mesothelioma cancer

Malignant mesotheliomas are highly aggressive diffuse tumors aris¬ing from
mesothelial-lined surfaces. Mesotheliomas spread along mesothelial-lined
surfaces to involve the pericardium, contralateral hemithorax, and peritoneal
cavity by invasion through the diaphragm. The resulting tumor often forms
diffuse thickening of involved surfaces rather than solitary rounded lesions as
seen in other neoplasms (1,2). Malignant mesotheliomas also invade the
underlying basement mem¬brane and produce metastases in up to 80% of patients
(3–5). Invasion through needle biopsy tracts and incision in the thoracic wall
is a common feature in malignant mesotheliomas (6,7). During this process
mesothelioma cells must interact with extracellular matrix proteins, growth
factors embedded in it, and stromal cells, which participate in synthesis and
modifications of this microenvironment. Today, the cen¬tral theme of research
about tumor etiology, progression, and metasta¬sis focuses more on the crosstalk
between tumor cells, extracellular matrix, and a variety of host cells rather
than the behavior of individ¬ual tumor cells taken out of their
microenvironmental context (8).

This chapter summarizes evidence describing various aspects of mesothelioma
interactions with different components of the extracel¬lular matrix, and the
possible role of these interactions in the invasive behavior of this tumor.

Extracellular Matrix

Extracellular matrix (ECM) can be defined as a complex mixture of proteins,
proteoglycans, and adhesive glycoproteins that provides structural and
mechanical support to cells and tissues (9,10). Moreover, it is a reservoir of
active and latent growth factors (11,12). The compo¬nents of the ECM act in
concert with growth factors and other cells and molecules present in it, to
regulate a wide variety of cellular processes both in health and disease.

The ECM appears during evolution with the onset of multicellular life (13).
Depending on the tissue environment, the cells interacting with the ECM respond
through appropriate matrix receptors by chang¬ing gene expression and
differentiation (14). Other cellular events affected by cell–matrix interactions
include cell growth, cell death, adhesion, migration, and invasion. In turn,
these cell–matrix interac¬tions regulate physiologic processes such as embryonic
development, tissue morphogenesis, and angiogenesis (14,15).

Under normal physiologic conditions, ECM units called basement membrane (16) and
underlying tissue stroma maintain highly ordered and complex tissue architecture
(17). Thus, these matrix boundaries delineate tissues and suppress inappropriate
mixing of cells. During dynamic phases such as morphogenesis and wound healing,
mainte¬nance of tissue architecture is governed through signaling by soluble and
solid-phase molecules of the ECM as well as by cell–cell commu¬nication (18,19).
In malignancy there is an imbalance in these signals leading to violation of
normal tissue boundaries (20). With acquisition of malignant phenotype, sooner
or later, altered cell–ECM and cell–cell signals lead to release of normal
constraints, enabling some malignant cells to migrate out of their original site
and invade adjacent tissues (21,22). Today we have abundant evidence showing
that ECM should no longer be considered as a reactive component without major
bio¬logic significance but rather an active player in tumor development,
invasion, and metastasis.

Basement Membrane and Stroma Composition

Basement membrane is a dense matrix of collagen and glycoproteins such as
fibronectin, laminin, and proteoglycans (23). Its primary role is physical cell
support, control of cell polarity, and differentiation. Basement membranes, with
few exceptions, do not contain any pores large enough to allow cell
transmigration. It follows, then that invasion of the basement membrane is an
active process.

Basement membrane is normally produced and deposited by epithe¬lial,
endothelial, or mesothelial cells, which then remain in close contact with its
components (17). These contacts are mediated by integrin and nonintegrin
receptors that recognize glycoproteins such as fibronectin, laminin, and
collagen type IV (24–28).

Interstitial stroma is composed of various components of the ECM and stromal
cells. Solid-phase and soluble components of stroma include glycoproteins,
collagens, glycosaminoglycans, and elastin (17,29,30). The predominant cell of
the stroma is fibroblast, which is responsible for the production of different
collagens, proteolytic enzymes and their inhibitors, as well as growth factors.
Other cells represented in the stromal compartment include myofibroblasts,
immune cells such as lym¬phocytes and dendritic cells, and inflammatory cells
such as monocytes, granulocytes, and vascular cells (31).

