1. Introduction
Malignant mesothelioma (MM) is a highly aggressive tumor which arises from the mesothelial cell lining of the serosal surfaces, most cases (>90%) being of pleural origin (Attanoos & Gibbs, 1997; Robinson & Lake, 2005). The pathogenesis of MM has been mainly associated with previous asbestos exposure (Berman & Crump, 2008), with a latency period of up to 40 years, although other agents such as Simian virus 40 (SV40) or genetic susceptibility factors have been linked to the development of this tumor (Carbone et al., 2002; Pisick & Salgia, 2005). Indeed, human mesothelial cells are highly susceptible to SV40-mediated transformation in vitro and SV40 DNA sequences and large T antigen (Tag) have been detected in human MM cells (Bocchetta et al., 2000; Carbone et al., 2012; Gazdar et al., 2003).
MM is largely unresponsive to conventional chemotherapy or radiotherapy and, despite its low metastatic efficiency, it is highly invasive to surrounding tissues so that its extensive growth leads to the failure of the organs underlying the serosal membranes (Astoul, 1999). In fact, the primary cause of fatality in MM is related to the propensity of the tumor cells to invade locally, even though MM metastasis are more common after surgery and, at the autopsy, metastatic diffusion is observed in 50% of patients (Astoul, 1999). At present, the median survival from diagnosis of MM is less than two years (Palumbo et al., 2008).
The mesothelium is not just a passive protective surface, but a highly dynamic membrane (Mutsaers, 2004). It consists of a single layer of elongated, flattened, squamous-like cells of mesodermal origin, characterized by dual epithelial/mesenchymal features. Cuboidal mesothelial cells can also be found at various locations in physiological conditions. Further, mesothelial cells can adopt a cuboidal morphology, which reflects a metabolically activated state, after injury or stimulation of the serosal surface (Mutsaers, 2004). Indeed, mesothelial cells are sentinel cells that can sense and respond to a variety of signals within their microenvironment. They participate in serosal inflammation by secreting both pro- and anti-inflammatory as well as immunomodulatory mediators. Besides, these cells can act as antigen presenting cells for T lymphocytes (Hausmann et al., 2000), regulate tissue repair, control fibrin deposition and breakdown, and modulate adhesion, growth and dissemination of tumor cells metastasizing to the serosal membranes (Mutsaers, 2002). In particular, in response to different types of stimuli, including cytokines and asbestos fibers, mesothelial cells have been reported to release prostaglandins, chemokines, reactive oxygen and nitrogen species and growth factors which represent key effectors in the modulation of inflammatory reactions that occur in response to pleural injury (Fleury-Feith et al., 2003; Mutsaers, 2002).
2. Asbestos-induced carcinogenesis as an inflammation-driven process
The association between exposure to asbestos fibers and development of lung cancer and mesothelioma is well established in both humans and animals models (Greillier & Astoul, 2008; Huang et al., 2011; Mossman & Churg, 1998; Yarborough, 2007). A variety of mediators, either generated directly from asbestos fibers or elaborated intracellularly or extracellularly by cells exposed to asbestos, are implicated in the initiation and promotion of mesothelial cell transformation.
The mechanisms underlying asbestos-induced carcinogenesis involve mutagenic and non-mutagenic pathways, the latter including inflammation, enhanced mitogenesis, cell signaling alterations, and cytotoxic apoptosis/necrosis. Neither of these two mechanisms alone fully accounts for the complex biological abnormalities produced by asbestos fibers, even though in MM asbestos appears to act as a complete carcinogen (Dong et al., 1994; Huang et al., 2011). Still, the chronic inflammatory response induced by asbestos inhalation seems to play a critical role in mesothelial cell transformation.
Asbestos exposure induces an inflammatory reaction with a large component of mononuclear phagocytes (Antony et al., 1993; Branchaud et al., 1993; Carbone et al., 2012; Choe et al., 1997). Upon differentiation into macrophages, these cells phagocytize asbestos fibers and, in response, release numerous cytokines and reactive oxygen species with mutagenic properties (Robledo & Mossman, 1999). Thus, many of the pathological consequences occurring in the lung following exposure to asbestos fibers are believed to arise from an inflammatory cascade involving both autocrine and paracrine events (Hillegass et al., 2010). Persistent pulmonary inflammation is observed in animal models of asbestosis that can be correlated with fibroproliferative responses (Mossman & Churg, 1998).
Experimental models, as well as in vitro studies, have shown that mesothelial cells are particularly susceptible to the cytotoxic effects of asbestos (Baldys et al., 2007; BéruBé et al., 1996; Broaddus et al., 1996). Asbestos does not induce transformation of primary human mesothelial cells in vitro, instead, it is very cytotoxic to this cell type, causing extensive cell death. This finding raised an apparent paradoxical issue of how asbestos causes MM if human mesothelial cells exposed to this mineral die (Liu et al., 2000). This apparent paradox is reconciled by the current hypothesis that the chronic inflammation induced by asbestos leads to the persistent activation of the nuclear factor kappa B (NF-κB) transcription factor, which in turn mediates the activation of prosurvival genes and prevents apoptosis of the damaged mesothelial cells (Mantovani et al., 2008; Micheau & Tschopp, 2003; Philip et al., 2004). This allows mesothelial cells with asbestos-induced DNA damage to survive and divide rather than die and, if sufficient genetic damage accumulates, to eventually develop into a MM (Miura et al., 2006; Nymark, 2007). In fact, apoptosis is an important mechanism by which cells with DNA damage are eliminated without eliciting an inflammatory response (Ullrich et al., 2008; Yoshida et al., 2010). However, failure of apoptosis in cells with unrepaired DNA and chromosomal damage after chronic exposure to asbestos may lead to permanent genetic alterations and trigger the development of a clone of cancerous cells (Roos & Kaina, 2006; Wu, 2006). Consistently, MM cells are found to be apoptosis-resistant as compared to primary cultured mesothelial cells (Fennel & Rudd, 2004; Villanova et al., 2008).
2.1. Tumor Necrosis Factor-α and other pro-inflammatory cytokines
Tumor Necrosis Factor-α (TNF-α) is probably the most studied candidate for initiating inflammatory and fibrotic events linked to lung diseases such as asbestosis. Asbestos fibers cause the accumulation of macrophages in the pleura and lung. When these macrophages encounter asbestos, they release TNF-α. At the same time, asbestos induces the secretion of TNF-α and the expression of TNF-α receptor I (TNF-RI) in mesothelial cells (Yang et al., 2006). Remarkably, treatment of mesothelial cells with TNF-α significantly reduced asbestos cytotoxicity. Indeed, TNF-α activates NF-κB, which in turn promotes mesothelial cell survival and resistance to the cytotoxic effects of asbestos. Thus, TNF-α signaling through NF-κB-dependent mechanisms increases the percentage of mesothelial cells that survive asbestos exposure, thereby increasing the pool of asbestos-damaged cells susceptible to malignant transformation (Haegens et al., 2007; Janssen-Heininger et al., 1999; Yang et al., 2006).
It has been reported that rats receiving a single intratracheal instillation of fibrogenic chrysotile asbestos developed lung chronic inflammatory reactions characterized by the accumulation of alveolar macrophages producing elevated levels of both Interleukin (IL)-1 and IL-6 (Lemaire & Ouellet, 1996). An increased production and/or release of these cytokines triggers inflammatory cell recruitment, thus amplifying and sustaining local inflammation. It has also been demonstrated that crocidolite asbestos and TNF-α can stimulate a dose-dependent increase in IL-6 expression and secretion from cultured, transformed and normal, human alveolar type II epithelial cells that is dependent upon intracellular redox potential (Simeonova et al., 1997). Interestingly, although MM cells appear to express low levels of IL-6 receptor (IL-6R), IL-6 can act as a growth factor for these cells through a trans-signaling mechanism involving the interaction of macromolecular complexes of IL-6 and soluble IL-6R (sIL-6R) with the transmembrane glycoprotein gp130 expressed on the surface of MM cells (Adachi et al., 2006; Rose-John et al., 2007). High levels of both IL-6 and sIL-6R are typical of several chronic inflammatory conditions (Rose-John et al., 2007).
Thus, inflammatory cytokines such as TNF-α and IL-6 appear to play a dual role in MM pathogenesis: they induce and sustain pleural inflammation and at the same time can act as survival or mitogenic factors for normal and transformed mesothelial cells, respectively.
2.2. Reactive Oxygen and Nitrogen Species (ROS/RNS)
The mechanisms of injury and disease development caused by asbestos fibers are presumed to be related to their greater fibrogenic and carcinogenic properties in comparison to other minerals. Asbestos–induced mutagenicity is mediated through both direct and indirect pathways. Asbestos fibers may induce mutagenicity and genotoxicity directly through physical interaction with the mitotic machinery after being phagocytized by the target cells, or indirectly as a result of DNA and chromosome damage caused by asbestos-induced reactive oxygen (ROS) and nitrogen species (RNS) (Kamp & Weitzman, 1999; Shukla et al., 2003a, 2003b). ROS and RNS can be generated primarily by asbestos fibers or secondarily through fiber-induced inflammation (Aust et al., 2011; Gulumian, 2005; Hoidal, 2001). Free radicals generated from asbestos fibers plus the direct damage induced by the fibers are linked to cell signaling, inflammation, and a plethora of other responses (mutagenesis, proliferation, etc.) associated with the pathogenesis of asbestos-associated diseases (Heinz et al., 2010; Manning et al., 2002; Shukla et al., 2003a, 2003b).
Several evidences indicate that a main factor in determining the surface and biological reactivity of different types of asbestos fibers is their ability to participate in redox reactions that generate free radicals (Kamp & Weitzman, 1999; Shukla et al., 2003a). Although the nature of the free radical-generating surface sites on asbestos fibers is not yet clear, asbestos fibers have an intrinsic redox activity and contain ferrous iron, which catalyzes reactions generating active oxygen intermediates on the fiber surface. Within the tissues several asbestos fiber types can produce reactive oxygen free radicals from hydrogen peroxide, a common product of intermediary tissue metabolism. Epidemiological studies have identified crocidolite as one of the most potent forms of asbestos associated with the induction of MM (Heintz et al., 2010). Crocidolite has a greater surface-area and a higher ferrous iron content compared to other fiber types such as chrysotile, and it is more biologically active in the generation of free radicals (Toyokuni, 2009). However, the ability of asbestos fibers to elicit these effects is not related to total iron content, suggesting the presence of specific iron active sites at the fibers’ surface (Shukla et al., 2003a).
