mesothelioma cancer

Growth factors can act as positive or negative modulators of cell
pro¬liferation, differentiation, motility, and angiogenesis. The interaction of
these signal molecules with their membrane receptors triggers a number of
intracellular signaling pathways, resulting in the activa¬tion or repression of
various subset of genes. Aberrations in these biochemical signals are linked to
developmental abnormalities or to a series of chronic diseases, including
cancer. Tumor malignant cells arise as the result of a stepwise progression of
genetic events, includ¬ing deregulated expression of growth factors or of
molecules involved in their signaling pathways (1).
The proliferation of normal human and rodent mesothelial cells is regulated by
exposure to several growth factors, including epidermal growth factor (EGF)
(2,3), tumor necrosis factor-a (TNF-a) (4), platelet-derived growth factor
(PDGF) (5), hepatocyte growth factor (HGF) (6), and keratinocyte growth factor
(KGF) (7).
This chapter focuses on the several growth factors expressed by mesothelial and
malignant mesothelioma cells (MMCs), and discusses how deregulation of their
biologic activities is responsible for the onset and progression of this tumor
(Table 7.1).

Epidermal Growth Factor and Its Related Molecules

Epidermal growth factor (EGF) has a profound effect on the differen¬tiation of
specific cells in vivo and is a potent mitogenic factor for a variety of
cultured cells of both ectodermal and mesodermal origin. The EGF precursor
exists as a membrane-bound molecule that is proteolytically cleaved to generate
the 53-amino acid peptide growth factor that stimulates cells to divide (8).
Epidermal growth factor is a powerful mitogen for human mesothe-lial cells too.
Autotransphosphorylation and activation of the EGF tyro-sine kinase receptor
(EGFR) occurs after exposure to asbestos triggering the mitogen-activated
protein kinase/extracellular signal-regulated kinase (MAPK/ERK) cascade. The
MAPK activation by asbestos is

attenuated by generic inhibitors of growth factor receptor
interactions, like suramin, as well as by tyrphostin AG 1478, a specific
inhibitor of the EGFR tyrosine kinase activity (3). Although both
asbestos-transformed MMCs and spontaneously transformed mesothelial cells
express functional EGFRs, only cells transformed by exposure to asbestos fibers
express into conditioned medium TGF-α, a growth factor with high affinity for
EGFR (9). Interestingly, while TGF-a inhibits the growth of spontaneously
transformed mesothelial cells, it stimulates the proliferation of
asbestos-transformed cells, as demon-strated by the inhibition of growth
observed after incubation with neutralizing antibody raised against TGF-α. Taken
together, these data indicate that TGF-a acts as an autocrine growth factor for
asbestos-transformed rat mesothelial cells and suggest that differences in
mesothelioma etiology may be linked to differences in the molecular alterations
present in these tumors (10).
Epidermal growth factor is not only a mitogen but it may also play a role in the
process of cell differentiation and the synthesis of glycosaminoglycans in
mesothelial cells (11). In addition, it has been recently demonstrated that many
different growth factors including EGF, TGF-α, amphiregulin, heparin-binding
EGF, beta-cellulin (BTC), stem cell factor, insulin-like growth factors I and
II, acidic and basic fibroblast growth factors, and HGF regulate the expression
in malig¬nant mesothelioma cells of the extracellular matrix metalloproteinases
(MMPs), molecules playing a key role in tumor cell invasion and metastasis (12).

Transforming Growth Factor-β

Transforming growth factor-b (TGF-β) 1 and 2 are dimeric multifunc¬tional
polypeptide that control proliferation, differentiation, and other functions in
many cell types. Many cells synthesize TGF-β1 and essen¬tially all of them have
specific receptors for this peptide. TGF-β1 regu¬lates the actions of many other
peptide growth factors and determines a positive or negative direction of their
effects.
Both TGF-β1 and -β2 are secreted by human and murine MMCs through an autocrine
mechanism. They may both reduce T-lymphocyte infiltration into tumors and
modulate malignant growth of tumor cells, as demonstrated by experiments with
antisense oligonucleotides in vitro and in vivo (13). Moreover, TGF-β is
responsible of evident mor¬phologic changes in mesothelial cells (14). Both
mesothelial cells and cells infiltrating in the pleural space can secrete TGF-a,
because high levels of this growth factor were found in pleural effusions and in
pleural tissues during disease processes. Also, TGF-b may participate in the
regulation of pleural inflammation and enhance both cell prolif¬eration and
pleural fluid formation (15), partially due to induction of vascular endothelial
growth factor (VEGF) (16). Cell lines derived from MM patients show considerably
higher levels of TGF-β messenger RNA (mRNA) expression when compared with normal mesothelial cells. Treatment with exogenous TGF-β has no effects on growth of
the MM cells, while the proliferation of the mesothelial cells is slightly
induced (17).

