MM was extremely rare until the second half of the 20^th century. The incidence of MM has increased significantly, and currently there are about 2,000 to 3,000 cases per year in the United States [4]. The continuing increase in MM incidence has been associated with widespread use of asbestos in the past century. Asbestos was widely used in the shipbuilding and construction industries, especially between the 1940s and 1979 in the United States and Europe, due to its fire-resistant properties [5]. The latency period between the time of initial exposure and diagnosis is about 30 years and ranges from 20 to 50 years [6]. Two-thirds of MM patients are between 50 to 70 years of age. Males are at a much higher risk for MM than females, likely due to occupational exposure. The expected peak incidence of MM varies among countries. Price et al. proposed that MM has already reached its peak incidence in the United State [7]. This hypothesis remains to be confirmed. However, about 70,000 new MM cases are expected in the United States over the course of the next 20 years. In Europe, the anticipated peak year of MM incidence is in the period of 2015–2020, with a predicted incidence of 250,000 cases over the next 40 years [8].

The incidence of MM shows marked variations from one country to another. In some countries, MM incidence is low even though there is high asbestos [9, 10]. The reasons that account for these differences are unclear. Epidemiological studies found that about 5% of individuals with heavy prolonged asbestos exposure develop MM, although it has been proposed that approximately 80% of patients with MM in the United States have been exposed to asbestos. However, there is a significant difference in the percent of MM linked to asbestos exposure by different studies: from zero in some studies to 100% in others [11]. Geographical differences as well as different technical approaches used to attribute exposure are the likely cause of many of these very discrepant results. For example, some investigators will use lung content analysis studies. (i.e. The amount of asbestos found in 1cc or less of lung tissue). To attribute exposure, others will use patients interviews. It should not be unexpected that such different approaches will generate different results. What may appear as a surprise is that even within each of these 2 categories (i.e. Lung content analysis and interviews), the results vary significantly. This is also caused by different approaches in each category. For example, some investigators establish a background level of asbestos in the general population and count only fibers with the length of 5 µm or longer. Others will measure if any type of asbestos fiber is present in the lung, and if it is, they will attribute MM to asbestos (i.e. in other words, in these studies, there is no threshold set for background accounts nor for fiber size). Obviously, such studies will produce very different results. The interview system is even more unreliable when it comes to compare different studies. Some studies rely on work histories and on patients interviews; others are much less stringent and include interviews of friends and relatives when patients are no longer alive. Now it is hard to imagine how accurate friends and relatives could be in reporting whether a given patient was or was not exposed to asbestos 30–50 years before. Conflict of interest related to litigation further contribute to make the whole issue even more difficult to interpret.

The association between amphibole asbestos exposure and MM development is well accepted. In particular, crocidolite is generally considered to be the most oncogenic type of asbestos. The long and thin fibers (especially ≥ 8 µm in length ≤ 0.25 µm in width) are thought to be more dangerous, because they have longer biopersistance in the pleura. These fibers are able to penetrate the lung and cause repeated damage, tissue repair and local inflammation.

Chrysotile is the most common type of asbestos and accounts for about 90% of the world’s asbestos production. Whether chrysotile causes MM is still controversial. Some scientists suggested that chrysotile plays an important role in the pathogenesis of MM, because chrysotile fibers induce DNA damage and chromosome abnormalities in human and rat mesothelial cells in vitro, and cause MM in animals. Some authors suggested that chrysotile may cause MM but at a lower rate compared to amphibole asbestos. Hodgson and Darnton suggested that the exposure specific risk of MM is broadly in the ratio of 1:100:500 for chrysotile, amosite and crocidolite, respectively [14]. Instead, Suzuki et al. proposed that chrysotile is the main contributor to the causation of MM based on their analysis of lung and mesothelial tissues taken from 168 cases of MM, in which they found that chrysotile was the most common asbestos type [15]. Other authors have instead proposed that chrysotile does not cause MM and that it is the amphibole that often contaminates chrysotile that causes MM [16]. Some studies show that chrysotile asbestos is considerably less biopersistent than amphibole asbestos once inhaled in the lungs, and chrysotile fibers do not cause a pronounced inflammatory response compared to the amphibole tremolite [17]. Some of us conducted an extensive review of the literature and found that the data were so radically contradictory and, at times, flawed by conflict of interest that it was not possible to conclude whether chrysotile does or does not cause MM [18].