Cells exposed to asbestos have also been reported to produce a higher amount of nitric oxide (NO). In this regard, it has been reported that in human mesothelial cells crocidolite increases the expression of the inducible NO synthase (NOS) isoform (iNOS), the activity of the constitutive endothelial NOS (eNOS), and the synthesis of NO via NF-κB and Akt activation (Riganti et al., 2007). Thus, the asbestos-induced upregulation of iNOS or NO in the lungs, as well as the induction of inflammation by fibers, may contribute along with ROS, to the pathogenesis of lung and pleural injury (Hussain et al., 2003; Tanaka et al., 1998). Indeed, ROS and RNS can cause breakage of DNA, lipid peroxidation, release of inflammatory cytokines such as TNF-α, and the modification of cellular proteins including phosphatases involved in cell signaling cascades (Gossart et al., 1996; Hussain et al., 2003), so that their increased synthesis by various cell types may have multiple roles in cellular events critical to the establishment of lung and pleural inflammation and uncontrolled cell proliferation.
Finally, in mesothelial and lung epithelial cells asbestos fibers, as opposed to nonpathogenic minerals, cause a persistent induction of the redox-sensitive transcription factors NF-κB and Activator Protein-1 (AP-1), which is accompanied by chronic alterations in gene expression (Heintz et al., 1993; Janssen et al., 1995). As mentioned above, the aberrant activation of the NF-κB pathway is regarded as a critical event for mesothelial cell transformation (Toyooka et al., 2008).
2.3. Transcription factors
2.3.1. NF-κB
NF-κB proteins are dimeric transcription factors composed of five different subunits, namely p65 (RelA), RelB, c-Rel, NF-κB1 p50 and NF-κB2 p52, which regulate gene expression events that impact on cell survival and differentiation. Moreover, since activation of NF-κB is critical in up-regulating the expression of many genes linked to proliferation, apoptosis resistance, and chemokine/cytokine production, this is undoubtedly a critical transcription factor in inflammatory responses occurring in target cells of asbestos-related diseases (Janssen et al., 1995, 1997).
In unstimulated cells, the NF-κB transcription dimers are retained in the cytoplasm in an inactive state through the interaction with a family of inhibitors called IκBs (Inhibitors of κB) or with the p50 and p52 precursor proteins, p105 and p100, respectively (Hayden & Ghosh, 2008; Scheidereit, 2006). Indeed, p50 and p52 are translated as precursors proteins containing an IκB-like C-terminal portion (Sun, 2011).
Two different NF-κB-activation pathways exist: the classical and the alternative NF-κB pathway. The classical NF-κB pathway is initiated by signals elicited by diverse receptors, including TNF receptors type 1/2, Toll/IL-1 receptor, T-cell and B-cell receptors and EGF receptor, and also by cellular stresses and DNA damage (Hayden & Ghosh 2004; Le Page et al., 2005). These signals induce the activation of the IκB kinase (IKK) complex, which is composed by the catalytic subunits IKKα and IKKβ and by the regulatory subunit IKKγ/NEMO (Hayden & Ghosh, 2008; Scheidereit, 2006; Sun, 2011). The activated IKK complex phosphorylates IκB proteins, thereby triggering their proteasomal degradation. As a consequence, NF-κB dimers are released and can translocate into the nucleus. This pathway mainly leads to the activation of p50:RelA dimers (Sun, 2011). Conversely, the alternative NF-κB pathway predominantly targets activation of RelB:p52 complexes. This pathway relies on the inducible processing of p100 triggered by signaling from TNF receptor family members via the NF-κB-inducing kinase (NIK): NIK activates IKKα, which, in turn, phosphorylates p100 and triggers its processing to p52. This event results in the conversion of p100-inhibited NF-κB complexes into p52-containing NF-κB dimers, capable of translocating into the nucleus (Hayden & Ghosh, 2008; Scheidereit, 2006; Sun, 2011).
NF-κB-regulated genes have distinct requirements for NF-κB dimers. For instance, the NF-κB binding site of the IL-2 gene has been reported to bind preferentially c-Rel homodimers and p50:c-Rel, while that of the gene encoding IL-8 has been found to selectively bind Rel A (Hoffman et al., 2003, 2006). On the other hand, several genes are redundantly induced by more than one dimer (Hoffman et al., 2003, 2006; Saccani et al., 2003).
A number of studies have shown that nuclear retention and DNA binding of NF-κB protein complexes are increased following exposure of various cell types to a variety of extracellular stimuli that include oxidative stress (Bowie & O'Neill, 2000), hypoxia (Jung et al., 2003; Royds et al., 1998) and inflammatory cytokines (Mantovani et al., 2008). These observations are consistent with the hypothesis that persistent activation of NF-κB can contribute to the induction of multiple genes that are critical to the pathogenesis of asbestos-associated diseases, since oxidants, local hypoxia and inflammatory cytokines are all components involved in the effects induced by asbestos exposure.
It is noteworthy that among various carcinogenic and non-carcinogenic fibers studied for their effect on nuclear translocation of NF-κB, only carcinogenic fibers were found to cause a dose-dependent translocation of this transcription factor to the nucleus, and this effect was reported to be oxidative stress-dependent (Brown et al., 1999). In lung macrophages, the asbestos-induced expression and secretion of TNF-α are mediated by iron-catalyzed ROS products (Simeonova & Luster, 1995) through a process that involves NF-κB activation (Cheng et al., 1999). In rat alveolar type 2 cells, the crocidolite-induced activation of NF-κB as well as the expression of the macrophage inflammatory protein-2 (MIP-2) gene have also been shown to be dependent on mitochondrial-derived oxidative stress (Driscoll et al., 1998).
2.3.2. AP-1
AP-1 is a homo- or heterodimeric transcription factor composed by proteins encoded by the
AP-1 is a redox-sensitive transcription factor typically associated with cell proliferation and tumor promotion (Eferl & Wagner, 2003). The first evidence showing that asbestos exerts regulatory effects linked to aberrant transcriptional responses, cell proliferation and cell transformation derives from studies in which asbestos fibers caused induction of
The persistent induction of AP-1 by asbestos suggests a model of asbestos-induced carcinogenesis involving chronic stimulation of cell proliferation through activation of early response genes (Schonthaler et al., 2011). Of note, early response genes are a set of genes whose transcription is rapidly induced in response to growth factors. Furthermore, AP-1 activity is induced by growth factors, pro-inflammatory cytokines and genotoxic stress (Jochum et al., 2001; Shaulian & Karin, 2002). These stimuli activate mitogen-activated protein kinase (MAPK) cascades through the phosphorylation of distinct substrates such as ERK, JNK and p38 MAPK (Chang & Karin, 2001). Indeed, the MAPK signal transduction pathway uses AP-1 as a converging point not only to regulate the expression of various genes but also to autoregulate AP-1 gene transcription (Reuter et al., 2010).
Several genes, which play very important roles in injury, repair, and differentiation, contain binding site(s) for AP-1 in their promoter and/or enhancer regions (Chang & Karin, 2001). These genes include extracellular matrix metalloproteinases (MMPs), antioxidant enzymes, growth factors and their receptors, differentiation markers, cytokines, chemokines and other transcription factors (Shaulian & Karin, 2001).
2.3.3. Nuclear Factor of Activated T Cells (NFAT)
The Nuclear Factor of Activated T cells (NFAT) family of transcription factors consists of five proteins that are evolutionarily related to the Rel/NF-κB family. NFAT can be present in both the cytoplasm and the nucleus. In the cytoplasm NFAT is in a highly phosphorylated, inactive state. Cell stimuli leading to the elevation of intracellular Ca2+ levels induce the activation of the phosphatase PP2B/Calcineurin which dephosphorylates NFAT. This results in its nuclear relocalization and transcriptional activation. Interestingly, NFAT family members can act synergistically with AP-1 on composite DNA elements which contain adjacent NFAT and AP-1 binding sites (Macián et al., 2001). A functional cooperation has also been reported to occur between NFAT and NF-κB (Jash et al., 2012).
Initially, NFAT was identified in lymphocytes and was reported to be expressed in activated but not resting T cells (Macián et al., 2005; Shaw et al., 1988). NFAT regulates not only T cell activation and differentiation but also the function of other immune cells, including dendritic cells (DCs), B cells and megakaryocytes. In addition, NFAT has crucial roles in numerous developmental programs in vertebrates.
Dysregulation of NFAT signalling is now known to be associated with malignant transformation and the development of cancer (Mancini & Toker, 2009; Müller & Rao, 2010). The observation that NFAT can be activated by asbestos-induced oxidative stress suggests that this transcription factor may play multiple roles in asbestos-induced inflammation and carcinogenesis (Li et al., 2002). Indeed, NFAT mediates the expression of several inflammatory cytokines, including TNF-α, and is involved in cell transformation, proliferation, invasive migration, tumor cell survival and tumor angiogenesis (Mancini & Toker, 2009).
3. Multifaceted role of angiogenic growth factors in MM
Angiogenesis is a common feature of solid tumors. Indeed, the development of a clinically observable tumor requires the neoformation of a vascular network sufficient to sustain tumor growth (Ribatti et al., 2007). Tumor angiogenesis is stimulated by the secretion of angiogenic molecules which induce endothelial cells from nearby vessels to switch from a quiescent to an activated state. Further, upon the stimulation of angiogenic growth factors, activated endothelial cells disrupt the extracellular matrix, proliferate and migrate (Ribatti et al., 2007). Angiogenic growth factors include, among the others, Vascular Endothelial Growth Factor (VEGF), Placenta Growth Factor (PlGF), Platelet-Derived Growth Factor (PDGF) and acidic and basic Fibroblast Growth Factors (FGF-1 and -2, respectively). VEGF is regarded as the most important player in angiogenesis (Ono, 2008).
