**1. Introduction**

30 Malignant Mesothelioma

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It is well known that malignant mesothelioma is caused by exposure to asbestos, which comprises a group of naturally occurring fibrous minerals. However, the mechanism by which asbestos causes malignant mesothelioma remains unclear. Many researchers have examined the effect of exposure to asbestos on the body. To date, it has been confirmed that asbestos can cause various forms of damage to cells, including cellular toxicity and mutagenicity, as well as produce reactive oxygen species (ROS) (Mossman & Churg, 1998; Mossman et al., 1996; Sporn & Roggli, 2004). The levels of oxidized pyrimidine and alkylated bases correlate with the period of occupational exposure to asbestos (Dusinska et al., 2004), and the increase in mutation frequency of lung DNA is caused by instillation of asbestos through the trachea (Topinka et al., 2004). All of these factors are thought to generate the tumorigenic effect of asbestos on mesothelial cells. However, the development of malignant mesothelioma caused by exposure to asbestos shows the noteworthy characteristics of this condition, which differ from those induced by other toxic materials. Malignant mesothelioma develops under a relatively low or medium dose of exposure to asbestos. A high dose of exposure to asbestos causes the development of pneumoconiosis, i.e., asbestosis rather than mesothelioma. Thus, the development of mesothelioma caused by exposure to asbestos cannot be explained only by a general rule regarding a dose-response relationship of toxic materials. In addition, it takes a long period of about forty years to develop malignant mesothelioma after exposure to asbestos. These findings suggest the existence of other factors related to the development of malignant mesothelioma that are modified by exposure to asbestos in the body, and which differ from the well-known

© 2012 Nishimura et al., licensee InTech. This is an open access chapter distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. © 2012 Nishimura et al., licensee InTech. This is a paper distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

tumorigenic effect of asbestos on mesothelial cells. One possible factor seems to be the effect of exposure to asbestos on anti-tumor immunity. In the body, the development of tumors is protected by anti-tumor immunity, composed of various kinds of cells including dendritic cells (DC), natural killer (NK) cells, helper T (Th) cells, cytotoxic T lymphocytes (CTLs), and so on. Exposure to asbestos might cause a suppressive effect on anti-tumor immunity in addition to the tumorigenic effect on mesothelial cells, and the combination of immunesuppressive and tumorigenic effects of asbestos might contribute to the development of malignant tumor (Fig. 1).

Effect of Asbestos on Anti-Tumor Immunity

and Immunological Alteration in Patients with Malignant Mesothelioma 33

brain barrier (Miserocchi et al., 2008). Thus, immune competent cells have many opportunities to encounter asbestos fibers in the body, and the primary place where these

**Figure 2.** Places where immune competent cells encounter asbestos. Inhaled asbestos fibers reach the lung and translocate into the lung-draining lymph nodes. Therefore, the primary places where immune

> Long incubation period after asbestos exposure Short life expectancy of patients with mesothelioma Difficulty in diagnosis for malignant mesothelioma Less information for people positive for pleural plaque

**Figure 3.** Present problems in malignant mesothelioma and the demand for a new parameter useful in making a diagnosis of malignant mesothelioma. Due to the problems shown in the top box, more useful and easy parameters to detect malignant mesothelioma in people exposed to asbestos are needed, to

Investigation of asbestos-related immunological alteration

Demand for more useful and easy parameters to make a diagnosis of mesothelioma in people exposed to asbestos

which our investigation of asbestos-related immunological alteration might contribute.

cells encounter asbestos seem to be the lung-draining lymph nodes.

cells meet asbestos seems to be the lung-draining lymph nodes (Fig. 2).

**Figure 1.** Hypothesis concerning the development of malignant mesothelioma caused by the immunological and tumorigenic effects of asbestos exposure. Many researchers have attempted to examine the tumorigenic effect of asbestos, thought to cause malignant mesothelioma (left). We propose the hypothesis that immune-suppressive effects, including the effect on NK- and T-cell functions, and the tumorigenic effects of asbestos exposure might contribute to the development of malignant mesothelioma (right).

