**4. Cross-talk between inflammation and angiogenic growth factors**

Experimental and epidemiological evidences indicate that chronic inflammation is associated with most, if not all, tumors and supports their progression (Coussens & Werb 2002; Mantovani et al., 2008; Mantovani et al., 2010; Porta et al., 2009). Chronic inflammation appears to have a versatile function in tumor onset and progression. Indeed, as discussed above, a long-lasting inflammation can contribute to cancer initiation through the production ROS and RNS with DNA-damaging properties. On the other hand, it can also participate in cancer promotion and progression by increasing the availability of mediators (growth factors, cytokines, chemokines, prostaglandins) which contribute to the growth of initiated cells and to neoangiogenesis (Mantovani, 2010). Besides, once a tumor is established, cancer cells promote a constant influx of myelomonocytic cells that express inflammatory mediators supporting pro-tumoral functions. In this regard, myelomonocytic cells are key orchestrators of cancer-related inflammatory processes supporting proliferation and survival of malignant cells, subversion of adaptive immune responses, stromal remodeling and angiogenesis (David Dong et al., 2009; Loges et al., 2009; Porta et al., 2009).

60 Malignant Mesothelioma

channels (Knights & Cook, 2010).

tyrosine kinase receptors designated FGF receptors (FGFR1 to FGFR5), whereas a smaller number of FGF isoforms does not bind FGFRs but interacts with voltage-gated sodium

FGFs regulate cell proliferation, differentiation, survival, wound healing and angiogenesis. In cancer, FGF signaling is frequently de-regulated, resulting in mitogenic, anti-apoptotic and angiogenic responses (Knights & Cook, 2010). FGF-1 and -2, but also other less-studied FGF isoforms, exert pro-angiogenic effects by modulating proliferation and migration of endothelial cells and by stimulating the production of proteases (Lieu et al., 2011; Saylor et al., 2012). Worthy of note, it has been demonstrated that FGF-2 can synergize with both VEGF and PDGF-BB in stimulating neovascularization, this synergism relying on multiple mechanisms. For instance, FGF-2 promotes hypoxia-induced VEGF release by cancer cells and the expression of both VEGF and VEGFRs in endothelial cells, whereas VEGF, in turn, upregulates the expression of FGF-2 (Lieu et al., 2011; Saylor et al., 2012). Moreover, FGF-2 upregulates PDGFRs expression and increases the responsiveness to PDGF-BB in endothelial cells, whereas PDGF-BB enhances FGFR1 expression and FGF-2 responsiveness in vascular smooth muscle cells (Cao et al., 2008; Liu et al., 2011). Remarkably, FGFs are thought to play a critical role in the resistance to anti-VEGF therapy (Lieu et al., 2011; Saylor et al, 2005). Besides, both FGF-1 and -2 may also be involved in tumor cell growth through

FGF-1 and -2 are expressed in the majority of MMs *in vivo* and high levels of FGF-2 in tumor tissues, serum or pleural effusions are associated with a worse prognosis in MM patients (Davidson et al., 2004; Kumar-Singh et al., 1999; Strizzi et al., 2001b). Furthermore, the combined expression levels of FGF-1, FGF-2, VEGF and Transforming Growth Factor beta (TGFβ) in MM tissues correlates with both IMD and a poorer prognosis (Kumar-Singh et al., 1999). In addition to their role in tumor angiogenesis, FGFs act as autocrine growth factors for MM cells. Indeed, MM cells express FGFs and FGF receptors and the transfection with short interfering RNAs to FGF-1 and FGF-2 reduces MM cell proliferation (Kumar-Singh et al., 1999; Liu & Klominek, 2003; Stapelberg et al., 2005). It has also been reported that treatment of MM cells with exogenous FGF-2 stimulates the secretion of matrix metalloproteinases involved in tumor invasion and angiogenesis (Liu & Klominek, 2003).

**4. Cross-talk between inflammation and angiogenic growth factors** 

Experimental and epidemiological evidences indicate that chronic inflammation is associated with most, if not all, tumors and supports their progression (Coussens & Werb 2002; Mantovani et al., 2008; Mantovani et al., 2010; Porta et al., 2009). Chronic inflammation appears to have a versatile function in tumor onset and progression. Indeed, as discussed above, a long-lasting inflammation can contribute to cancer initiation through the production ROS and RNS with DNA-damaging properties. On the other hand, it can also participate in cancer promotion and progression by increasing the availability of mediators (growth factors, cytokines, chemokines, prostaglandins) which contribute to the growth of initiated cells and to neoangiogenesis (Mantovani, 2010). Besides, once a tumor is

cell-autonomous, autocrine mechanisms (Kumar-Singh et al., 1999).