The link between angiogenesis and tumor progression is provided by the negative prognostic value of intratumoral microvascular density (IMD) (Folkman, 2006; Kerbel, 2008). In MM the IMD has an independent prognostic value (Kumar-Singh et al., 1997). MM demonstrates a higher IMD than colon and breast tumors and, consistently, presents with minimal central necrosis despite its huge size (Gasparini & Harris, 1995; Kumar-Singh et al., 1997).
On the other hand, the involvement of angiogenic growth factors in MM goes beyond the stimulation of angiogenesis. Indeed, as discussed below, MM cells express receptors for several angiogenic factors which, accordingly, can directly modulate MM cell behavior.
3.1. Angiogenic growth factors of the VEGF family
The human VEGF family consists of five members: VEGF (VEGF-A), VEGF-B, VEGF-C, VEGF-D and PlGF. These growth factors are secreted as dimers and their biological effects are mediated by binding to three tyrosine kinase receptors,
3.1.1. VEGF
VEGF is regarded as the major mediator of tumor angiogenesis. It is expressed in the majority of cancers and has a central role in tumor growth and metastasis. In fact, this growth factor is essential for the mobilization of bone-marrow-derived endothelial precursors in neovascularization (Asahara et al., 1999), and stimulates vascular endothelial cells mobility, proliferation and survival (Waltenberger et al., 1994).
High levels of VEGF are present both in malignant and non-malignant pleural effusions leading to increased vascular permeability. On the other hand, VEGF levels in serum or pleural effusions of MM patients are higher than those found in patients with non-malignant pleuritis or lung cancer involving malignant pleural effusions. Further, in MM patients elevated serum or pleural effusion levels of VEGF correlate with a worse prognosis and may also contribute to increase resistance to chemotherapy (Hirayama et al., 2011; Yasumitsu et al., 2010; Zebrowski et al., 1999). In fact, VEGF status has proved to be of value in predicting the effectiveness of radiotherapy and chemotherapy on different cancers (Choi et al., 2008; Kumar et al., 2009; Toi et al., 2001).
In addition to its role in tumor vascularization, VEGF can directly affect the behavior of cancer cells in an autocrine or paracrine manner. Indeed, many tumor cell types express VEGF receptors. VEGF has been found to promote the growth of transformed cell lines in vitro (Masood et al., 2001) and to act as a survival factor for tumor cells by enhancing the expression of the antiapoptotic factors bcl-2 (Harmey & Bouchier-Hayes, 2002) and survivin (Kanwar et al., 2011). In this context, MM cells have been shown to express high amounts of VEGF, VEGF receptors and co-receptors both in vitro and in vivo, and VEGF has been demonstrated to act as an autocrine growth factor for this tumor cell type (Albonici et al., 2009; Ohta et al., 1999; Pompeo et al., 2009; Strizzi et al., 2001a).
VEGF-R1 participates in cell migration; it has an important role in monocyte chemotaxis and promotes recruitment of circulating endothelial precursor cells from bone marrow (Hattori et al., 2002). Its expression is increased in various tumors, correlates with disease progression and can predict poor prognosis, metastasis and recurrent disease in humans (Dawson et al., 2009; Fischer et al., 2008; Kerber et al., 2008). This receptor is also expressed by MM cells
VEGF-R2 is the main mediator of VEGF-stimulated endothelial cell migration, proliferation, survival and enhanced vascular permeability (Olsson et al., 2006; Shibuya, 2006). VEGF-R2 expression is induced in conjunction with active angiogenesis, such as during the reparative process, and in pathological conditions associated with neovascularization, such as cancer (Plate et al., 1993). VEGF-R2 is overexpressed in MM cells and specimens, and VEGF-R2 silencing by small intefering RNA has been shown to induce cell death in MM or immortalized mesotelial cells
3.1.2. PlGF
PlGF, originally identified in the placenta during the early embryonic development (Khaliq et al., 1996; Maglione et al., 1991), is expressed in several other organs including the heart, lung, thyroid, skeletal muscle and adipose tissue (Persico et al., 1999) but not normal mesothelium (Albonici et al., 2009).
Although the role exerted by PlGF in tumor growth is controversial yet, PlGF can stimulate vessel growth and maturation directly by affecting endothelial and mural cells, as well as indirectly by recruiting pro-angiogenic cell types (Barillari et al., 1998; Carmeliet, 2003). It also promotes the recruitment and maturation of angiogenesis-competent myeloid progenitors to growing sprouts and collateral vessels (Hattori et al., 2002; Luttun et al., 2002; Rafii et al., 2003). Further, PlGF is able to protect endothelial cells from apoptosis, in a similar manner as VEGF, by inducing the expression of antiapoptotic genes such as survivin (Adini et al., 2002).
Under pathological conditions, PlGF abundance is elevated in various cell types and tissues, including vascular endothelial cells, and many different tumor cells (Albonici et al., 2009; Cao et al., 1996; Fischer et al., 2007; Oura et al., 2003). PlGF expression is switched on in hyperplastic/reactive mesothelium and in MM cells (Albonici et al., 2009). Moreover, in MM as well as in different types of cancer, including melanoma, gastric, colorectal and breast carcinomas, PlGF plasma levels and intratumoral expression have been found to correlate with tumor stage, vascularity, recurrence, metastasis and survival (Chen et al., 2004; Marcellini et al., 2006; Parr et al. 2005; Pompeo et al.; 2009; Wei et al., 2005).
PlGF binds VEGF-R1 and the co-receptors neuropilin-1 and -2, but, unlike VEGF, it does not bind VEGF-R2. Accordingly, it can act independently of VEGF in cells which primarily express VEGF-R1 (Fischer et al., 2007). Worthy of note, even though VEGF and PlGF both bind VEGF-R1, PlGF was reported to stimulate the phosphorylation of specific VEGF-R1 tyrosine residues and the expression of distinct downstream target genes as compared to VEGF (Autiero et al., 2003). On the other hand, PlGF can also sustain VEGF activity through different mechanisms involving both VEGF-R1 and VEGF-R2. One of these mechanisms relies on the formation of PlGF:VEGF heterodimers. Indeed, PlGF:VEGF heterodimers have been isolated from cells producing both factors and shown to bind VEGF-R1:VEGF-R2 receptor complexes, thus inducing receptor cross-talk and activation of VEGF-R2, the major mediator of VEGF activities (Autiero et al., 2003; Cao et al., 1996). In addition, the activation of VEGF-R1 by PlGF homodimers may induce the intermolecular transphosphorylation and activation of VEGF-R2 (Carmeliet et al., 2001).
It is noteworthy that
3.2. PDGF
PDGFs comprise a family of dimeric growth factors structurally and functionally related to VEGFs (Andrae et al., 2008). PDGF homodimers are formed by four different chains,
An increased PDGF activity has been linked with tumors, vascular and fibrotic diseases (Andrae et al., 2008). Autocrine PDGF signaling leading to enhanced proliferation of tumor cells occurs in several types of cancer (Ostman, 2004). In addition, PDGF secretion by cancer cells and activated endothelial cells promotes the formation of both fibrous and vascular tumor stroma. In particular, PDGF-BB participates in tumor angiogenesis by stimulating endothelial cell motility and pericyte recruitment to neoformed vessels, thus leading to vessel stabilization, tumor cell survival and growth. Instead, both PDGF-AA and PDGF-BB appear involved in tumor recruitment of PDGFR-positive fibroblasts which, in turn, can be activated by PDGFs to produce VEGF and other tumor-promoting growth factors (Andrae et al., 2008; Cao et al., 2008; Homsi & Daud, 2007).
Either high PDGF-AB serum levels or a strong expression of PDGFR signaling effectors in MM tissues have been associated with a lower survival in MM patients (Filiberti et al., 2005; Kothmaier et al., 2008). In fact, several evidence support a role for PDGF in MM promotion and progression through both autocrine and paracrine mechanisms.
While PDGFRα expression levels are lower in MM than in normal mesothelial cells, PDGFRβ, PDGF-A and PDGF-B are overexpressed in MM cells as compared to their non-transformed counterparts (Langerak et al., 1996a, 1996b; Metheny-Barlow et al., 2001). Functional studies have shown that transduction of MM cells with a hammerhead ribozyme against PDGFRβ mRNA reduced both PDGFRβ expression and MM cell proliferation, demonstrating the involvement of a PDGF-BB autocrine loop in MM cell growth (Dorai et al., 1994). Conversely, the role of PDGF-A in MM cell proliferation is controversial. Indeed, the transfection of MM cells with antisense oligonucleotides to PDGF-A has been reported to either inhibit or stimulate MM cell growth
3.3. FGF
The FGF family encompasses 22 structurally related ligands in mammals. The effects of most FGF family members, including FGF-1 and -2, are mediated by binding to a family of 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 channels (Knights & Cook, 2010).
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 cell-autonomous, autocrine mechanisms (Kumar-Singh et al., 1999).
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 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).
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 co-cultured 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).
5. Cooperation between asbestos and angiogenic growth factors in MM onset and progression
As reported above, asbestos stimulates the expression of
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
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
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
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).
References
- 1.
Interleukin-6 induces both cell growth and VEGF production in malignant mesotheliomas. Int. J. Cancer,Adachi Y. Aoki C. Yoshio-Hoshino N. Takayama K. Curiel D. T. Nishimoto N. 119 6 September2006 1303 1311 0020-7136 - 2.
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.,62 10 May 2002),2749 2752 0008-5472 - 3.
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 malignant mesotelioma cells. Int. J. Immunopathol. Pharmacol.,22 2 April-June 2009),389 401 0394-6320 - 4.
Andrae J. Gallini R. Betsholtz C. 2008 Role of platelet-derived growth factors in physiology and medicine. Genes Dev.,22 10 May 2008),1276 1312 0890-9369 - 5.
Angelo L. S. Kurzrock R. 2007 Vascular endothelial growth factor and its relationship to inflammatory mediators. Clin. Cancer Res.,13 10 May 2007),2825 2830 1078-0432 - 6.
0022-1767 12 151 7216 7223 Antony, V. B., Godbey, S. W., Kunkel, S. L., Hott, J. W., Hartman, D. L., Burdick, M. D. & Strieter, R. M. (1993). Recruitment of inflammatory cells to the pleural space. Chemotactic cytokines, IL-8, and monocyte chemotactic peptide-1 in human pleural fluids. J. Immunol., Vol. 151, No. 12, (December 1993), pp. 7216-7223, ISSN 0022-1767 - 7.