Extracellular matrix composition varies somewhat between different organs.
Depending on the specific tissues and organs, appropriate cells

deposit matrix proteins that support specialized physiologic functions. Under
normal conditions ECM is not permeable for cell movement. However, during wound
healing, angiogenesis, inflammation, or tumor cell invasion, ECM undergoes
enzymatic degradation and remodeling, allowing appropriate cells to transmigrate
(32). Migration occurs along different components of the ECM in concert with
growth factors or motility factors (33–36).

Basement Membrane and Stroma in Normal Mesothelium and Mesotheliomas

Composition and function of the pleura and peritoneum have been studied in
different animals and humans. Key features such as pres¬ence of single cell
layer basement membrane and underlying stroma are a constant finding between
species (37–42). Normal mesothelium of pleura or the abdominal cavity is a
single layer of distinctly polar¬ized mesothelial cells that rests on a
continuous basement membrane (Fig. 11.1). Besides providing mechanical support
and controlling architectural arrangement of these cells, basement membrane is
also involved in modulation of permeability characteristics of the pleura and
peritoneum (43–45).

In early quantitative studies of pleural ECM, collagens as a group and
particularly, collagen type I, were described to compose a major portion of the
pleural connective tissue (46–48). Subsequent studies allowed more precise
identification of individual collagen types and other ECM components of the
basement membrane.

Collagens

The collagens are a family of at least 20 different molecules character¬ized by
common structural features (49). These include a triple helical region,
nonhelical regions, and globular domains. Collagens provide mechanical stability
and strength, interacting with one another or with other ECM components.
Fibrillar collagen types I, II, III, V, and XI are predominant components of
stroma. Collagen types IV, VI, VIII, and

X do not form fibrils but are cross-linked into a three-dimensional network
(50).

Normal mesothelium rests on a basement membrane that contains collagen types I,
III, and IV (40,51). Studies of paraffin-embedded tis¬sues from normal adults
and adults with active pleuritis showed that areas of mesothelial cell injury
were associated with loss of the sub-mesothelial basement membrane and that
mesothelial cells play an active role in production of ECMs during healing of
pleural injury (42).

The presence of collagen in malignant mesotheliomas has been noted by light
(1,52,53), and electron microscopy (54,55). Large amounts of collagenous matrix
were particularly prominent in the desmoplastic variant of malignant
mesothelioma (56,57). Besides demonstration of tumor cells and tumor cell
invasion, the presence of collagenous matrix is a key diagnostic feature of
desmoplastic tumors (58,59), including malignant mesothelioma (60). Collagenous
matrix is also present in the sarcomatous and epithelial types of mesothelioma
(Fig. 11.2) (60).

These early light and electron microscopic findings have later been corroborated
using immunohistochemical methods. Using polyclonal anticollagen type I and type
IV antibodies, both types of collagen have been demonstrated in clinical
specimens of malignant mesothelioma (61,62). The data from these studies
indicated that malignant mesothe-liomas have the ability to synthesize basement
membrane components such as collagen type IV (3,62). Using monoclonal antibodies
to colla-

gen type IV, Di Muzio et al (63) demonstrated the presence of this mol¬ecule
around individual mesothelioma cells of epithelial subtype. This feature
distinguished epithelial mesotheliomas from peripheral lung adenocarcinomas.
Additional data confirming collagen synthesis were obtained from studies of
malignant mesotheliomas in culture. In these studies, light microscopic,
chemical, and immunohistochemical methods were used to demonstrate production of
collagens in malig¬nant mesotheliomas (64–67).

Collagens and other components of the ECM act in concert with growth factors and
motility factors during tumor cell invasion and metastasis (32,33,36). Growth
factors with motility-inducing properties such as hepatocyte growth factor
(HGF), have been shown to stimulate chemotaxis, chemokinesis, and invasiveness
in malignant mesothe-lioma cell lines in the presence of matrix proteins
(66,68). Malignant mesotheliomas synthesize and secrete ECM proteins and growth
factors such as HGF (66,69,70). The same cells also express appropriate
receptors for these molecules (70,71) and migrate to these self-secreted matrix
proteins and growth factors. Taken together, the findings indicate a possible
autocrine motility-stimulating loop in malignant mesotheliomas. Accordingly,
these in vitro properties of malignant mesothelioma cells may provide some clues
to the highly motile, inva¬sive characteristics of this tumor in vivo (66,70).