Tumor Necrosis Factor-α

Tumor necrosis factor-a (TNF-α) is a homotrimer multifunctional proinflammatory
cytokine localized in membrane belonging to the tumor necrosis factor
superfamily. It also exists as an extracellular soluble form derived from the
membrane form by proteolytic process¬ing. This cytokine is mainly secreted by
macrophages that can bind to, and thus functions through, its receptors
TNFRSF1A/TNFR1 and TNFRSF1B/TNFBR. It is involved in the regulation of a wide
spectrum of biologic processes including cell proliferation, differentiation,
apo-ptosis, lipid metabolism, and coagulation, and has been implicated in a
variety of diseases, including autoimmune diseases, insulin resis¬tance, and
cancer. Knockout studies in mice also suggested the neuro-protective function of
this cytokine.
In human mesothelial cells TNF-α induces the acquisition of fibro-blastoid
morphology and upregulates the synthesis of matrix metalloproteinase-9 (MMP-9)
and type I collagen, which may facilitate peritoneal extracellular matrix
remodeling and fibrogenesis (18). Also, TNF-a induces a significant increase in
cell proliferation and collagen production of rat pleural mesothelial cells in
vitro, suggesting a role for this molecule in healing of the pleura after tissue
injury (19).
Platelet-Derived Growth Factors AA, AB, and BB
The proteins AA, BB, and AB are members of the platelet-derived growth factor
(PDGF) family and are mitogenic factors for cells of mes-enchymal origin
characterized by a motif of eight cysteines. They can exist either as homodimers
(AA and BB) or as a heterodimer (AB) sta¬bilized by disulfide bonds. The PDGF-a
receptor binds all three dimeric forms of PDGF, whereas the PDGF-b receptor
binds PDGF-BB with high affinity and PDGF-AB with lower affinity, but not
PDGF-AA (20) (Fig. 7.1). They are released by platelets upon wounding and play
an important role in stimulating adjacent cells to grow and thereby heal the
wound.
Expression of the PDGF receptor (PDGFR) has been detected both in normal
mesothelial cells and in MMCs. However, several MMC lines, but not normal
mesothelial cells, display constitutively enhanced expression of the c-sis
(PDGF-BB) and PDGF-AA genes. This PDGF-dependent autocrine circuit has been
postulated to play a role in

Figure 7.1. Selective binding of platelet-derived growth factor (PDGF) ligands (PDGF-AA, -AB, and -BB) to PDGF receptors.