Asahara T. Takahashi T. Masuda H. Kalka C. Chen D. Iwaguro H. Inai Y. Silver M. Isner J. M. 1999 VEGF contributes to postnatal neovascularization by mobilizing bone marrow-derived endothelial progenitor cells. EMBO J.,18 14 July 1999),3964 3972 0261-4189 - 8.
Astoul P. 1999 Pleural mesothelioma. Curr. Opin. Pulm. Med.,5 4 July 1999),259 268 1070-5287 - 9.
Attanoos R. L. Gibbs A. R. 1997 Pathology of malignant mesothelioma. Histopathology,30 5 May 1997),403 418 0309-0167 - 10.
Aust A. E. Cook P. M. Dodson R. F. 2011 Morphological and chemical mechanisms of elongated mineral particle toxicities. J. Toxicol. Environ. Health. B Crit. Rev.,14 1-4 40 75 1093-7404 - 11.
Autiero M. Waltenberger J. Communi D. Kranz A. Moons L. Lambrechts D. Kroll J. Plaisance S. De Mol M. Bono F. Kliche S. Fellbrich G. Ballmer-Hofer K. Maglione D. Mayr-Beyrle U. Dewerchin M. Dombrowski S. Stanimirovic D. Van Hummelen P. Dehio C. Hicklin D. J. Persico G. Herbert J. M. Communi D. Shibuya M. Collen D. Conway E. M. Carmeliet P. 2003 Role of PlGF in the intra- and intermolecular cross-talk between the VEGF receptors Flt-1 and Flk-1. Nat. Med.,9 7 July 2003),936 943 1078-8956 - 12.
Baldys A. Pande P. Mosleh T. Park S. H. Aust A. E. 2007 Apoptosis induced by crocidolite asbestos in human lung epithelial cells involves inactivation of Akt and MAPK pathways. Apoptosis,12 2 February 2007),433 447 1360-8185 - 13.
Barillari G. Albonici L. Franzese O. Modesti A. Liberati F. Barillari P. Ensoli B. Manzari V. Santeusanio G. 1998 The basic residues of placenta growth factor type 2 retrieve sequestered angiogenic factors into soluble form. Implication for tumor angiogenesis. Am. J. Pathol.,152 5 May 1998),1161 1166 0002-9440 - 14.
Barleon B. Sozzani S. Zhou D. Weich H. A. Mantovani A. Marmé D. 1996 Migration of human monocytes in response to vascular endothelial growth factor (VEGF) is mediated via the VEGF receptor flt-1. Blood,87 8 April 1996),3336 3343 0006-4971 - 15.
Berman D. W. Crump K. S. 2008 A meta-analysis of asbestos-related cancer risk that addresses fiber size and mineral type. Crit. Rev. Toxicol.,38 Suppl. 1,49 73 1040-8444 - 16.
Béru Bé. K. A. Quinlan T. R. Fung H. Magae J. Vacek P. Taatjes D. J. Mossman B. T. 1996 Apoptosis is observed in mesothelial cells after exposure to crocidolite asbestos. Am. J. Respir. Cell. Mol. Biol.,15 1 July 1996),141 147 1044-1549 - 17.
Human mesothelial cells are unusually susceptible to simian virus 40-mediated transformation and asbestos cocarcinogenicity. Proc. Natl. Acad. Sci. USA,Bocchetta M. Di Resta I. Powers A. Fresco R. Tosolini A. Testa J. R. Pass H. I. Rizzo P. Carbone M. 97 18 August2000 10214 10219 0027-8424 - 18.
Bowie A. O’Neill L. A. 2000 Oxidative stress and nuclear factor-kappaB activation: a reassessment of the evidence in the light of recent discoveries. Biochem. Pharmacol.,59 1 January 2000),13 23 0006-2952 - 19.
Branchaud R. M. Garant L. J. Kane A. B. 1993 Pathogenesis of mesothelial reactions to asbestos fibers. Monocyte recruitment and macrophage activation. Pathobiology,61 3-4 154 163 1015-2008 - 20.
Broaddus V. C. Yang L. Scavo L. M. Ernst J. D. Boylan A. M. 1996 Asbestos induces apoptosis of human and rabbit pleural mesothelial cells via reactive oxygen species. J. Clin. Invest.,98 9 November 1996),2050 2059 0021-9738 - 21.
Brown D. Beswick P. Donaldson K. 1999 Induction of nuclear translocation of NF-κB in epithelial cells by respirable mineral fibres. J. Pathol.,189 2 October 1999),258 264 0022-3417 - 22.
Circulating and tumor-infiltrating myeloid cells predict survival in human pleural mesothelioma. Cancer,Burt B. M. Rodig S. J. tilleman T. R. Elbardissi A. W. Bueno R. Sugarbaker D. J. 117 22 November2011 5234 5244 0000-8543 X - 23.
Cacciotti P. Strizzi L. Vianale G. Iaccheri L. Libener R. Porta C. Tognon M. Gaudino G. Mutti L. 2002 The presence of simian-virus 40 sequences in mesothelioma and mesothelial cells is associated with high levels of vascular growth factor. Am. J. Respir. Cell. Mol. Biol.,26 2 February 2002),189 193 1044-1549 - 24.
Cao Y. Cao R. Hedlund E. M. 2008 R Regulation of tumor angiogenesis and metastasis by FGF and PDGF signaling pathways. J Mol. Med. (Berl.),86 7 July 2008),785 789 0946-2716 - 25.
Cao Y. Chen H. Zhou L. Chiang M. K. Anand-Apte B. Weatherbee J. A. Wang Y. Fang F. Flanagan J. G. Tsang M. L. 1996 Heterodimers of placenta growth factor/vascular endothelial growth factor. Endothelial activity, tumor cell expression, and high affinity binding to Flk-1/KDR. J. Biol. Chem.,271 6 February 1996),3154 3162 0021-9258 - 26.
Carbone M. Kratzke R. A. Testa J. R. 2002 The pathogenesis of mesothelioma. Semin. Oncol.,29 1 February 2002),2 17 0093-7754 - 27.
Carbone M. Ly B. H. Dodson R. F. Pagano I. Morris P. T. Dogan U. A. Gazdar A. F. Pass H. I. Yang H. 2012 Malignant mesothelioma: Facts, myths and hypotheses. J. Cell. Physiol.,227 1 January 2012),44 58 0021-9541 - 28.
Carmeliet P. 2003 Angiogenesis in health and disease. Nat. Med.,9 6 June 2003),653 660 1078-8956 - 29.
Synergism between vascular endothelial growth factor and placental growth factor contributes to angiogenesis and plasma extravasation in pathological conditions. Nat. Med.,Carmeliet P. Moons L. Luttun A. Vincenti V. Compernolle V. De Mol M. Wu Y. Bono F. Devy L. Beck H. Scholz D. Acker T. Di Palma T. Dewerchin M. Noel A. Stalmans I. Barra A. Blacher S. Vandendriessche T. Ponten A. Eriksson U. Plate K. H. Foidart J. M. Schaper W. Charnock-Jones D. S. Hicklin D. J. Herbert J. M. Collen D. Persico M. G. 7 5 May2001 575 583 1078-8956 - 30.
Catalano A. Lazzarini R. Di Nuzzo S. Orciari S. Procopio A. 2009 The plexin-A1 receptor activates vascular endothelial growth factor-receptor 2 and nuclear factor-kappaB to mediate survival and anchorage-independent growth of malignant mesothelioma cells. Cancer Res.,69 4 February 2009),1485 1493 0008-5472 - 31.
Catalano A. Romano M. Martinotti S. Procopio A. 2002 Enhanced expression of vascular endothelial growth factor (VEGF) plays a critical role in the tumor progression potential induced by simian virus 40 large T antigen. Oncogene,21 18 April 2002),2896 2900 0950-9232 - 32.
Chang L. Karin M. 2001 Mammalian MAP kinase signalling cascades. Nature,410 6824 March 2001),37 40 0028-0836 - 33.
Chen C. N. Hsieh F. J. Cheng Y. M. Cheng W. F. Su Y. N. Chang K. J. Lee P. H. 2004 The significance of placenta growth factor in angiogenesis and clinical outcome of human gastric cancer. Cancer Lett.,213 1 September 2004),73 82 0304-3835 - 34.
Cheng N. Shi X. Ye J. Castranova V. Chen F. Leonard S. S. Vallyathan V. Rojanasakul Y. 1999 Role of transcription factor NF-kappaB in asbestos-induced TNFalpha response from macrophages. Exp. Mol. Pathol.,66 3 August 1999),201 210 0014-4800 - 35.
Pleural macrophage recruitment and activation in asbestos-induced pleural injury. Environ. Health Perspect.,Choe N. Tanaka S. Xia W. Hemenway D. R. Roggli V. L. Kagan E. 105 Suppl. 5, (September1997 1257 1260 0091-6765 - 36.
Choi C. H. Song S. Y. Choi J. J. Park Y. A. Kang H. Kim T. J. Lee J. W. Kim B. G. Lee J. H. Bae D. S. 2008 Prognostic significance of VEGF expression in patients with bulky cervical carcinoma undergoing neoadjuvant chemotherapy. BMC Cancer,8 October 2008),295 1471-2407 - 37.
Costa C. Incio J. Soares R. 2007 Angiogenesis and chronic inflammation: cause or consequence? Angiogenesis,10 3 149 166 0969-6970 - 38.
Coussens L. M. Werb Z. 2002 Inflammation and cancer. Nature,420 6917 December 2002),860 867 0028-0836 - 39.
David Dong. Z. M. Aplin A. C. Nicosia R. F. 2009 Regulation of angiogenesis by macrophages, dendritic cells, and circulating myelomonocytic cells. Curr. Pharm. Des.,15 4 365 379 1381-6128 - 40.
Davidson B. Vintman L. Zcharia E. Bedrossian C. Berner A. Nielsen S. Ilan N. Vlodavsky I. Reich R. 2004 Heparanase and basic fibroblast growth factor are co-expressed in malignant mesothelioma. Clin. Exp. Metastasis,21 5 469 476 0262-0898 - 41.