Fibronectin

Fibronectin is a multifunctional glycoprotein that is found in two dif¬ferent
forms: soluble, found in body fluids, and solid, found in loose connective
tissue and most basement membranes. In vivo, physiologic sources of fibronectin
are hepatocytes that produce soluble forms and fibroblasts, and endothelial
cells (and many others) that synthesize solid forms of this molecule (72–74).
Fibronectin acts through several distinct domains that promote cell adhesion,
cell migration, and matrix assembly. In addition, fibronectin is an essential
component mediating cell–collagen interactions. The interactions among collagen,
proteogly-cans, and fibronectin are important in matrix assembly and in
devel¬opment of the structural organization of the ECM (75,76). In tumors,
fibronectin often accumulates in the stroma (77,78). Interestingly, at the
invasive edge of mammary carcinomas, fibronectin is lost in a major¬ity of cases
(79).

Cultured normal mesothelial cells and their malignant counterparts synthesize
and secrete fibronectin in vitro (66,67,80,81). In addition, normal and
malignant mesothelial cells have the ability to assemble fibronectin into
homogeneous fibrillar arrays of organized matrix, located primarily between the
cells (66,82). Evidence from other tumors, such as synovial sarcoma, indicates
that these tumors have the ability to produce and secrete fibronectin in vivo
(58). However, in patients with mesothelioma, fibronectin has been identified
only in pleural fluids (83).

Experiments with malignant mesothelioma cell lines indicate that these cells
adhere, spread, and migrate in response to both soluble

and solid forms of fibronectin (66,67,71). In analogy to collagens and laminin,
the presence of fibronectin is an absolute requirement for growth factor–induced
migration of both normal and malignant mesothelial cells (84,85).

Laminin

Laminins are major components of basement membranes mediating a variety of
functions such as cell adhesion, cell migration, neurite out¬growth, cellular
proliferation, and basement membrane assembly (86). Laminin was first isolated
from the matrix of mouse EHS tumor (87) and is now known to consist of a family
of proteins that is composed of variably expressed chains that generate several
different isoforms that vary in size, composition, and structure (88). Laminins
are pro¬duced by a large variety of cells (9). Together with collagen type I V,
laminin forms the structural framework of basement membrane, where it is
responsible for induction of epithelial cell differentiation and estab¬lishment
of cell polarity (89). In malignancy, laminin has been sug-gested to mediate
adhesion of tumor cells to the basement membrane prior to invasion (90). In
experimental models, adhesion to laminin plays a role in cell attachment, cell
migration, and hematogenous metastasis (21,91,92).

Normal and malignant mesothelial cells synthesize and secrete laminins in vitro
and in vivo (62,66,67,80). In histologic sections of malignant mesotheliomas,
laminin staining was primarily located in the cytoplasm, but in some areas
laminin was also demonstrated extra-cellularly. However, demonstration of
laminin immunoreactivity in mesotheliomas has no diagnostic or prognostic value
(62). Laminin production by primary breast carcinomas was also investigated
using immunohistochemistry on archival specimens from a retrospective series
with long-term follow-up. Laminin production was found to be independent of the
clinical and pathologic variables analyzed (93).

In malignant mesotheliomas in cell culture, laminin induced cell adhesion,
spreading, and chemotactic and haptotactic migration, indicating its role in
tumor cell invasion (66,67,71).

Thrombospondin

Thrombospondins (TSPs) are a family of secreted, modular glycopro-teins whose
functions are not well understood. Unlike the various structural proteins of the
ECM, TSPs do not appear to contribute directly to the integrity of a physical
entity, such as a fiber or a base¬ment membrane (94). Rather, it seems that
these proteins act contextu-ally to influence cell function by modulating
cell–matrix interactions (95).

The role of thrombospondin-1 was investigated in relation to prognosis in
surgically resected malignant pleural mesothelioma. Expression of thrombospondin
messenger RNA (mRNA) has been demonstrated both in normal pleural tissue and
normal lung tissue. Significantly higher expression was found in a majority of
resected malignant mesotheliomas (96). These results were consistent with pre-

vious data gathered from investigations of other tumors (97). Although
thrombospondin-1 was overexpressed in the majority of mesothe-liomas, the level
of expression had little prognostic value (96).