the etiology of this type of malignancy (21). Several independent
studies demonstrated that normal mesothelium is responsive to PDGF predominantly
via PDGFR-a and at lesser extent via PDGFR-b receptor, whereas the autocrine
stimulation of growth in mesothe-lioma cells hangs on the PDGF/PDGFR-b
interaction (5,22,23). The pattern of PDGF and PDGF receptor expression in
mesothelial cells largely corresponds to expression of PDGF and its receptors in
vitro (24).
There are two PDGF-AA transcript isoforms differing in the presence or absence
of an alternative exon-derived sequence. However, both normal mesothelial cells
and MMCs predominantly express the PDGF-AA transcript lacking the exon-6-derived
sequence, which encodes a cell-retention signal. This means that the PDGF-AA
protein is most likely secreted by both cell types and may be involved in
autocrine growth stimulation via PDGF-a receptors in mesothelial cells. As well,
it might also have a paracrine function if it is secreted by malig¬nant
mesothelial cells that do not express the receptor. Moreover, the enhancement of
transcription seems to be the most likely mechanism for the elevated mRNA levels
of PDGF-AA gene in human malignant mesothelioma cells (25). In addition, TGF-b1,
secreted in active form by mesothelial cells, may play a role in the regulation
of differential PDGF-R expression, by downregulation of a still lower PDGF-a
recep¬tor mRNA level in malignant mesothelioma cells (24).
Overexpression of PDGF-AA is responsible for autocrine down-regulation of its
receptor. Surprisingly, the PDGF-AA/PDGFR autocrine loop is antiproliferative
for mesothelioma cells in vitro, whereas proliferation is stimulated by
abrogation of PDGF-a expres¬sion. This suggests that PDGF-AA does not contribute
to tumorigenic-ity by the autocrine stimulation of growth. On the other hand, in
vivo PDGF-AA overexpression is associated with augmented tumorigenic-ity, and
abrogation of PDGF-AA expression decreases tumor incidence and increases latency
period to tumor formation. Thus, the tumorigenic effect of PDGF-AA must act
through paracrine mechanisms relevant at early stages of tumor initiation (26).
The absence of alterations of PDGF expression in rat mesothelioma, in contrast
to what occurs in the human disease, suggests that the production of this growth
factor by transformed mesothelial cells may be a species-specific mechanism
(27).
Platelet-derived growth factor stimulates mesothelial cell prolifera¬tion in
vitro and in vivo (28) as well as hyaluronan synthesis in patients with
mesothelioma, as demonstrated by partial inhibition by an anti-serum raised
against PDGF (29). Moreover, PDGF stimulates collagen synthesis that, if
combined with increased proliferation, may be impor¬tant in healing the pleura
injured during the progression of the disease (2). Finally, migration of
mesothelioma cells on fibronectin, laminin, or collagen-type IV in response to
PDGF-BB and inhibition of this effect after pretreatment with blocking
antibodies to a3b1 integrin were described, suggesting that cooperation between
PDGFR-b and integrin a3b1 is necessary for the motile response of MMCs to
PDGF-BB (30).

Insulin-Like Growth Factors

Insulin-like growth factors I and II (IGFs) are polypeptides structurally and
functionally related to insulin but having a much higher growth and
differentiation-promoting activity.
Cell lines derived from normal rat mesothelium as well as cell lines derived
only from spontaneous rat mesotheliomas, but not from asbestos-induced rat
mesotheliomas, showed expression of RNA tran¬scripts for IGF-II. All these cell
lines expressed receptors for IGF-I and IGF-II, as well as insulin receptors.
Coexpression of IGF-II and its cognate receptor suggests that IGF-II acts as an
autocrine growth factor in the spontaneously immortalized cells and in the cells
derived from the spontaneous rat tumors. Growth induced by IGF-II secreted into
conditioned medium can be inhibited using an IGF-II–specific antibody in a
dose-dependent manner. These data suggest that IGF-II expression may be involved
in the spontaneous alteration of rat mesothelial cells and may function as an
autocrine or paracrine growth factor to mod¬ulate the growth of these cells in
vitro and in vivo. Ubiquitous expres¬sion of IGF-II by cells that have not been
exposed to asbestos and the lack of IGF-II expression by asbestos-transformed
cells suggest that the mechanisms of changes in growth factor expression differ
in mesothe-lial cells transformed by different mechanisms (31). Similar results
were also observed in vitro with IGF-I in human mesothelial cells (32). It was
also shown that the existence of stimulatory effects of IGF-I on matrix
proteoglycan synthesis was mediated via receptor-growth factor complexes and the
protein tyrosine kinase intracellular pathway (33). The inhibitory effect of
IGF-1 receptor antisense transcripts on hamster mesothelioma has been
demonstrated by decreased growth and tu-morigenicity in vitro and in vivo. These
results may suggest interest¬ing implications for a therapy of the human
mesothelioma (34).