The mechanisms of asbestos carcinogenicity are not fully understood. During the long latency period of MM, many pathogenentic events may occur that can contribute to MM. Compared to other cell types tested, human mesothelial cells are very susceptible to asbestos cytotoxicity. For example, when exposed to amosite asbestos, mesothelial cells were 10 and 100 times more sensitive to the cytotoxic effects of asbestos than normal human bronchial epithelial or fibroblastic cells. Asbestos fibers induce toxicity in a dose-dependent manner. In tissue culture, doses equal to or higher than 5 µg/cm² of crocidolite fibers induce 100% cell death in less than a week [19]. This observation raises the issue of how can asbestos cause MM if human mesothelial cells exposed to asbestos die. Recent work addressed this paradox and demonstrated a critical role for tumor necrosis factor-alpha (TNF-α) and NF-κB signaling in mediating responses of human mesothelial cells to asbestos [20]. In vivo studies have revealed that, following asbestos exposure there is an inflammatory reaction with a large component of mononuclear phagocytes [21]. Upon differentiation into macrophages, these cells phagocytize asbestos and, in response, release TNF-α. At the same time, asbestos induces human mesothelial cells to express TNF-α receptor TNF-R1 and also stimulates the secretion of TNF-α (both paracrine and autocrine effects). TNF-α binds to its receptor and activates the NF-κB pathway, which increases the percentage of human mesothelial cells that survive asbestos exposure [20]. Human mesothelial cells exposed to asbestos can accumulate DNA damages. Asbestos causes DNA strand breaks mediated by iron-catalyzed free radicals. In addition, by causing the release of reactive oxygen species (ROS) and reactive nitrogen species (RNS), asbestos fibers can indirectly induce genotoxicity including base substitutions, deletions, rearrangements, insertions, sister chromatid exchanges, and chromosomal aberrations which may lead to a broad spectrum of mutations in mammalian cells [22, 23]. The activation of the NF-κB pathway stimulated by TNF-α allows mesothelial cells with asbestos-induced DNA damage to divide rather than die, and if sufficient specific genetic damage accumulates to eventually develop into a MM [20] (Figure 1).

In addition to TNF-α, other growth factors and cytokines have been implicated in asbestos carcinogenesis and their role in MM pathogenesis is being investigated. These include: transforming growth factor beta (TGF-β), which might have a role in stimulating tumor growth; platelet-derived growth factor (PDGF), which may act as a regulatory factor in MM cell proliferation, insulin-like growth factor (IGF), which promotes tumor proliferation and cell migration [24]; interleukins such as IL-6 and IL-8, which may promote tumor growth and the development of new capillaries [25]; vascular endothelial growth factor (VEGF), which also promotes tumor angiogenesis [26], and hepatocyte growth factor (HGF), which stimulates mesothelioma cell migration and tumor invasiveness [27].

After interaction with mesothelial cells, asbestos triggers multiple cell-signaling pathways. Crocidolite fibers can induce autophosphorylation of the epidermal growth factor receptor, which stimulates the extracellular signal regulated kinase (ERK1/2) signaling pathway. This effect in turn increases activator protein (AP)-1 activity and mitosis of mesothelial cells [28]. Asbestos also activates the NF-κB pathway, which leads to the activation of multiple pro-survival genes that promote tumor development [20].

Although over 50 different laboratories have reported a positive association of SV40 with MM, some have not, and this has caused a controversy [38]. For example, Lopez-Rios et al. reported that initially they detected SV40 in about 60% of MM specimens, and then they determined that most of the positive results were caused by plasmid PCR contamination, and that only 6% of the initially positive samples were confirmed to contain SV40 DNA [39]. It appears possible that some studies that lacked proper controls may have reported false positive results. However, many carefully designed and controlled studies have showed the presence of SV40 in human specimens by using several other techniques besides PCR, including Southern blotting, immunostaining, RNA in situ hybridization, microdissection, and electron microscopy [40]. Analysis of human MMs revealed that SV40 sequences are present in tumor cells but not in the normal adjacent tissue [41, 42]. Animal experiments demonstrated a clear association between SV40 and MM. For instance, 100% of hamsters injected intrapleurally with SV40 and 60% of those injected intracardially developed MM within 6 months.

SV40 produces two proteins that are oncogenic: Large T and small t antigens. In human MM biopsies, the large T antigen (Tag) was found to bind and inhibit p53 and pRb tumor suppressor proteins, thus contributing to MM carcinogenesis. A recent study demonstrated that Tag-p53 complex also has growth stimulatory activities that are required for malignant cell growth [43]. This investigation revealed that a multi-protein complex “Tag-p53-pRb-p300” binds to the promoter of the gene encoding insulin-like growth factor I (IGF-I), thereby stimulating IGF-I expression and IGF-I signaling and leading to enhanced cell growth. In other words, the binding of Tag to p53, p300, pRb, on one hand, inactivates the tumor suppressor activities of these proteins, on the other, the Tag-p53-pRb-p300 multi-protein complex acquire its own oncogenic activity by activating the IGF-1/IGF1R pathway. The small t antigen (tag) inhibits the cellular phosphatase 2A (PP2A), a protein involved in the dephosphorylation of many protein substrates, including components of the MAP-kinase (MAPK) pathway. Through inhibition of PP2A, tag may activate MAPK signaling and induce AP-1 activity. In addition, SV40 induces HGF/Met receptor activation [27], telomerase activity [44], and Notch-1 activation in human mesothelial cells and MM biopsies [45].