Elastin

Elastin, a cross-linked protein of the ECM, is the major component of several
elastic tissues such as lung, blood vessels, and skin (98). Elastin as part of
ECM was shown to mediate cell adhesion of monocytes, fibroblasts, and tumor
cells (99). Elastin-derived peptides, especially a hexapeptide, VGVAPG, is
chemotactic for several types of cells such as monocytes and fibroblasts and for
certain tumor cells (100). Elastin pro¬duction has been demonstrated in normal
mesothelial cells in culture (80) but not in malignant mesotheliomas. However, a
67-kd elastin/ laminin receptor has been identified in human malignant
mesothe-liomas by immunohistochemistry (62). Interestingly, experimental
evi¬dence from other tumors links a 67-kd elastin/laminin receptor to invasion
and metastasis formation and poor prognosis in breast cancer patients
(27,32,101).

Glycosaminoglycans and Proteoglycans

Glycosaminoglycans (GAGs) are linear polysaccharides consisting of repeating
disaccharide units. They include heparan sulfate, chondroitin sulfate, dermatan
sulfate, keratan sulfate, and hyaluronic acid (HA) (17,102,103).

Among GAGs, hyaluronic acid is the molecule that has been most extensively
studied. It has been proposed to have functional impor¬tance in processes such
as embryogenesis, angiogenesis, cell growth and migration, wound healing, and
the formation of high molecular mass aggregates with various proteoglycans
(103,104). Its role in malig¬nancy is at least threefold: it functions as a
template for assembly of other pericellular macromolecules, it interacts
directly with cell sur¬face receptors that transduce intracellular signals, and
it promotes anchorage-independent growth and invasiveness (105).

Mayer and Chaffee (106) had observed the association between hyaluronic acid and
malignant mesothelioma as early as 1939. Since then a large number of studies
have investigated the functional and diagnostic importance of HA in this tumor
(107–112). These and other studies not mentioned in this chapter, frequently
identify elevated HA levels in pleural effusions or serum of patients with
malignant mesothelioma. High levels of HA in pleural effusions appear to be
related to the epithelial differentiation of malignant mesothelioma, whereas low
or “normal” levels of HA are found more frequently in fibrous mesotheliomas
(113). Elevated HA can also be found in pleural effusions of patients with
rheumatoid arthritis and other inflammatory conditions, adding to the
controversy surrounding the clinical useful¬ness of this test in mesothelioma
and limiting its wide acceptance (114). The source of HA in patients with
malignant mesothelioma has also been subject to controversy. Microscopic
examination of mesothelioma biopsies often reveals the presence of
noncollagenous matrix sur-

rounding mesothelioma cells (60,109). Hyaluronic acid was also demonstrated on
human malignant mesothelioma cells growing in nude mice xenografts (54).
However, in 1993 Asplund et al (115) pro¬posed that normal human mesothelial
cells rather than their malignant counterparts were the source of HA in
malignant mesothelioma, and that secretion of HA into pleural fluids was induced
by growth factors.

Hyaluronic acid synthases (HAS) are enzymes responsible for syn¬thesis of HA in
plasma membrane. Using reverse-transcription poly-merase chain reaction
(RT-PCR), HAS1 was identified in malignant mesothelioma of the epithelial
subtype (115). In addition, increasing concentrations of newly synthesized HA,
chondroitin sulfate, and heparan sulfate was demonstrated in cultured malignant
mesothe-lioma cells (117,118). Addition of growth factors such as
platelet-derived growth factor BB (PDGF-BB) to malignant mesothelioma culture
medium led to a 10-fold increase of HA synthesis (118). Taken together, these
data show that at least some malignant mesotheliomas synthesize HA and other
glycosaminoglycans. Recent data indicate that HA contributes also to malignant
phenotype in malignant meso-thelioma, as it has the capacity to stimulate
proliferation and migration through interaction with HA receptor CD44 (119).

The proteoglycan family of ECM and cell surface molecules contains more than 30
molecules that perform a variety of different functions in the ECM.
Proteoglycans act as tissue organizers, influence cell growth and the maturation
of specialized tissues, play a role as biologic filters, modulate growth factor
activities, regulate collagen fibrillogenesis and skin tensile strength, affect
tumor cell growth and invasion, and influ¬ence corneal transparency and neurite
outgrowth (120).

The term proteoglycan refers to its molecular structure, consisting of a protein
core to which glycosaminoglycan side chains are attached. Functional
characterization of proteoglycans reflects the location of the molecule, whether
mainly found in association with the cell surface or the ECM (120).