Dawson M. R. Duda D. G. Fukumura D. Jain R. K. 2009 VEGFR1-activity-independent metastasis formation. Nature,461 7262 September 2009),E4 E5 0028-0836 - 42.
Ding Y. Huang Y. Song N. Gao X. Yuan S. Wang X. Cai H. Fu Y. Luo Y. 2010 NFAT1 mediates placental growth factor-induced myelomonocytic cell recruitment via the induction of TNF-alpha. J. Immunol.,184 5 March 2010),2593 2601 0022-1767 - 43.
Dong H. Y. Buard A. Renier A. Levy F. Saint-Etienne L. Jaurand M. C. 1994 Role of oxygen derivatives in the cytotoxicity and DNA damage produced by asbestos on rat pleural mesothelial cells in vitro. Carcinogenesis,15 6 June 1994),1251 1255 0143-3334 - 44.
Dorai T. Kobayashi H. Holland J. F. Onhuma T. 1994 Modulation of platelet-derived growth factor-beta mRNA expression and cell growth in a human mesothelioma cell line by a hammerhead ribozyme. Mol. Pharmacol.,46 3 September 1994,437 444 0002-6895 X - 45.
Driscoll K. Carter J. Howard B. Hassenbein D. Janssen Y. Mossman B. T. 1998 Crocidolite activates NF-κB and MIP-2 gene expression in rat alveolar epithelial cells. Role of mitochondrial-derived oxidants. Environ. Health Perspect.,106 Suppl. 5, (October 1998),1171 1174 0091-6765 - 46.
Eferl R. Wagner E. F. 2003 AP1: a double-edged sword in tumorigenesis. Nature Rev. Cancer,3 11 November 2003),859 868 0147-4175 X - 47.
Fennell D. A. Rudd R. M. 2004 Defective core-apoptosis signaling in diffuse malignant pleural mesothelioma: opportunities for effective drug development. Lancet Oncol.,5 6 June 2004),354 362 1470-2045 - 48.
Ferrara N. Gerber H. P. Le Couter J. 2003 The biology of VEGF and its receptors. Nat. Med.,9 6 June 2003),669 676 1078-8956 - 49.
Filiberti R. Marroni P. Neri M. Ardizzoni A. Betta P. G. Cafferata M. A. Canessa P. A. Puntoni R. Ivaldi G. P. Paganuzzi M. 2005 Serum PDGF-AB in pleural mesotelioma. Tumour Biol.,26 5 September-October 2005),221 226 1010-4283 - 50.
Anti-PlGF inhibits growth of VEGF(R)-inhibitor-resistant tumors without affecting healthy vessels. Cell,Fischer C. Jonckx B. Mazzone M. Zacchigna S. Loges S. Pattarini L. Chorianopoulos E. Liesenborghs L. Kock M. De Mol M. Autiero M. Wyns S. Plaisance S. Moons L. van Rooijen N. Giacca M. Stassen J. M. Dewerchin M. Collen D. Carmeliet P. 131 3 November2007 463 475 0092-8674 - 51.
Fischer C. Mazzone M. Jonckx B. Carmeliet P. 2008 FLT1 and its ligands VEGFB and PlGF: drug targets for anti-angiogenic therapy? Nat. Rev. Cancer.,8 12 December 2008),942 956 0147-4175 X - 52.
Fleury-Feith J. Pilatte Y. Jaurand M. C. 2003 Cells in the pleural cavity, In: Textbook of pleural diseases, Light, R. W. & Lee, Y. C. G.,17 34 Arnold Publishers,978-0-34080-794-1 London. - 53.
Folkman J. 2006 Angiogenesis. Annu. Rev. Med.,57 1 18 0066-4219 - 54.
Gabrilovich D. I. Chen H. L. Girgis K. R. Cunningham H. T. Meny G. M. Nadaf S. Kavanaugh D. Carbone D. P. 1996 Production of vascular endothelial growth factor by human tumors inhibits the functional maturation of dendritic cells. Nat. Med.,2 10 October 1996),1096 1103 1078-8956 - 55.
Garlepp M. J. Leong C. C. 1995 Biological and immunological aspects of malignant mesothelioma. Eur. Respir. J.,8 4 April 1995),643 650 0903-1936 - 56.
Gasparini G. Harris A. L. 1995 Clinical importance of the determination of tumor angiogenesis in breast carcinoma: much more than a new prognostic tool. J. Clin. Oncol.,13 3 March 1995),765 782 0073-2183 X - 57.
Gazdar A. F. Carbone M. 2003 Molecular pathogenesis of malignant mesothelioma and its relationship to simian virus 40. Clin. Lung Cancer,5 3 November 2003),177 181 1525-7304 - 58.
Gossart S. Cambon C. Orfila C. Séquélas M. H. Lepert J. C. Rami J. Carrè P. Pipy B. 1996 Reactive oxygen intermediated as regulators of TNF-alpha production in rat lung inflammation induced by silica. J. Immunol.,156 4 February 1996),1540 1548 0022-1767 - 59.
Greillier L. Astoul P. 2008 Mesothelioma and asbestos-related pleural diseases. Respiration,76 1 1 15 0025-7931 - 60.
Gulumian M. 2005 An update on the detoxification processes for silica particles and asbestos fibers: successess and limitations. J. Toxicol. Environ. Health. B Crit. Rev.,8 6 November-December 2005),453 483 1093-7404 - 61.
Haegens A. Barrett T. F. Gell J. Shukla A. Macpherson M. Vacek P. Poynter M. E. Butnor K. J. Janssen-Heininger Y. M. Steele C. Mossman B. T. 2007 Airway epithelial NF-kappaB activation modulates asbestos-induced inflammation and mucin production in vivo. J. Immunol.,178 3 February 2007),1800 1808 0022-1767 - 62.
Harmey J. H. Bouchier-Hayes D. 2002 Vascular endothelial growth factor (VEGF), a survival factor for tumour cells: implications for anti-angiogenic therapy. Bioessays,24 3 March 2002),280 283 0265-9247 - 63.
Hattori K. Heissig B. Wu Y. Dias S. Tejada R. Ferris B. Hicklin D. J. Zhu Z. Bohlen P. Witte L. Hendrikx J. Hackett N. R. Crystal R. G. Moore M. A. Werb Z. Lyden D. Rafii S. 2002 Placental growth factor reconstitutes hematopoiesis by recruiting VEGFR1(+) stem cells from bone-marrow microenvironment. Nat. Med.,8 8 August 2002),841 849 1078-8956 - 64.
Hausmann M. J. Rogachev B. Weiler M. Chaimovitz C. Douvdevani A. 2000 Accessory role of human peritoneal mesothelial cells in antigen presentation and T-cell growth. Kidney Int.,57 2 February 2000),476 486 0085-2538 - 65.
Hayden M. S. Gosh S. 2004 Signaling to NF-κB. Genes Dev.,18 18 Spetember 2004),2195 2224 0890-9369 - 66.
Hayden M. S. Ghosh S. 2008 Shared principles in NF-kappaB signaling. Cell,132 3 February 2008),344 362 0092-8674 - 67.
Heintz N. H. Janssen Y. M. Mossman B. T. 1993 Persistent induction of c-fos and c-jun expression by asbestos. Proc. Natl. Acad. Sci. USA,90 8 April 1993),3299 3303 0027-8424 - 68.
Heintz N. H. Janssen-Heininger Y. M. Mossman B. T. 2010 Asbestos, lung cancers, and mesotheliomas: from molecular approaches to targeting tumor survival pathways. Am. J. Respir. Cell Mol. Biol.,42 2 February 2010),133 139 1044-1549 - 69.
Hillegass J. M. Shukla A. Lathrop S. A. Mac Pherson. M. B. Beuschel S. L. Butnor K. J. Testa J. R. Pass H. I. Carbone M. Steele C. Mossman B. T. 2010 Inflammation precedes the development of human malignant mesotheliomas in a SCID mouse xenograft model. Ann. N. Y. Acad. Sci.,1203 August 2010),7 14 0077-8923 - 70.
Hirayama N. Tabata C. Tabata R. Maeda R. Yasumitsu A. Yamada S. Kuribayashi K. Fukuoka K. Nakano T. 2011 Pleural effusion VEGF levels as a prognostic factor of malignant pleural mesothelioma. Respir. Med.,105 1 January 2011),137 142 0954-6111 - 71.
Hoffmann A. Natoli G. Baltimore D. 2003 Genetic analysis of NF-kappaB/Rel transcription factor defines functional specificities. EMBO J.,22 20 October 2003),5530 5539 0261-4189 - 72.
Hoffmann A. Natoli G. Ghosh G. 2006 Transcriptional regulation via the NF-kappaB signaling module. Oncogene,25 51 October 2006),6706 6716 0950-9232 - 73.
Hoidal J. R. 2001 Reactive oxygen species and cell signaling. Am. J. Respir. Cell Mol. Biol.,25 6 December 2001),661 663 1044-1549 - 74.
Holmes D. I. Zachary I. 2004 Placental growth factor induces FosB and c-Fos gene expression via Flt-1 receptors. FEBS Lett.,557 1-3 January 2004),93 98 0014-5793 - 75.
Homsi J. Daud A. I. 2007 Spectrum of activity and mechanism of action of VEGF/PDGF inhibitors. Cancer Control,14 3 July 2007),285 294 1073-2748 - 76.
Huang S. Robinson J. B. Deguzman A. Bucana C. D. Fidler I. J. 2000 Blockade of nuclear factor-kappaB signaling inhibits angiogenesis and tumorigenicity of human ovarian cancer cells by suppressing expression of vascular endothelial growth factor and interleukin 8. Cancer Res.,60 19 October 2000),5334 5539 0008-5472 - 77.
Huang S. X. Jaurand M. C. Kamp D. W. Whysner J. Hei T. K. 2011 Role of mutagenicity in asbestos fiber-induced carcinogenicity and other diseases. J. Toxicol. Environ. Health B. Crit. Rev.,14 1-4 179 245 1093-7404 - 78.
Hussain S. P. Hofseth L. J. Harris C. C. 2003 Radical causes of cancer. Nat. Rev. Cancer.,3 4 April 2003),276 285 0147-4175 X - 79.