Vascular Endothelial Growth Factor

Vascular endothelial growth factor (VEGF) is a potent angiogenic pro¬tein with a
selective mitogenic effect on endothelial cells known to be involved in many
normal and pathologic processes.
Coexpression of VEGF and its receptors flt-1 and KDR has been re¬ported in
samples of mesothelioma, suggesting a potential autocrine loop for malignant
pleural mesothelioma cells (35). Malignant meso-thelioma cells produce
significantly higher VEGF levels than normal mesothelial cells, and this growth
factor is found at higher levels in the pleural effusions of MM patients than in
the effusions of patients with nonmalignant pleural disease. In addition, VEGF
induces increased proliferation of MMCs in a dose-dependent way, via activation
of its tyrosine kinase receptor, and can have an impact on patient survival, not
only by promoting angiogenesis but also by directly stimulating tumor growth
(36).
Simian virus 40 (SV40)–large-tumor antigen (Tag) expression potently increases
VEGF protein and mRNA levels in several human
mesothelial cell (HMC) lines and concomitant expression of SV40– small-tumor
antigen (tag) enhances Tag function, suggesting that VEGF regulation by SV40
transforming proteins can represent a key event in SV40 signaling relevant for
tumor progression (37,38). The closely related molecule, VEGF-C, is also
implicated in malignant mesothelioma growth; VEGF-C and its cognate receptor
VEGFR-3 are coexpressed in mesothelioma cell lines, and a functional VEGF-C
autocrine growth loop was demonstrated in mesothelioma cells (39). Moreover,
human MMCs, but not normal mesothelial cells, express a catalytically active
lipoxygenases (5-LO), a key regulator of MMC pro¬liferation and survival via a
VEGF-related circuit (40).
Angiogenesis is an important part of normal and pathologic pro¬cesses, including
tumor growth, metastasis, inflammation, and wound healing, and VEGF is the best
known angiogenic factor, implicated in tumor-associated microvascular
hyperpermeability and carcinogene-sis. An increased expression of VEGF was found
in biphasic and epithelioid mesotheliomas and malignant pleural effusions.
Vascular permeability was proportionally increased with VEGF levels in the
malignant pleural effusions (41).

Fibroblast Growth Factors 1 and 2

Acidic and basic fibroblast growth factors (FGF-1 and -2) are potent angiogenic
cytokines. These proteins are members of the fibroblast growth factor (FGF)
family, and FGF family members possess broad mitogenic and cell survival
activities and are involved in a variety of biologic processes, including
embryonic development, cell growth, morphogenesis, tissue repair, tumor growth,
and invasion. These pro¬teins function as modifiers of endothelial cell
migration and prolifera¬tion, as well as angiogenic factors. They act as
mitogens for a variety of mesoderm- and neuroectoderm-derived cells in vitro,
and thus are thought to be involved in organogenesis.
Their expression levels correlate significantly with a poor survival of MM
patients, supporting the assumption that selective angiogenic cytokines might
contribute to the progressive changes of mesothelioma by tumor angiogenesis
(42). The expression of angiogenic factors may represent useful markers for
diagnosis and prediction of disease outcome. Basic fibroblast growth factor
(bFGF) is a potent angiogenic factor that promotes in vitro growth of
endothelial cells and in vivo vessel formation. It displays stimulatory effects
for the synthesis of hyaluronan and proteoglycans, via protein tyrosine kinase
activity elicited by receptor-ligand complexes through an autocrine stimulatory
mechanism (11).

Hepatocyte Growth Factor

Hepatocyte growth factor (HGF), also known as scatter factor (SF), is a
multifunctional factor involved both in development and tissue
repair, as well as pathologic processes such as cancer and metastasis. It is a
dimer of an alpha chain and a beta chain linked by a disulfide bonds and
contains four kringle domains. It is a potent mitogen for mature parenchymal
hepatocyte cells, seems to be an hepatotrophic factor, and acts as growth factor
for a broad spectrum of tissues and cell types. It has no detectable protease
activity. It has been identified in vivo in many types of tumors together with
its tyrosine kinase recep¬tor, c-Met.
Hepatocyte growth factor and its receptor c-Met are often expressed by normal
human mesothelial cells and MMCs. Moreover, coexpres-sion of HGF and its
receptor was also observed in many samples of mesothelioma, suggesting that the
HGF/c-Met signaling system may play a role in the development of this tumor, by
either autocrine or paracrine mechanisms. In addition, c-Met expression was
found in cells obtained from pleural fluids of patients with mesothelioma (6).
In vitro HGF acts as a strong chemoattractant for human MMCs and stimulates
motility in all mesothelioma cell lines tested. Furthermore, HGF can stimulate
mesothelioma cell migration that can be blocked in the presence of neutralizing
anti-HGF monoclonal antibodies. Addition of HGF to mesothelioma cells cultured
on collagen type IV is associated with a change of morphology and induction of
bipolar shape and protrusion of prominent pseudopodia. Moreover, HGF is
mitogenic for mesothelioma cells, suggesting that expression of HGF/c-Met is
involved not only in mesothelioma progression but also in its growth (6). In
addition, the ability to secrete HGF/SF seems to be correlated with the
fibroblast-like morphology, and in general the biologic activity of this growth
factor is dependent on the cell phenotype, because HGF induces both
cell-spreading and prolifera¬tion in epithelioid cells but only stimulation of
cell motility in fibrob-lastoid cells (43). This growth factor also enhances
cell adhesion and invasion, as demonstrated by the HGF-induced synthesis of many
matrix metalloproteinases and serine proteases critical for tumor progression
(44). On the basis of the significantly higher microvessel density values of
malignant mesotheliomas overexpressing HGF/SF, it is absolutely possible that
HGF/SF also may be an additional rele¬vant factor in tumor angiogenesis in
malignant pleural mesotheliomas (45).
Interestingly, the urokinase-type plasminogen activator receptor (uPAR)
expression is induced by exposure to asbestos at the surface of rabbit and human
mesothelial cells, suggesting that altered expression of this receptor could be
involved in asbestos-induced remodeling of the pleural mesothelium, partially
due to the uPAR-dependent HGF activation (46). Finally, other findings suggest
that when SV40 infects HMCs, it causes Met activation via an autocrine loop,
replicates in HMCs, and infects other adjacent HMCs, inducing an HGF-dependent
Met activation, change of morphology, and increase of S-phase entry (Fig. 7.2).
This mechanism may explain how a limited number of SV40-positive cells may be
sufficient to direct noninfected HMCs toward malignant transformation (47).