Syndecans are a cell-associated proteoglycans that interact with growth factors,
ECM components, enzymes, protease inhibitors, and chemokines. In malignant
mesotheliomas, syndecan-1 expression was demonstrated in epithelial subtype and
epithelial components in biphasic form. In the sarcomatous type of mesothelioma,
expression of syndecan-1 was weak or absent, indicating that this molecule is
related to differentiation of mesotheliomas (116,121).

Integrins

The integrins are a large family of membrane glycoproteins consist¬ing of an a
and b subunit, where a single b subunit is noncovalently associated with one of
several possible a subunits (122). Integrins mediate cell–matrix and cell–cell
adhesion, a function that has been implicated in processes like development, the
immune response, hemostasis, and maintenance of tissue architecture (26,123).
Integrins also participate in a number of pathologic conditions, such as
inflam¬mation, tumor cell invasion, and metastasis (25). At present there are

at least 24 ab heterodimers formed of nine different b subunits and 18 a
subunits.

Integrin ECM ligands include a variety of molecules such as colla¬gen type I and
IV, laminin, fibronectin, vitronectin, von Willebrand’s factor, and
thrombospondin (26). Integrins also have a signaling func¬tion where signals can
be transduced in both directions, so-called inside-out and outside-in signaling
(124). Malignant cells often have abnormal integrin function (124). Tumor cells
generally show decreased integrin function, which occurs either because the
cells have fewer integrins as a result of dedifferentiation, or because integrin
function is suppressed through oncogenic transformation (125). In carcinomas,
there is a shift in integrin expression from those that favor the ECM present in
normal epithelium to other integrins (e.g., a3b1 and avb3) that preferentially
bind the degraded stromal components produced by matrix proteases (126,127).

Normal human mesothelial cells and malignant mesothelioma cells express a rather
homogeneous pattern of a and b integrin subunits (Table 11.1) (71). Notably,
high levels of a3b1 integrin are consistently expressed in both normal and
malignant mesothelial cells (71,128,129), whereas expression of classic
lymphocyte fibronectin receptor is generally absent or very low (71,128,130).
Vitronectin receptors avb3 and avb5 are also a constant feature of both normal
and malignant mesothelial cells. Vitronectin is a multifunctional adhesive
protein present in large concentrations in serum. In addition, vitronectin
dif-fuses into ECM, where it may bind and become concentrated as com¬pared with
other serum proteins (131), and may also be found in pleural and bronchoalveolar
lavage fluid (132). Experimental evidence indicates that normal mesothelial
cells recognize and internalize vitronectin-coated asbestos fibers via avb5
integrin (132). Thus, this finding provides clues to how integrins participate
in asbestos-induced biologic effects.

In malignant mesotheliomas, integrins appear to have two distinct functions:
they mediate cell attachment to ECM, and cell migration (71,130). Experiments
with antiintegrin antibodies revealed that prein-cubation of mesothelioma cells
with antibodies to b1, a2, a5, and a6 sub-units inhibited both cell attachment
and cell migration to fibronectin, laminin, and collagen type IV. Interestingly,
in some mesothelioma cell lines preincubation of cells with a3 antibodies
inhibited cell migration, without any effect on cell attachment (71). These
observations confirm an important role of integrins in attachment and migration
of tumor cells and may contribute to our understanding of the highly motile,
invasive behavior of malignant mesotheliomas.

Crosstalk between integrins and growth factor receptors is an impor¬tant
mechanism during normal development and pathologic processes (133). In malignant
mesothelioma cells crosstalk between a3 integrin and PDGF receptor b is a
prerequisite for PDGF-BB–induced chemo-taxis (34). In vivo, PDGF is synthesized
and released by several stromal cell types during wound healing (134). The PDGF
produced around damaged tissue could attract certain mesothelioma cells to
invade biopsy tracts and incisions as often seen in patients with malignant

mesotheliomas (135). We hypothesize that inhibition of PDGF-induced cell
migration using novel small molecular drugs could contribute to the reduction of
mesothelioma cell invasion into needle biopsy tracts and incisions.

Matrix Metalloproteases

Degradation of and migration through ECM barriers, such as basement membrane and
stroma, is a complex process that requires the produc¬tion, release, and
activation of extracellular degrading enzymes (20). Inappropriate overexpression
of one or more of these enzymes has been shown to occur in almost all cells of
the tumor–host microenvironment, for example, tumor cells, fibroblasts, and
recruited macrophages (136). Remodeling of the ECM is confined to the immediate
pericellular envi¬ronment of the cell and is not solely dependent on the amount
of pro-teolytic enzymes present but on the balance of activated proteases and
their naturally occurring inhibitors (137).