Ikuta K. Yano S. Trung V. T. Hanibuchi M. Goto H. Li Q. Wang W. Yamada T. Ogino H. Kakiuchi S. Uehara H. Sekido Y. Uenaka T. Nishioka Y. Sone S. 2009 E7080, a multi-tyrosine kinase inhibitor, suppresses the progression of malignant pleural mesothelioma with different proangiogenic cytokine production profiles. Clin. Cancer Res.,15 23 December 2009),7229 7237 1078-0432 - 80.
Izzi V. Chiurchiù V. D’Aquilio F. Palumbo C. Tresoldi I. Modesti A. Baldini P. M. 2009 Differential effects of malignant mesothelioma cells on THP-1 monocytes and macrophages. Int. J. Oncol.,34 2 February 2009),543 550 1019-6439 - 81.
Janssen-Heininger Y. M. Macara I. Mossman B. T. 1999 Cooperativity between oxidants and tumor necrosis factor in the activation of nuclear factor (NF)-kappaB: requirement of Ras/mitogen-activated protein kinases in the activation of NF-kappaB by oxidants. Am. J. Respir. Cell. Mol. Biol.,20 5 May 1999),942 952 1044-1549 - 82.
Janssen Y. M. Barchowsky A. Treadwell M. Driscoll K. E. Mossman B. T. 1995 Asbestos induces nuclear factor-κB (NF-κB) DNA-binding activity and NF-κB-dependent gene expression in tracheal epithelial cells. Proc. Natl. Acad. Sci. USA,92 18 August 1995),8458 8462 0027-8424 - 83.
Janssen Y. M. Driscoll K. E. Howard B. Quinlan T. R. Treadwell M. Barchowsky A. Mossman B. T. 1997 Asbestos causes translocation of p65 protein and increases NF-kappa B DNA binding activity in rat lung epithelial and pleural mesothelial cells. Am. J. Pathol.,151 2 August 1997),389 401 0002-9440 - 84.
Jash A. Sahoo A. Kim G. C. Chae C. S. Hwang J. S. Kim J. E. Im S. H. 2012 Nuclear factor of activated T cells 1 (NFAT1) induced permissive chromatin modification facilitates nuclear Factor-κB (NF-κB) mediated interleukin-9 (IL-9) transactivation. J. Biol. Chem., (March 2012), Epub ahead of print,0108-3351 1083 351 X - 85.
Jochum W. Passegué E. Wagner E. F. 2001 AP-1 in mouse development and tumorigenesis. Oncogene,20 19 April 2001),2401 2412 0950-9232 - 86.
Jung Y. J. Isaacs J. S. Lee S. Trepel J. Neckers L. 2003 IL-1beta-mediated up-regulation of HIF-1alpha via an NF-kappaB/COX-2 pathway identifies HIF-1 as a critical link between inflammation and oncogenesis. FASEB J.,17 14 November 2003),2115 2117 0892-6638 - 87.
Kamp D. W. Weitzman S. A. 1999 The molecular basis of asbestos induced lung injury. Thorax,54 7 July 1999),638 652 0040-6376 - 88.
Kanwar J. R. Kamalapuram S. K. Kanwar R. K. 2011 Targeting surviving in cancer: the cell-signalling perspective. Drug Discov. Today,16 11-12 June 2011),485 494 1359-6446 - 89.
Kerbel R. S. 2008 Tumor angiogenesis. N. Engl. J. Med.,358 19 May 2008),2039 2049 0028-4793 - 90.
Kerber M. Reiss Y. Wickersheim A. Jugold M. Kiessling F. Heil M. Tchaikovski V. Waltenberger J. Shibuya M. Plate K. H. Machein M. R. (2008 2008 Flt-1 signaling in macrophages promotes glioma growth in vivo. Cancer Res.,68 18 September 2008),7342 7351 0008-5472 - 91.
Khaliq A. Li X. F. Shams M. Sisi P. Acevedo C. A. Whittle M. J. Weich H. Ahmed A. 1996 Localization of placenta growth factor (PlGF) in human term placenta. Growth Factors,13 3-4 243 250 0897-7194 - 92.
Knights V. Cook S. J. 2010 De-regulated FGF receptors as therapeutic targets in cancer. Pharmacol. Ther.,125 1 January 2010),105 117 0163-7258 - 93.
Koch S. Tugues S. Li X. Gualandi L. Claesson-Welsh L. 2011 Signal transduction by vascular endothelial growth factor receptors. Biochem J.,437 2 July 2011),169 183 0000-0264 - 94.
Kothmaier H. Quehenberger F. Halbewedl I. Morbini P. Demirag F. Zeren H. Comin C. E. Murer B. Cagle P. T. Attanoos R. Gibbs A. R. Galateau-Salle F. Popper H. H. 2008 EGFR and PDGFR differentially promote growth in malignant epithelioid mesothelioma of short and long term survivors. Thorax,63 4 April 2008),345 351 0040-6376 - 95.
Kumar S. Guleria R. Singh V. Bharti A. C. Mohan A. Das B. C. 2009 Efficacy of plasma vascular endothelial growth factor in monitoring first-line chemotherapy in patients with advanced non-small cell lung cancer. BMC Cancer,9 December 2009),421 1471-2407 - 96.
Kumar-Singh S. Vermuelen P. B. Weyler J. Segers K. Wejn B. Van Daele A. Dirix L. Y. Van Oosterom A. T. Van Mark E. 1997 Evalutation of tumor angiogenesis as a prognostic marker in malignant mesothelioma. J. Pathol.,182 2 June 1997),211 216 0022-3417 - 97.
Kumar-Singh S. Weyler J. Martin M. J. Vermeulen P. B. Van Marck E. 1999 Angiogenic cytokines in mesothelioma: a study of VEGF, FGF-1 and-2, and TGF beta expression. J. Pathol.,189 1 September 1999),72 82 0022-3417 - 98.
A. W., van der Linden-van Beurden, C. A. & Versnel, M. A. (Langerak A. W. van der Linden-van Beurden. C. 1996a Regulation of differential expression of platelet-derived growth factor alpha- and beta-receptor mRNA in normal and malignant human mesothelial cell lines. Biochim. Biophys. Acta.,1305 1-2 February 1996),63 70 0006-3002 - 99.
A., Van Der Linden-Van Beurden, C. A., Delahaye, M., Van Der Kwast, T. H., Hoogsteden, H. C., Benner, R. & Versnel, M. A. (Langerak A. W. De Laat P. A. Van Der Linden Van Beurden. C. 1996b Expression of platelet-derived growth factor (PDGF) and PDGF receptors in human malignant mesothelioma in vitro and in vivo. J. Pathol.,178 2 February 1996),151 160 0022-3417 - 100.
Lawrence T. 2011 Macrophages and NF-κB in cancer. Curr. Top. Microbiol. Immunol.,349 171 184 0007-0217 X - 101.
Lemaire I. Ouellet S. 1996 Distinctive profile of alveolar macrophage-derived cytokine release induced by fibrogenic and nonfibrogenic mineral dusts. J. Toxicol. Environ. Health.,47 5 April 1996),465 478 0098-4108 - 102.
Le Page C. Koumakpayi I. H. Lessard L. Mes-Masson A. M. Saad F. 2005 EGFR and Her-2 regulate the constitutive activation of NF-kappaB in PC-3 prostate cancer cells. Prostate,65 2 October 2005),130 140 0270-4137 - 103.
Li J. Huang B. Shi X. Castranova V. Vallyathan V. Huang C. 2002 Involvement of hydrogen peroxide in asbestos-induced NFAT activation. Mol. Cell. Biochem, 234-235 1-2 May-June 2002), pp. 161-168,0300-8177 - 104.
Li Q. Wang W. Yamada T. Matsumoto K. Sakai K. Bando Y. Uehara H. Nishioka Y. Sone S. Iwakiri S. Itoi K. Utsugi T. Yasumoto K. Yano S. 2011 Pleural mesothelioma instigates tumor-associated fibroblasts to promote progression via a malignant cytokine network. Am. J. Pathol.,179 3 September 2011),1483 1493 0002-9440 - 105.
Lieu C. Heymach J. Overman M. Tran H. Kopetz S. 2011 Beyond VEGF: inhibition of the fibroblast growth factor pathway and antiangiogenesis. Clin. Cancer Res.,17 19 October 2011),6130 6139 1078-0432 - 106.
Lin Y. L. Liang Y. C. Chiang B. L. 2007 Placental growth factor down-regulates type 1 T helper immune response by modulating the function of dendritic cells. J. Leukoc. Biol.,82 6 December 2007),1473 1480 0741-5400 - 107.
Lin W. W. Karin M. 2007 A cytokine-mediated link between inmate immunity, inflammation, and cancer. J. Clin. Invest.,117 5 May 2007),1175 1182 0021-9738 - 108.
Liu W. Ernst J. D. Broaddus V. C. 2000 Phagocytosis of crocidolite asbestos induces oxidative stress, DNA damage, and apoptosis in mesothelial cells. Am. J. Respir. Cell. Mol. Biol.,23 3 September 2000),371 378 1044-1549 - 109.
Liu Z. Klominek J. 2003 Regulation of matrix metalloprotease activity in malignant mesothelioma cell lines by growth factors. Thorax,58 3 March 2003),198 203 0040-6376 - 110.
Loges S. Schmidt T. Carmeliet P. 2009 Antimyeloangiogenic" therapy for cancer by inhibiting PlGF. Clin. Cancer Res.,15 11 June 2009),3648 3653 1078-0432 - 111.
Luttun A. Tjwa M. Carmeliet P. 2002 Placenta growth factor (PlGF) and its receptor Flt-1 (VEGFR-1): novel therapeutic targets for angiogenic disorders. Ann. N. Y. Acad. Sci.,979 December 2002),80 93 0077-8923 - 112.
Macian F. 2005 NFAT proteins: key regulators of T-cell development and function. Nature Rev. Immunol.,5 6 June 2005),472 484 1474-1733 - 113.
Macián F. López-Rodríguez C. Rao A. 2001 Partners in transcription: NFAT and AP-1. Oncogene,20 19 April 2001),2476 2489 0950-9232 - 114.