Figure 7.2. Hepatocyte growth factor (HGF)/Met autocrine loop induces change of morphology (upper panel) and S-phase entry (lower panel) in SV40 human mesothelial cells.

References

1. Comoglio PM, Boccaccio C. Scatter factors and invasive growth. Semin Cancer
Biol 2001;11:153–165.
2. Owens MW, Milligan SA. Growth factor modulation of rat pleural mesothelial
cell mitogenesis and collagen synthesis. Effects of epidermal growth factor and
platelet-derived factor. Inflammation 1994;18:77–87.
3. Zanella CL, Posada J, Tritton TR, Mossman BT. Asbestos causes stimula¬tion of
the extracellular signal-regulated kinase 1 mitogen-activated protein kinase
cascade after phosphorylation of the epidermal growth factor recep¬tor. Cancer
Res 1996;56:5334–5338.
4. Goldberg JL, Zanella CL, Janssen YM, et al. Novel cell imaging techniques
show induction of apoptosis and proliferation in mesothelial cells by asbestos.
Am J Respir Cell Mol Biol 1997;17:265–271.
5. Gerwin BI, Lechner JF, Reddel RR, et al. Comparison of production of
trans¬forming growth factor-beta and platelet-derived growth factor by normal
human mesothelial cells and mesothelioma cell lines. Cancer Res 1987;
47:6180–6184.
6. Klominek J, Baskin B, Liu Z, Hauzenberger D. Hepatocyte growth factor/
scatter factor stimulates chemotaxis and growth of malignant mesothe-lioma cells
through c-met receptor. Int J Cancer 1998;76:240–249.
7. Adamson IY, Bakowska J. KGF and HGF are growth factors for mesothe-lial cells
in pleural lavage fluid after intratracheal asbestos. Exp Lung Res
2001;27:605–616.
8. Mroczkowski B, Reich M, Chen K, Bell GI, Cohen S. Recombinant human epidermal
growth factor precursor is a glycosylated membrane protein with biological
activity. Mol Cell Biol 1989;9:2771–2778.
9. Bermudez E, Everitt J, Walker C. Expression of growth factor and growth
factor receptor RNA in rat pleural mesothelial cells in culture. Exp Cell Res
1990;190:91–98.
10. Walker C, Everitt J, Ferriola PC, Stewart W, Mangum J, Bermudez E. Auto-crine
growth stimulation by transforming growth factor alpha in asbestos-transformed
rat mesothelial cells. Cancer Res 1995;55:530–536.
11. Tzanakakis GN, Hjerpe A, Karamanos NK. Proteoglycan synthesis induced by
transforming and basic fibroblast growth factors in human malignant mesothelioma
is mediated through specific receptors and the tyrosine kinase intracellular
pathway. Biochimie 1997;79:323–332.
12. Liu Z, Klominek J. Regulation of matrix metalloprotease activity in
malig¬nant mesothelioma cell lines by growth factors. Thorax 2003;58:198–203.
13. Marzo AL, Fitzpatrick DR, Robinson BW, Scott B. Antisense oligonu-cleotides
specific for transforming growth factor beta2 inhibit the growth of malignant
mesothelioma both in vitro and in vivo. Cancer Res 1997;57: 3200–3207.
14. Ikubo A, Morisaki T, Katano M, et al. A possible role of TGF-beta in the
formation of malignant effusions. Clin Immunol Immunopathol 1995;77: 27–32.
15. Lee YC, Lane KB. The many faces of transforming growth factor-beta in
pleural diseases. Curr Opin Pulmon Med 2001;7:173–179.
16. Gary Lee YC, Melkerneker D, Thompson PJ, Light RW, Lane KB. Trans¬forming
growth factor beta induces vascular endothelial growth factor elaboration from