Tissue infiltration by macrophages is a dramatic and common feature of inflammation, angiogenesis and cancer (Pollard, 2004; Sica, 2010). High densities of tumor-infiltrating macrophages are associated with poor survival in patients with MM (Burt et al., 2011). In fact, the recruitment and infiltration of macrophages in the tumor microenvironment can activate them to support the malignant progression of cancer cells. These macrophages are called tumor-associated macrophages (TAMs) (Lawrence, 2011; Sica, 2010). Cancer cells cocultured with macrophages and incubated with inflammatory cytokines are synergistically stimulated to produce various angiogenesis-related factors (Izzi et al., 2009; Ono, 2008). This inflammatory angiogenesis is mediated, in part, by activation of NF-κB and AP-1 (Angelo & Kurzrock, 2007; Huang et al., 2000; Ono, 2008). In fact, treatment of both vascular endothelial cells and cancer cells with IL-1α/β, TNF-α and ROS *in vitro* results in a marked induction of VEGF and FGF-2, through the transcriptional activation of NF-κB, Specificity protein 1 (Sp-1), AP-1 and hypoxia response elements.

In addition to macrophages, other tumor-infiltrating immune cells including T cells, B cells, natural killer cells and neutrophils can release cytokines, such as IL-1α/β, TNF-α and IL-6, able to sustain the synthesis of angiogenic growth factors (Angelo & Kurzrock, 2007). As for, IL-6, this pro-inflammatory cytokine has been reported to play a critical role in the stimulation of VEGF synthesis by different cell types, including MM cells (Adachi et al., 2006; Angelo & Kurzrock, 2007). Of note, MMs usually produce high levels of IL-6 but express low levels of IL-6R, so that the presence of sIL-6Rs, which may be provided by inflammatory cells recruited to the tumor region, is essential for the IL-6-dependent stimulation of VEGF expression by MM cells (Adachi et al., 2006). Inflammation can also induce the expression of receptors for angiogenic growth factors. In this regard, the expression of PDGFRs is known to be induced by inflammatory cytokines such as TNF-α and IL-1 (Andrae et al., 2008). Besides, inflammatory cells themselves can directly release angiogenic factors such as VEGF, PlGF, FGF-2 and PDGF, among many others, which exert mitogenic and migratory effects on surrounding cells (Sica 2010, Ono 2008). Inflammatory cells recruited in the tumor microenvironment can also produce matrix metalloproteinases which promote the formation of new vessels by degrading the basement membrane and by releasing angiogenic growth factors, such as VEGF, PlGF-2 and FGF-2, stored in the extracellular matrix (Barillari et al.,1998; Cao et al., 2008; Lieu et al., 2011).

The high amount of chemokines/cytokines, growth factors, proteolytic enzymes, proteoglycans, lipid mediators and prostaglandins which is typically found in the tumor microenvironment sustains and exacerbates both inflammation and angiogenesis (Costa et al., 2007; Lin & Karin, 2007; Ono, 2008). In this context, the cross-talk between inflammation and angiogenesis is further corroborated by the evidence that, if on one hand inflammatory mediators have significant effects on angiogenesis, on the other hand angiogenic factors can

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 macrophages (Adini et al., 2002).

Role of Inflammation and Angiogenic Growth Factors in Malignant Mesothelioma 63

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

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

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

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

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

Adachi, Y., Aoki, C., Yoshio-Hoshino, N., Takayama, K., Curiel, D. T. & Nishimoto N. (2006). Interleukin-6 induces both cell growth and VEGF production in malignant mesotheliomas. *Int. J. Cancer*, Vol. 119, No. 6, (September 2006), pp. 1303-1311, ISSN

Adini, A., Kornaga, T., Firoozbakht, F. & Benjamin, L. E. (2002). Placenta growth factor is a survival factor for human endothelial cells and macrophages. *Cancer Res.,* Vol. 62, No.

Albonici, L., Doldo, E., Palumbo, C., Orlandi, A., Bei, R., Pompeo, E., Mineo, T. C., Modesti, A. & Manzari, V. (2009). Placenta growth factor is a survival factor for human

(Cao et al., 2008; Ikuta et al., 2009; Homsi & Daud, 2007; Lieu et al., 2011).

immunosuppressive, tumor-promoting roles to the tumor stroma.

mesothelial cell transformation and MM progression.

Loredana Albonici, Camilla Palumbo and Vittorio Manzari

10, (May 2002), pp. 2749-2752, ISSN 0008-5472

MM antigens.

**6. Conclusions** 

**Author details** 

**7. References** 

0020-7136

*Rome, Italy* 