Matrix metalloproteases (MMPs) are a family of zinc atom-dependent
endopeptidases with specific and selective activities against many components of
ECM. This family currently consists of at least 20 members, and most of them are
secreted as zymogens that must be activated extracellularly (20).

The expression of MMPs in human tumors is the result of a complex interaction
between tumor cells and stromal host cells (e.g., fibroblasts, endothelial
cells, and inflammatory cells), which all actively participate in the production
of these enzymes (138). The proteolytic remodeling of the ECM by MMPs does more
than allow tumor cells to locally invade and form metastases. Another major
consequence of matrix degradation by MMPs is the release of ECM-sequestered
growth factors, several of which play an important role in tumor cell survival
and proliferation, as well as angiogenesis (139). Importantly, similar
mechanisms are shared by physiologic and tumorigenic invasion. The difference
between them is that physiologic invasion is regulated, whereas tumorigenic
invasion appears to be perpetual (140).

Normal human pleural and peritoneal mesothelial cells secrete MMP-2 and MMP-9
and the counterregulatory tissue inhibitors of me-talloproteases (TIMP).
Secretion of these enzymes is probably involved in ECM turnover following
serosal injury (141).

Malignant mesotheliomas in culture produce several proteases belonging to the
MMP family of enzymes. These include MMPs 1, 2, 3, 7, 9, 10, membrane-bound
MT1-MMP, and TIMP 1, 2, and 3 (68,142,143). Production of these enzymes was
regulated by growth factors such as HGF, epidermal growth factor (EGF),
transforming growth factor-a, b-cellulin, heparin-binding EGF, amphiregulin,
insulin-like growth factor I, and acidic and basic fibroblast growth factors
(68,142–144). Interestingly, several of these growth factors also stimulate
migration of malignant mesothelioma cells (Fig. 11.3) (70,144,145).

In addition to the known MMPs, malignant mesothelioma cells secrete not yet
characterized enzymes that specifically degrade fi-

bronectin, vitronectin, and laminin but not collagen (142). While these results
do not provide specific answers to how these enzymes partici¬pate in matrix
remodeling in vivo, it is apparent that mesotheliomas produce a wide array of
matrix-degrading proteases that may con¬tribute to highly invasive behavior of
this tumor.

Conclusion

Malignant mesotheliomas synthesize, secrete, and assemble a wide array of matrix
proteins. They also express receptors that bind these matrices and secrete
enzymes that have the capacity to degrade ECM components alone or in
collaboration with host cells. New knowledge of interactions between
mesothelioma cells and their microenvironment creates new possibilities, which
will allow us to better understand the etiology, progression, and spreading of
this tumor. These new insights that are emerging within the field of tumor
biology and mesothelioma research will help us to generate new questions and
ideas that in the near future will translate into diagnostic and therapeutic
modalities. Here are some examples: one of the longstanding questions in
mesothe-lioma research is the cellular origin of this tumor. Are mesothelial or
submesothelial cells responsible? Perhaps we should rephrase the ques¬tion and
ask how mesothelial cells interact with submesothelial cell

populations and its surrounding matrix to give rise to mesothelioma. Erlotinib
(Tarceva), Gefitinib (Iressa), and Imatinib (Gleevec) are new small-molecule
drugs that target receptor tyrosine kinases (EGF recep¬tor, c-kit, and PDGF
receptor) expressed often on mesothelioma cells. Interestingly, these drugs not
only are cytostatic but also act in the mesothelioma microenvironment by
inhibiting cell migration and MMP production (146). In the near future, results
of clinical trials with these drugs will be available. Other drugs that act in
the mesothelioma microenvironment are MMP inhibitors. Despite initial
disappointments in clinical trials, MMP inhibitors may have a role in treatment
and pre¬vention of invasion and metastases (147). Finally, cDNA microarray
studies of malignant mesotheliomas reveal distinct genes that may support
development of new diagnostic tools for mesothelioma or become potential drug
targets for treatment of this tumor.

Acknowledgments

This work was supported by research grants from the Swedish Heart and Lung
Foundation. We also thank Drs. Anders Hjerpe and Arrigo Capitanio for providing
photographs of normal mesothelium and malignant mesothelioma.

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