**5. Cooperation between asbestos and angiogenic growth factors in MM onset and progression**

As reported above, asbestos stimulates the expression of *c-fos* and *c-jun* mRNA in mesothelial cells in a dose-dependent fashion (Heintz et al., 1993; Ramos-Nino et al., 2002). One of the mechanisms by which VEGF and PlGF elicit biological responses is the induction of Fos-B and c-Fos expression in endothelial cells and monocytes (Holmes & Zachary, 2004). The coexistence of different stimuli, such as asbestos fibers and angiogenic growth factors, concurring to the activation of early response genes might lead to the persistent induction of AP-1 in mesothelial cells and to the chronic stimulation of mesothelial cell proliferation, thus favoring cell transformation.

Further, asbestos and angiogenic growth factors can cooperate in inducing an immunosuppressive tumor microenvironement. Indeed, asbestos has been found to possess immunosuppressive properties. For example, chrysotile fibers have been shown to depress the *in vitro* proliferation of phytohemagglutinin-stimulated peripheral blood lymphocytes and to suppress natural killer activity. Moreover, asbestos significantly reduces the generation and activity of lymphokine-activated killer (LAK) cells, which are immune effectors with a strong lytic activity against MM cells (Manning et al., 1991; Valle et al., 1998).

Immunosuppressive properties have been reported for angiogenic growth factors as well (Ohm et al., 2001; Ziogas et al., 2012). Impaired antigen-presenting function in DCs as a result of abnormal differentiation is an important mechanism of tumor escape from immune control. It has been demonstrated that VEGF can inhibit the maturation of DCs induced by lipopolysaccharide (Takahashi et al., 2004). VEGF can also affect the ability of hematopoetic progenitor cells (HPCs) to differentiate into functional DCs during the early stages of hematopoiesis *in vivo* (Gabrilovich et al., 1996; Oyama et al., 1998)*.* In this regard, it has been shown that VEGF binds to specific receptors on the surface of HPCs and this binding appears to involve VEGF-R1. Interestingly, the number of binding sites available for VEGF decreased with DC maturation and correlated with decreased levels of VEGF-R1 mRNA expression in the late-stage cells (Gabrilovich et al., 1996). PlGF was also found to inhibit the activation and maturation of human DCs effectively and rapidly through the NF-κB pathway (Lin et al., 2007). The results of this study further indicate that by modulating the function of DCs, PlGF can down-regulate T helper immune responses (Lin et al., 2007). In addition, both VEGF and PlGF are also involved in the recruitment of macrophages with immunosuppressive, tumor-promoting roles to the tumor stroma.

On the whole, these findings suggest mechanisms by which tumor-derived soluble factors such as VEGF or PlGF may synergize with asbestos to down-regulate immune responses to MM antigens.

### **6. Conclusions**

62 Malignant Mesothelioma

macrophages (Adini et al., 2002).

**onset and progression** 

favoring cell transformation.

1998).

effectively promote inflammation. As a matter of fact, in addition to their angiogenic role, VEGF and PlGF appear to act as direct proinflammatory mediators in the pathogenesis of different inflammatory conditions (Angelo & Kurzrock, 2007; Yoo et al., 2008). In this regard, VEGF was found to increase the production of TNF-α and IL-6 by human peripheral blood mononuclear cells and macrophages (Yoo et al., 2008). Moreover, VEGF stimulates monocyte recruitment to tumor areas (Barleon et al., 1996). An additional link between inflammatory and angiogenic growth factors has been provided with the demonstration that in myelomonocytic cells TNF-α is upregulated by PlGF in a NFAT1-dependent manner and, in turn, contributes to PlGF-induced myelomonocytic cell recruitment (Ding et al., 2010). PlGF can also contribute to inflammation by acting as survival factor for monocytes and

**5. Cooperation between asbestos and angiogenic growth factors in MM** 

As reported above, asbestos stimulates the expression of *c-fos* and *c-jun* mRNA in mesothelial cells in a dose-dependent fashion (Heintz et al., 1993; Ramos-Nino et al., 2002). One of the mechanisms by which VEGF and PlGF elicit biological responses is the induction of Fos-B and c-Fos expression in endothelial cells and monocytes (Holmes & Zachary, 2004). The coexistence of different stimuli, such as asbestos fibers and angiogenic growth factors, concurring to the activation of early response genes might lead to the persistent induction of AP-1 in mesothelial cells and to the chronic stimulation of mesothelial cell proliferation, thus