pleural mesothelial cells in vivo and in vitro. Am J Respir Crit Care Med
2002;165:88–94.
17. Kuwahara M, Takeda M, Takeuchi Y, Harada T, Maita K. Transforming growth
factor beta production by spontaneous malignant mesothelioma cell lines derived
from Fischer 344 rats. Virchows Arch 2001;438:492–497.
18. Zhu Z, Yao J, Wang F, Xu Q. TNF-alpha and the phenotypic transforma¬tion of
human peritoneal mesothelial cell. Chin Med J (Engl) 2002;115: 513–517.
19. Owens MW, Grimes SR. Pleural mesothelial cell response to inflammation:
tumor necrosis factor-induced mitogenesis and collagen synthesis. Am J Physiol
1993;265:L382–388.
20. Heldin CH, Backstrom G, Ostman A, et al. Binding of different dimeric forms
of PDGF to human fibroblasts: evidence for two separate receptor types. EMBO J
1988;7:1387–1393.
21. Versnel MA, Hagemeijer A, Bouts MJ, van der Kwast TH, Hoogsteden HC.
Expression of c-sis (PDGF B-chain) and PDGF A-chain genes in ten human malignant
mesothelioma cell lines derived from primary and metastatic tumors. Oncogene
1988;2:601–605.
22. Ascoli V, Scalzo CC, Facciolo F, Nardi F. Platelet-derived growth factor
receptor immunoreactivity in mesothelioma and nonneoplastic mesothe-lial cells
in serous effusions. Acta Cytol 1995;39:613–622.
23. Ramael M, Buysse C, van den Bossche J, Segers K, van Marck E. Immunore-activity
for the beta chain of the platelet-derived growth factor receptor in malignant
mesothelioma and non-neoplastic mesothelium. J Pathol 1992; 167:1–4.
24. Langerak AW, van der Linden-van Beurden CA, Versnel MA. 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 1996;1305:63–70.
25. Langerak AW, Dirks RP, Versnel MA. Splicing of the
platelet-derived-growth-factor A-chain mRNA in human malignant mesothelioma cell
lines and regulation of its expression. Eur J Biochem 1992;208:589–596.
26. Metheny-Barlow LJ, Flynn B, van Gijssel HE, Marrogi A, Gerwin BI.
Para¬doxical effects of platelet-derived growth factor-A overexpression in malig-
nant mesothelioma. Antiproliferative effects in vitro and
tumorigenic stim¬ulation in vivo. Am J Respir Cell Mol Biol 2001;24:694–702.
27. Walker C, Bermudez E, Stewart W, Bonner J, Molloy CJ, Everitt J.
Charac¬terization of platelet-derived growth factor and platelet-derived growth
factor receptor expression in asbestos-induced rat mesothelioma. Cancer Res
1992;52:301–306.
28. Mutsaers SE, McAnulty RJ, Laurent GJ, Versnel MA, Whitaker D, Papadimitriou
JM. Cytokine regulation of mesothelial cell proliferation in vitro and in vivo.
Eur J Cell Biol 1997;72:24–29.
29. Asplund T, Versnel MA, Laurent TC, Heldin P. Human mesothelioma cells
produce factors that stimulate the production of hyaluronan by mesothe-lial
cells and fibroblasts. Cancer Res 1993;53:388–392.
30. Klominek J, Baskin B, Hauzenberger D. Platelet-derived growth factor (PDGF)
BB acts as a chemoattractant for human malignant mesothelioma cells via PDGF
receptor beta-integrin alpha3beta1 interaction. Clin Exp Metastasis
1998;16:529–539.
31. Rutten AA, Bermudez E, Stewart W, Everitt JI, Walker CL. Expression of
insulin-like growth factor II in spontaneously immortalized rat mesothe-lial and
spontaneous mesothelioma cells: a potential autocrine role of insulin-like
growth factor II. Cancer Res 1995;55:3634–3639.