Maglione D. Guerriero V. Viglietto G. Delli-Bovi P. Persico M. G. 1991 Isolation of a human placenta cDNA coding for a protein related to the vascular permeability factor. Proc. Natl. Acad. Sci. USA,88 20 October 1991),9267 9271 0027-8424 - 115.
Mancini M. Toker A. 2009 NFAT proteins: emerging roles in cancer progression. Nature Rev. Cancer.,9 11 November 2009),810 820 0147-4175 X - 116.
Manning C. B. Vallyathan V. Mossman B. T. 2002 Diseases caused by asbestos: mechanisms of injury and disease development. Int. Immunopharmacol.,2 2-3 February 2002),191 200 1567-5769 - 117.
Manning L. S. Davis M. R. Robinson B. W. 1991 Asbestos fibres inhibit the in vitro activity of lymphokine-activated killer (LAK) cells from healthy individuals and patients with malignant mesothelioma. Clin. Exp. Immunol.,83 1 January 1991),85 91 0009-9104 - 118.
Mantovani A. 2010 Molecular pathways linking inflammation and cancer. Curr. Mol. Med.,10 4 June 2010),369 373 1566-5240 - 119.
Mantovani A. Allavena P. Sica A. Balkwill F. 2008 Cancer-related inflammation. Nature,454 7203 July 2008),436 444 0028-0836 - 120.
Marcellini M. De Luca N. Riccioni T. Ciucci A. Orecchia A. Lacal P. M. Ruffini F. Pesce M. Cianfarani F. Zambruno G. Orlandi A. Failla M. C. 2006 Increased melanoma growth and metastasis spreading in mice overexpressing placenta growth factor. Am. J. Pathol.,169 2 August 2006),643 654 0002-9440 - 121.
Masood R. Cai J. Zheng T. Smith D. L. Hinton D. R. Gill P. S. 2001 Vascular endothelial growth factor (VEGF) is an autocrine growth factor for VEGF receptor-positive human tumors. Blood,98 6 September 2001),1904 1913 0006-4971 - 122.
Metheny-Barlow L. J. Flynn B. van Gijssel H. E. Marrogi A. Gerwin B. I. 2001 Paradoxical effects of platelet-derived growth factor-A overexpression in malignant mesothelioma. Antiproliferative effects in vitro and tumorigenic stimulation in vivo. Am. J. Respir. Cell Mol. Biol.,24 6 June 2001),694 702 1044-1549 - 123.
Micheau O. Tschopp J. 2003 Induction of TNF receptor I-mediated apoptosis via two sequential signaling complexes. Cell,114 2 July 2003),181 190 0092-8674 - 124.
Milde-Langosch K. 2005 The Fos family of transcription factors and their role in tumourigenesis. Eur. J. Cancer.,41 16 November 2005),2449 2461 0014-2964 - 125.
Miura Y. Nishimura Y. Katsuyama H. Maeda M. Hayashi H. Dong M. Hyodoh F. Tomita M. Matsuo Y. Uesaka A. Kuribayashi K. Nakano T. Kishimoto T. Otsuki T. 2006 Involvement of IL-10 and Bcl-2 in resistance against an asbestos-induced apoptosis of T cells. Apoptosis,11 10 October 2006),1825 1835 1360-8185 - 126.
Mossman B. T. Churg A. 1998 Mechanisms in the pathogenesis of asbestosis and silicosis. Am. J. Respir. Crit. Care Med.,157 5 May 1998),1666 1680 0107-3449 X - 127.
Müller M. R. Rao A. 2010 NFAT, immunity and cancer: a transcription factor comes of age. Nat. Rev. Immunol.,10 9 September 2010),645 656 1474-1733 - 128.
Mutsaers S. E. 2002 Mesothelial cells: Their structure, function and role in serosal repair. Respirology,7 3 September 2002),171 191 1323-7799 - 129.
Mutsaers S. E. 2004 The mesothelial cell. Int. J. Biochem. Cell Biol.,36 1 January 2004),9 16 1357-2725 - 130.
Nymark P. Lindholm P. M. Korpela M. V. Lahti L. Ruosaari S. Kaski S. Hollmén J. Anttila S. Kinnula V. L. Knuutila S. 2007 Gene expression profiles in asbestos-exposed epithelial and mesothelial lung cell lines. BMC Genomics,8 March 2007),62 1471-2164 - 131.
Ohm J. E. Carbone D. P. 2001 VEGF as a mediator of tumor-associated immunodeficiency. Immunol. Res.,23 2-3 263 272 0025-7277 X - 132.
Ohta Y. Shridhar V. Bright R. K. Kalemkerian G. P. Du W. Carbone M. Watanabe Y. Pass H. I. 1999 VEGF and VEGF type C play an important role in angiogenesis and lymphangiogenesis in human malignant mesothelioma tumours. Br. J. Cancer.,81 1 September 1999),54 61 0007-0920 - 133.
Olsson A. K. Dimberg A. Kreuger J. Claesson-Welsh L. 2006 VEGF receptor signaling- in control of vascular function. Nat. Rev. Mol. Cell. Biol.,7 5 May 2006),359 371 1471-0072 - 134.
Ono M. 2008 Molecular links between tumor angiogenesis and inflammation: inflammatory stimuli of macrophages and cancer cells as targets for therapeutic strategy. Cancer Sci.,99 8 August 2008),1501 1506 1347-9032 - 135.
1359-6101 4 15 275 286 Ostman, A. ( 2004 ). PDGF receptors-mediators of autocrine tumor growth and regulators of tumor vasculature and stroma. Cytokine growth Factor Rev., Vol. 15, No. 4, (August 2004), pp. 275-286, ISSN 1359-6101 - 136.
Oura, H., Bertoncini, J., Velasco, P., Brown, L. F., Carmeliet, P. & Detmar, M. (2003). A critical role of placenta growth factor in the induction of inflammation and edema formation. Blood, Vol. 101, No. 2, (January 2003), pp. 560-567, ISSN 0006-4971 - 137.
Oyama T. Ran S. Ishida T. Nadaf S. Kerr L. Carbone D. P. Gabrilovich D. I. 1998 Vascular endothelial growth factor affects dendritic cell maturation through the inhibition of nuclear factor-kappa B activation in hemopoietic progenitor cells. J Immunol.,160 3 February 1998),1224 1232 0022-1767 - 138.
Palumbo C. Bei R. Procopio A. Modesti A. 2008 Molecular targets and targeted therapies for malignant mesothelioma. Curr. Med. Chem.,15 9 855 867 0929-8673 - 139.
Parr C. Watkins G. Boulton M. Cai J. Jiang W. G. 2005 Placenta growth factor is over-expressed and has prognostic value in human breast cancer. Eur. J. Cancer,41 18 December 2005),2819 2827 0014-2964 - 140.
Persico M. G. Vincenti V. Di Palma T. 1999 Structure, expression and receptor-binding properties of placenta growth factor (PlGF). Curr. Top. Microbiol. Immunol.,237 31 40 0007-0217 X - 141.
Philip M. Rowley D. A. Schreiber H. 2004 Inflammation as a tumor promoter in cancer induction. Semin. Cancer Biol.,14 6 December 2004),433 439 0104-4579 X - 142.
Pisick E. Salgia R. 2005 Molecular biology of malignant mesothelioma: a review. Hematol. Oncol. Clin. North Am.,19 6 December 2005),997 1023 0889-8588 - 143.
Plate K. H. Breier G. Millauer B. Ullrich A. Risau W. 1993 Up-regulation of vascular endothelial growth factor and its cognate receptors in a rat glioma model of tumor angiogenesis. Cancer Res.,53 23 December 1993),5822 5827 0008-5472 - 144.
Pollard J. W. 2004 Tumor-educated macrophages promote tumor progression and metastasis. Nat. Rev. Cancer,4 1 January 2004),71 78 0000-1474 X - 145.
Pompeo E. Albonici L. Doldo E. Orlandi A. Manzari V. Modesti A. Mineo T. C. 2009 Placenta growth factor expression has prognostic value in malignant pleural mesothelioma. Ann. Thorac. Surg.,88 2 426 431 0003-4975 - 146.
Porta C. Larghi P. Rimoldi M. Totaro M. G. Allavena P. Mantovani A. Sica A. 2009 Cellular and molecular pathways linking inflammation and cancer. Immunobiology,214 9-10 761 777 0171-2985 - 147.
Rafii S. Avecilla S. Shmelkov S. Shido K. Tejada R. Moore M. A. Heissig B. Hattori K. 2003 Angiogenic factors reconstitute hematopoiesis by recruiting stem cells from bone marrow microenvironment. Ann. N. Y. Acad. Sci.,996 May 2003),49 60 0077-8923 - 148.
Ramos-Ninos M. Timblin C. Mossman B. T. 2002 Mesothelial cell transformation requires increased AP-1 binding activity and ERK-dependent Fra-1 expression. Cancer Res.,62 21 November 2002),6065 6069 0008-5472 - 149.
Biol. Med.,Reuter S. Gupta S. C. Chaturvedi M. M. Aggarwal B. B. Oxidative stress. inflammation cancer how. are they. linked? Free. Radic 49 11 December2010 1603 1616 0891-5849 - 150.
Ribatti D. Nico B. Crivellato E. Roccaro A. M. Vacca A. 2007 The history of the angiogenic switch concept. Leukemia,21 1 January 2007),44 52 0887-6924 - 151.
Riganti C. Orecchia S. Silvagno F. Pescarmona G. Betta P. G. Gazzano E. Aldieri E. Ghigo D. Bosia A. 2007 Asbestos induces nitric oxide synthesis in mesothelioma cells via Rho signaling inhibition. Am. J. Respir. Cell. Mol. Biol.,36 6 June 2007),746 756 1044-1549 - 152.
Robinson B. W. Lake R. A. 2005 Advances in malignant mesothelioma. N. Engl. J. Med.,353 15 October 2005),1591 1603 0028-4793 - 153.
Robledo R. Mossman B. 1999 Cellular and molecular mechanisms of asbestos-induced fibrosis. J. Cell. Physiol.,180 2 August 1999),158 166 0021-9541 - 154.