The lung is not the only place where immune competent cells are able to meet asbestos fibers. Inhaled asbestos fibers reach the lung via the trachea, but they do not remain at that site. Those fibers translocate into the lung-draining lymph nodes over a long period. Dodson et al. examined the amount of asbestos in the lungs, lymph nodes, and plaque in a cohort of former shipyard workers, and reported that an analysis of asbestos in the lymph nodes confirmed accumulation in these sites (Dodson et al., 1991). In addition, asbestos fibers in the lymph nodes can translocate into the blood and may be observed in any tissue of the body, even in the brain where the accumulation of asbestos is low because of the bloodbrain barrier (Miserocchi et al., 2008). Thus, immune competent cells have many opportunities to encounter asbestos fibers in the body, and the primary place where these cells meet asbestos seems to be the lung-draining lymph nodes (Fig. 2).

32 Malignant Mesothelioma

malignant tumor (Fig. 1).

mesothelioma (right).

tumorigenic effect of asbestos on mesothelial cells. One possible factor seems to be the effect of exposure to asbestos on anti-tumor immunity. In the body, the development of tumors is protected by anti-tumor immunity, composed of various kinds of cells including dendritic cells (DC), natural killer (NK) cells, helper T (Th) cells, cytotoxic T lymphocytes (CTLs), and so on. Exposure to asbestos might cause a suppressive effect on anti-tumor immunity in addition to the tumorigenic effect on mesothelial cells, and the combination of immunesuppressive and tumorigenic effects of asbestos might contribute to the development of

**Figure 1.** Hypothesis concerning the development of malignant mesothelioma caused by the immunological and tumorigenic effects of asbestos exposure. Many researchers have attempted to examine the tumorigenic effect of asbestos, thought to cause malignant mesothelioma (left). We propose the hypothesis that immune-suppressive effects, including the effect on NK- and T-cell functions, and the tumorigenic effects of asbestos exposure might contribute to the development of malignant

The lung is not the only place where immune competent cells are able to meet asbestos fibers. Inhaled asbestos fibers reach the lung via the trachea, but they do not remain at that site. Those fibers translocate into the lung-draining lymph nodes over a long period. Dodson et al. examined the amount of asbestos in the lungs, lymph nodes, and plaque in a cohort of former shipyard workers, and reported that an analysis of asbestos in the lymph nodes confirmed accumulation in these sites (Dodson et al., 1991). In addition, asbestos fibers in the lymph nodes can translocate into the blood and may be observed in any tissue of the body, even in the brain where the accumulation of asbestos is low because of the blood-

**Figure 2.** Places where immune competent cells encounter asbestos. Inhaled asbestos fibers reach the lung and translocate into the lung-draining lymph nodes. Therefore, the primary places where immune cells encounter asbestos seem to be the lung-draining lymph nodes.

**Figure 3.** Present problems in malignant mesothelioma and the demand for a new parameter useful in making a diagnosis of malignant mesothelioma. Due to the problems shown in the top box, more useful and easy parameters to detect malignant mesothelioma in people exposed to asbestos are needed, to which our investigation of asbestos-related immunological alteration might contribute.

The present diagnosis for malignant mesothelioma is based on X-ray and CT image analyses, as well as pathohistological analysis. However, diagnosis using these procedures is sometimes accompanied with a risk of radiation exposure or invasiveness, and results are not regarded equally among doctors because they have learned these analyses separately and it is not easy to master all of these methods. In addition, although it takes a long period to develop malignant mesothelioma after exposure to asbestos, the mean life expectancy of patients with malignant mesothelioma is short, and people exposed to asbestos need a safer analysis that can be used frequently in a year in order to detect malignant mesothelioma as early as possible. Recently, the use of products derived from mesothelioma cells for diagnosis has been proposed, including megakaryocyte potentiating factor (MPF) and mesothelin (Creaney et al., 2007; Onda et al., 2006). However, those products might not be observed in the blood that early because they will appear exactly after the development of mesothelioma, and it may take some time for those products to transfer from the pleural cavity into the blood stream. Many people exposed to asbestos worry about the development of malignant mesothelioma; however, there is little predictive information regarding the onset of mesothelioma. Therefore, there is a need to find a new parameter or method useful for the early diagnosis of malignant mesothelioma (Fig. 3). If some characteristic alteration of immune function is caused by exposure to asbestos that is also found in patients with malignant mesothelioma, which can be measured by checking lymphocytes or other cells in peripheral blood, the analysis for that alteration might contribute to the early detection of malignant mesothelioma.