32. Lee TC, Zhang Y, Aston C, et al. Normal human mesothelial cells and
mesothelioma cell lines express insulin-like growth factor I and associated
molecules. Cancer Res 1993;53:2858–2864.
33. Syrokou A, Tzanakakis GN, Hjerpe A, Karamanos NK. Proteoglycans in human
malignant mesothelioma. Stimulation of their synthesis induced by epidermal,
insulin and platelet-derived growth factors involves receptors with tyrosine
kinase activity. Biochimie 1999;81:733–744.
34. Pass HI, Mew DJ, Carbone M, Donington JS, Baserga R, Steinberg SM. The
effect of an antisense expression plasmid to the IGF-1 receptor on hamster
mesothelioma proliferation. Dev Biol Stand 1998;94:321–328.
35. Konig J, Tolnay E, Wiethege T, Muller K. Co-expression of vascular
endothelial growth factor and its receptor flt-1 in malignant pleural
mesothelioma. Respiration 2000;67:36–40.
36. Strizzi L, Catalano A, Vianale G, et al. Vascular endothelial growth factor
is an autocrine growth factor in human malignant mesothelioma. J Pathol
2001;193:468–475.
37. Cacciotti P, Strizzi L, Vianale G, et al. The presence of simian-virus 40
sequences in mesothelioma and mesothelial cells is associated with high levels
of vascular endothelial growth factor. Am J Respir Cell Mol Biol 2002;
26:189–193.
38. Catalano A, Romano M, Martinotti S, Procopio A. 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
2002;21:2896–2900.
39. Masood R, Kundra A, Zhu S, Xia G, Scalia P, Smith DL, Gill PS. Malignant
mesothelioma growth inhibition by agents that target the VEGF and VEGF-C
autocrine loops. Int J Cancer 2003;104:603–610.
40. Romano M, Catalano A, Nutini M, et al. 5-lipoxygenase regulates malig¬nant
mesothelial cell survival: involvement of vascular endothelial growth factor.
FASEB J 2001;15:2326–2336.
41. Zebrowski BK, Yano S, Liu W, et al. Vascular endothelial growth factor
levels and induction of permeability in malignant pleural effusions. Clin Cancer
Res 1999;5:3364–3368.
42. Kumar-Singh S, Weyler J, Martin MJ, Vermeulen PB, Van Marck E. Angio-genic
cytokines in mesothelioma: a study of VEGF, FGF-1 and -2, and TGF beta
expression. J Pathol 1999;189:72–78.
43. Harvey P, Warn A, Dobbin S, et al. Expression of HGF/SF in mesothelioma cell
lines and its effects on cell motility, proliferation and morphology. Br J
Cancer 1998;77:1052–1059.
44. Harvey P, Clark IM, Jaurand MC, Warn RM, Edwards DR. Hepatocyte growth
factor/scatter factor enhances the invasion of mesothelioma cell lines and the
expression of matrix metalloproteinases. Br J Cancer 2000;83: 1147–1153.
45. Tolnay E, Kuhnen C, Wiethege T, Konig JE, Voss B, Muller KM. Hepato-cyte
growth factor/scatter factor and its receptor c-Met are overexpressed and
associated with an increased microvessel density in malignant pleural
mesothelioma. J Cancer Res Clin Oncol 1998;124:291–296.
46. Perkins RC, Broaddus VC, Shetty S, Hamilton S, Idell S. Asbestos
upregu-lates expression of the urokinase-type plasminogen activator receptor on
mesothelial cells. Am J Respir Cell Mol Biol 1999;21:637–646.
47. Cacciotti P, Libener R, Betta P, et al. SV40 replication in human
mesothelial cells induces HGF/Met receptor activation: a model for viral-related
car-cinogenesis of human malignant mesothelioma. Proc Natl Acad Sci USA
2001;98:12032–12037.