Roos W. P. Kaina B. 2006 DNA damage-induced cell death by apoptosis. Trends Mol. Med.,12 9 September 2006),440 450 1471-4914 - 155.
Rose-John S. Waetzig G. H. Scheller J. Grötzinger J. Seegert D. 2007 The IL-6/sIL-6R complex as a novel target for therapeutic approaches. Expert Opin. Ther. Targets,11 5 May 2007),613 624 1472-8222 - 156.
Roskoski R. Jr 2007 Vascular endothelial growth factor (VEGF) signaling in tumor progression. Crit. Rev. Oncol. Hematol.,62 3 June 2007),179 213 1040-8428 - 157.
Royds J. A. Dower S. K. Qwarnstrom E. E. Lewis C. E. 1998 Response of tumour cells to hypoxia: role of p53 and NFkB. Mol. Pathol.,51 2 April 1998),55 61 1366-8714 - 158.
Saccani S. Pantano S. Natoli G. 2003 Modulation of NF-kappaB activity by Exchange of dimers. Mol. Cell,11 6 June 2003),1563 1574 1097-2765 - 159.
Saylor P. J. Escudier B. Michaelson M. D. 2012 Importance of Fibroblast Growth Factor Receptor in Neovascularization and Tumor Escape from Antiangiogenic Therapy. Clin. Genitourin. Cancer, (February 2012), Epub ahead of print,1558-7673 1558 7673 - 160.
Scheidereit C. 2006 IkappaB kinase complexes: gateways to NF-kappaB activation and transcription. Oncogene,25 51 October 2006),6685 6705 0950-9232 - 161.
Shaulian E. Karin M. 2001 AP-1 in cell proliferation and survival. Oncogene,20 19 April 2001),2390 2400 0950-9232 - 162.
Shaulian E. Karin M. 2002 AP-1 as a regulator of cell life and death. Nat. Cell Biol.,4 5 May 2002),E131 E136 1465-7392 - 163.
Shaw J. P. Utz P. J. Durand D. B. Toole J. J. Emmel E. A. Crabtree G. R. 1988 Identification of a putative regulator of early T cell activation genes. Science,241 4862 July 1988),202 205 0036-8075 - 164.
Shibuya M. 2006 Differential roles of vascular endothelial growth factor receptor-1 and receptor-2 in angiogenesis. J. Biochem. Mol. Biol.,39 5 September 2006),469 478 1225-8687 - 165.
Schonthaler H. B. Guinea-Viniegra J. Wagner E. F. 2011 Targeting inflammation by modulating the Jun/AP-1 pathway. Ann. Rheum, Dis.,70 Suppl. 1, (March 2011),i109 i112 0003-4967 - 166.
Shukla A. Gulumian M. Hei T. K. Kamp D. Rahman Q. Mossman B. T. 2003a Multiple roles of oxidants in the pathogenesis of asbestos-induced diseases. Free Radical Biol. Med.,34 9 May 2003),1117 1129 0891-5849 - 167.
Shukla A. Jung M. Stern M. Fukagawa N. K. Taatjes D. J. Sawyer D. Van Houte,n B. Mossman B. T. 2003b Asbestos induces mitochondrial DNA damage and dysfunction linked to the development of apoptosis. Am. J. Physiol. Lung Cell. Mol. Physiol.,285 5 November 2003),L1018 L1025 1040-0605 - 168.
Sica A. 2010 Role of tumour-associated macrophages in cancer-related inflammation. Exp. Oncol.,32 3 September 2010),153 158 1812-9269 - 169.
Simeonova P. Luster M. 1995 Iron and reactive oxygen species in the asbestos-induced tumor necrosis factor- response from alveolar macrophages. Am. J. Respir. Cell. Mol. Biol.,12 6 June 1995),676 683 1044-1549 - 170.
Simeonova P. P. Toriumi W. Kommineni C. Erkan M. Munson A. E. Rom W. N. Luster M. I. 1997 Molecular regulation of IL-6 activation by asbestos in lung epithelial cells: role of reactive oxygen species. J. Immunol.,159 8 October 1997),3921 3928 0022-1767 - 171.
Stapelberg M. Gellert N. Swettenham E. Tomasetti M. Witting P. K. Procopio A. Neuzil J. 2005 Alpha-tocopheryl succinate inhibits malignant mesothelioma by disrupting the fibroblast growth factor autocrine loop: mechanism and the role of oxidative stress. J. Biol. Chem.,280 27 July 2005),25369 25376 0021-9258 - 172.
Strizzi L. Catalano A. Vianale G. Orecchia S. Casalini A. Tassi G. Puntoni R. Mutti L. Procopio A. 2001a Vascular endothelial growth factor is an autocrine growth factor in human malignant mesothelioma. J. Pathol.,193 4 April 2001),468 475 0022-3417 - 173.
Strizzi L. Vianale G. Catalano A. Muraro R. Mutti L. Procopio A. 2001b Basic fibroblast growth factor in mesothelioma pleural effusions: correlation with patient survival and angiogenesis. Int. J. Oncol.,18 5 May 2001),1093 1098 1019-6439 - 174.
Sun S. C. 2011 Non-canonical NF-κB signaling pathway. Cell Res.,21 1 January 2011),71 85 1001-0602 - 175.
Takahashi A. Kono K. Ichihara F. Sugai H. Fuji H. Matsumoto Y. (2004 2004 Vascular endothelial growth factor inhibits maturation of dendritic cells induced by lipopolysaccharide, but not by proinflammatory cytokines. Cancer Immunol., Immunother.,53 6 June 2004),543 550 0340-7004 - 176.
Tanaka S. Choe N. Hemenway D. R. Zhu S. Matalon S. Kagan E. 1998 Asbestos inhalation induces reactive nitrogen species and nitrotyrosine formation in the lungs and pleura of the rat. J. Clin. Invest.,102 2 July 1998),445 454 0021-9738 - 177.
Toi M. Matsumoto T. Bando H. 2001 Vascular endothelial growth factor: its prognostic, predictive, and therapeutic implications. Lancet Oncol.,2 11 November 2001),667 673 1470-2045 - 178.
Toyokuni S. 2009 Mechanisms of asbestos-induced carcinogenesis. Nagoya J. Med. Sci.,71 1-2 February 2009),1 10 0027-7622 - 179.
Toyooka S. Kishimoto T. Date H. 2008 Advances in the molecular biology of malignant mesothelioma. Acta Med., Okayama,62 1 February 2008),1 7 0038-6300 X - 180.
Ullrich E. Bonmort M. Mignot G. Kroemer G. Zitvogel L. 2008 Tumor stress, cell death and the ensuing immune response. Cell Death Differ.,15 1 January 2008),21 28 1350-9047 - 181.
Valle M. T. Castagneto B. Procopio A. Carbone M. Giordano A. Mutti L. 1998 Immunobiology and immune defense mechanisms of mesothelioma cells. Monaldi Arch. Chest Dis.,53 2 April 1998),219 227 1122-0643 - 182.
Villanova F. Procopio A. Rippo M. R. 2008 Malignant mesothelioma resistance to apoptosis: recent discoveries and their implication for effective therapeutic strategies. Curr. Med. Chem.,15 7 631 641 0929-8673 - 183.
Waltenberger J. Claesson-Welsh L. Siegbahn A. Shibuya M. Heldin C. H. 1994 Different signal transduction properties of KDR and Flt1, two receptors for vascular endothelial growth factor. J. Biol. Chem.,269 43 October 1994),26988 26995 0021-9258 - 184.
Wei S. C. Tsao P. N. Yu S. C. Shun C. T. Tsai-Wu J. J. Wu C. H. Su Y. N. Hsieh F. J. Wong J. M. 2005 Placenta growth factor expression is correlated with survival of patients with colorectal cancer. Gut,54 5 May 2005),666 672 0017-5749 - 185.
Wu W. S. 2006 The signaling mechanism of ROS in tumor progression. Cancer Metastasis Rev.,25 4 December 2006),695 705 0167-7659 - 186.
Yang H. Bocchetta M. Kroczynska B. Elmishad A. G. Chen Y. Liu Z. Bubici C. Mossman B. T. Pass H. I. Testa J. R. Franzoso G. Carbone M. 2006 TNF-alpha inhibits asbestos-induced cytotoxicity via a NF-kappaB-dependent pathway, a possible mechanism for asbestos-induced oncogenesis. Proc. Natl. Acad. Sci. USA.,103 27 July 2006),10397 10402 0027-8424 - 187.
Yarborough C. M. 2007 The risk of mesothelioma from exposure to chrysotile asbestos. Curr. Opin. Pulm. Med.,13 4 July 2007),334 338 1070-5287 - 188.
Yasumitsu A. Tabata C. Tabata R. Hirayama N. Murakami A. Yamada S. Terada T. Iida S. Tamura K. Fukuoka K. Kuribayashi K. Nakano T. 2010 Clinical significance of serum vascular endothelial growth factor in malignant pleural mesothelioma. J. Thorac. Oncol.,5 4 April 2010),479 483 1556-0864 - 189.
Yoo S. A. Kwok S. K. Kim W. U. 2008 Proinflammatory role of vascular endothelial growth factor in the pathogenesis of rheumatoid arthritid: prospect for therapeutic intervention. Mediators Inflamm.,2008 Article ID 129873,0962-9351 - 190.
Yoshida K. Miki Y. 2010 The cell death machinery governed by the p53 tumor suppressor in response to DNA damage. Cancer Sci.,101 4 April 2010),831 835 1347-9032 - 191.
Zebrowski B. K. Yano S. Liu W. Shaheen R. M. Hicklin D. J. Putnam J. B. Ellis L. M. 1999 Vascular endothelial growth factor levels and induction of permeability in malignant pleural effusions. Clin. Cancer Res.,5 11 November 1999),3364 3368 1078-0432 - 192.
Ziogas A. C. Gavalas N. G. Tsiatas M. Tsitsilonis O. Politi E. Terpos E. Rodolakis A. Vlahos G. Thomakos N. Haidopoulos D. Antsaklis A. Dimopoulos M. A. Bamias A. 2012 VEGF directly suppresses activation of T cells from ovarian cancer patients and healthy individuals via VEGF receptor Type 2. Int. J. Cancer.,130 4 February 2012),857 864 0020-7136