Further, asbestos and angiogenic growth factors can cooperate in inducing an immunosuppressive tumor microenvironement. Indeed, asbestos has been found to possess immunosuppressive properties. For example, chrysotile fibers have been shown to depress the *in vitro* proliferation of phytohemagglutinin-stimulated peripheral blood lymphocytes and to suppress natural killer activity. Moreover, asbestos significantly reduces the generation and activity of lymphokine-activated killer (LAK) cells, which are immune effectors with a strong lytic activity against MM cells (Manning et al., 1991; Valle et al.,

Immunosuppressive properties have been reported for angiogenic growth factors as well (Ohm et al., 2001; Ziogas et al., 2012). Impaired antigen-presenting function in DCs as a result of abnormal differentiation is an important mechanism of tumor escape from immune control. It has been demonstrated that VEGF can inhibit the maturation of DCs induced by lipopolysaccharide (Takahashi et al., 2004). VEGF can also affect the ability of hematopoetic progenitor cells (HPCs) to differentiate into functional DCs during the early stages of hematopoiesis *in vivo* (Gabrilovich et al., 1996; Oyama et al., 1998)*.* In this regard, it has been shown that VEGF binds to specific receptors on the surface of HPCs and this binding appears to involve VEGF-R1. Interestingly, the number of binding sites available for VEGF decreased with DC maturation and correlated with decreased levels of VEGF-R1 mRNA expression in the late-stage cells (Gabrilovich et al., 1996). PlGF was also found to inhibit the Collectively, the reported findings demonstrate that a complex network involving asbestos, inflammation and angiogenic factors upregulation is involved in the pathogenesis of MM. In particular, the abnormal expression of angiogenic factors appears to play multiple roles in MM: it stimulates tumor neovascularization, increases pleural effusion formation by increasing vascular permeability, supports autocrine tumor cell growth and finally, in synergism with asbestos fibers, can sustain inflammation and bias host immune responses. Accordingly, the upregulation of angiogenic growth factors appears to be a crucial event in mesothelial cell transformation and MM progression.

Given the involvement of multiple angiogenic growth growth factors in the formation of tumor vessels, in tumor inflammation and MM cell growth and survival, the therapeutic development of antiangiogenic agents for the treatment of this tumor should be aimed at blocking multiple growth factor signaling pathways and their complex interactive network (Cao et al., 2008; Ikuta et al., 2009; Homsi & Daud, 2007; Lieu et al., 2011).

### **Author details**

Loredana Albonici, Camilla Palumbo and Vittorio Manzari

*Department of Experimental Medicine and Biochemical Sciences, University of Rome "Tor Vergata", Rome, Italy* 

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**Chapter 4** 

© 2012 Galati, 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 Galati, 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.

**The Role of Cyclooxygenase-2,** 

Additional information is available at the end of the chapter

Rossella Galati

**1. Introduction** 

http://dx.doi.org/10.5772/50674

**Epidermal Growth Factor Receptor** 

**and Aromatase in Malignant Mesothelioma** 

Malignant mesothelioma (MM) is a rare malignant disease originating from neoplastic mesothelial cells which compose the serous membranes of pleura, peritoneum, pericardium, or testis. Mesothelioma responds little to chemo and radiotherapy and is associated with a poor prognosis. In Western Europe, the incidence is increasing and is expected to peak in the year 2020 (Peto et al., 1999; Pelucchi et al., 2004) while in Japan and Australia, the peak is expected for 2025 and 2015 respectively. Thus in order to improve the clinical outcome in the pharmacological treatment of this refractory tumour, drugs directed against novel and/or characterized tumour-specific cellular targets are needed. Malignant pleural mesothelioma (MPM) originates from the pleural layers. Pleura is not just a limiting protective layer for lung, but a dynamic cellular structure regulating serial responses to injury, infection, and disease. Mesothelial cells are biologically active because they can sense and respond to signals within their microenvironment. The development of MM is associated in most patients with a history of asbestos exposure (Mossman et al., 1996). In addition, some investigations have implicated SV40 virus in the pathogenesis of a subset of mesotheliomas (Carbone et al., 2003). Exposure to asbestos typically occurs during mining and milling of the fibers or during industrial application of asbestos in textiles, insulation, shipbuilding, brake lining mechanics, and other areas. Non occupational exposure is usually related to asbestos fibers inadvertently released into the environment and transported by asbestos-contaminated clothing or other materials. After asbestos inhalation, fibers deposited in the lungs typically remain in close contact with lung epithelial cells. Since this fiber-cell interaction could potentially initiate or inhibit cellular functions, asbestos acts as a carcinogen by initiating the carcinogenic process. Carcinogens are known to modulate the transcription factors, anti-apoptotic proteins, proapoptotic proteins, protein kinases, cell cycle proteins, cell adhesion molecules, cyclooxygenase-2, and growth