Effect of Asbestos on Anti-Tumor Immunity

and Immunological Alteration in Patients with Malignant Mesothelioma 35

defense mechanisms against cancer (Imai et al., 2000). Therefore, we examined the effect of exposure to asbestos on cytotoxicity of NK cells and alteration in cytotoxicity of NK cells in

The mechanism of cytotoxicity in NK cells and CTLs can be separated into two parts. The role of one part is to recognize target cells, which is followed by transduction of the stimulation signal into the cytosol, while the other part acts to kill target cells. In the killing mechanism, both NK cells and CTLs use the common molecules perforin and granzymes. Perforin- and granzyme-induced apoptosis is the main pathway used by cytotoxic lymphocytes to eliminate virus-infected or transformed cells (Trapani & Smyth, 2002). Perforin and granzymes are produced and accumulate in the cytotoxic granules of NK cells. Once NK cells are optimally stimulated, perforin and granzymes are released into the gap of the immune synapse by degranulation and act on target cells to induce apoptosis. Perforin is the protein that can disrupt the cellular membrane and create a pore in the membrane of the target cell. Granzyme is a family of structurally related serine proteases, which enters target cells through the pore made by perforin, and induces apoptosis of the target cells. The second pathway to kill targets is Fas-mediated apoptosis, induced by ligation of the Fas ligand (FasL) expressed on NK cells or CTLs with Fas on target cells. In addition to these two pathways, tumor-necrosis factor-related apoptosis-inducing ligand (TRAIL) is also known to control the growth and metastasis of tumors (Smyth et al., 2001; Takeda et al., 2001). These killing mechanisms are followed by recognition of target cells by NK cells. In contrast to T cell, which utilizes the T cell receptor (TCR) to recognize targets, NK cells utilize various kinds of receptors for target recognition. These receptors could be of either type: inhibitory or activating. In the next section, we explain the significance of the

NK cells do not have clonal diversity like T cells, which include many repertoires, rearrangements, and somatic mutations of TCRs. However, NK cells can recognize various target cells using various kinds of receptors expressed on the cell surface of NK cells (Moretta, L. & Moretta, A., 2004; Yokoyama & Plougastel, 2003). Some NK cell receptors, the ligands of which are human leukocyte antigen (HLA) molecules, genetically differing among individuals and recognized by T cells with T cell receptor (TCR) to find abnormal cells, have the role of transducing an inhibitory signal. Those inhibitory receptors include a KIR family of receptors and heterodimer of NKG2A and CD94. The inhibitory signals derived from those receptors contribute to prohibition of cytotoxicity against normal self cells. In contrast, several other receptors transduce an activation signal after ligation with their respective ligands to induce cytotoxicity against abnormal target cells (Fig. 4). NKG2D is the best characterized activating receptor expressed on NK cells. NKG2D is a receptor belonging to the same group as NKG2A, NKG2 family, characterized by a lectin-like domain, but can transduce an activation signal unlike NKG2A. The signaling lymphocytic

patients with malignant mesothelioma.

**2.1. Mechanism of cytotoxicity in NK cells** 

expression levels of NK cell receptors for cytolytic activity.

**2.2. NK cell receptors** 

On the basis of these ideas, we started to investigate the immunological effect of exposure to asbestos and immunological alteration in patients with malignant mesothelioma. In this chapter, we show the results obtained from these studies concerning the effect of asbestos on anti-tumor immunity, focusing on NK and Th cells, and discuss the immune-suppressive effect of asbestos and the possible application of our results for the early diagnosis of malignant mesothelioma.
