of inflammatory proteins, which become crucial constituents of the tumor microenvironment and influence its development and metastasis. Specifically, the supernatants of asbestos-exposed mesothelioma cell lines contained higher levels of vascular endothelial growth factor (VEGF) than the supernatants of unstimulated normal mesothelial cells, and such differences were also noticed for fibroblast growth factor (FGF). Similarly, the serum levels of both proteins were found to be significantly higher in mesothelioma patients than in controls or patients with other malignancies [9].
TNF-α release and cooperation to the activation of the Ras/MAPK/NF-kB pathway is one of the described mechanisms by which tumor cell-macrophage crosstalk may enhance tumor growth and influence the over-expression of both CC and CXC chemokines in amplifying paracrine signaling loops [10], [11]. Nevertheless, the important contribution of IL-1b and TNF-α to mesothelial cell malignant transformation may be partially due to activation of AP-1 – or NF-kB – dependent gene expression [12].
The chronic inflammatory response to the asbestos cellular damage probably perpetrated by the Nod-like receptor protein 3 (NLRP3) inflammasome [13], [14] represents an important aspect of the pulmonary microenvironment, characterized by a strong interplay between high levels of soluble mediators, immune cells, airway epithelial cell proliferation and angiogenesis [3], [15], [16], [17]. Notably, independently of asbestos fiber deposition, an array of pro-angiogenic molecules, growth factors and pro-inflammatory cytokines has been detected during the abnormal growth and differentiation of mesothelial cells in visceral pleura. It is plausible that such changes, which precede tumor development, may be linked causally to PMM [18], [19], [20].
Malignant pleural mesothelioma is a clinically aggressive tumor and no single-modality therapy has proven effective in curing it, presumably because of the multiplicity of survival and chemoresistance pathways in this tumor. PMM seems to respond to immunotherapy and patients are known to mount an anti-tumor immune response [21]. Careful surveillance of patients exposed to asbestos is a key issue in controlling the development of asbestos-associated diseases and the identification of healthy, asymptomatic persons exposed to asbestos could be an important result.
Since the production of immune mediators is likely to be relevant for the biological response to asbestos exposure and PMM seems to be responsive to immunotherapy, we undertook the present study with the aim of investigating the associations between asbestos exposure, asbestos-related diseases and candidate immune mediators involved in multiple cellular pathways affecting the inflammatory response, cell survival and angiogenesis [22], [23], [24], [25], in a cohort of workers with a history of occupational asbestos exposure in a coastal area of North-East Italy with a high incidence of PMM [26].
Section snippets
Study population
For this cross-sectional study, 123 male workers with a history of definite occupational exposure to asbestos (amphibole types) were consecutively enrolled during either a health surveillance survey (n = 84) or during hospital attendance for diagnostic procedures at a Thoracic Surgery Unit (n = 39). These subjects had a past occupational history of asbestos use in dockyards (asbestos handling and transport) and shipyards (naval construction and/or repair activities) located in a coastal area of the
Characteristics of the study population
Table 2 reports the characteristics of the groups studied. The PMM workers were older (median: 69 y) and had greater length of occupational asbestos exposure (median: 25 y) than the other worker groups (p < 0.001). These findings are consistent with those of previous studies based on the local Mesothelioma Register [26], [27], [28]: in the 1022 PMM cases occurred over the calendar period 1995–2013, the age at diagnosis averaged 69 y and the duration of occupational exposure to asbestos varied, on
Discussion
The prognostic role of immune mediators in tumorigenesis has been investigated in several neoplastic diseases, including PMM of all subtypes [15], [48], [49], [50].
In the present study, a custom set of soluble immune mediators reported to be involved in PMM pathogenesis (Table 1) was evaluated in biological samples of asbestos-exposed workers with the aim of assessing their potential prognostic relevance for the development of asbestos-related diseases.
An important finding of our study was the
Conclusion
This in vivo study confirms that the damage to the mesothelium by prolonged exposure to asbestos fibers does not impair the capacity of mesothelial cells to regulate the level of expression of specific chemokines, dually involved in the early inflammatory response and in pro-tumoral activity. Moreover, the PMM microenvironment indicated that (i) PMM cells secrete these cytokines, (ii) the same proteins produced in response to asbestos fibers can be measured in the sera of patients, and (iii)
Conflict of interest
The authors declare no conflicts of interest.
Acknowledgment
This work was supported by a grant from Regione Friuli Venezia Giulia, L.R. 22/2001/decree 889/Area Prevenzione (APREV).
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