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).

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Although there is a considerable body of published literature concern¬ing the
putative role of immune status in the pathogenesis and pro¬gression of common
malignancies such as lung and breast cancers, this area of research previously
had been relatively neglected with respect to malignant mesothelioma, a
comparatively uncommon tumor. Over the past decade, however, the development of
animal mesothelioma models and the widespread availability of mesothelioma cell
lines to researchers has focused increasing interest in this area. Furthermore,
occupational and environmental asbestos exposure hitherto had been regarded as
the most important global causes of mesothelioma and, since inhaled asbestos
fibers have been shown to suppress innate cel¬lular immunity, studies of
asbestos-exposed individuals and of ex-perimental asbestos exposure have
provided valuable insight into how altered immune status may allow mesothelial
tumors to escape immune surveillance. It is also conceivable that variability in
host immune status, coupled with individual differences in genetic
suscep¬tibility to mesothelioma among similarly exposed subjects (1,2), may
account for the considerable variation in incidence of mesothelioma in different
exposure settings, which can span two orders of magnitude (3–5). Given the now
well-recognized association of simian virus 40 (SV40) with malignant
mesothelioma (6), opportunities now exist to study the immune status and to
develop vaccination protocols of seropositive subjects at risk.

Innate Immunity Against Mesothelioma Cells

Non–major histocompatibility complex (MHC)-restricted cytotoxic lym-phocytes
have the capacity to lyse tumor cell targets of various origins and comprise
natural killer (NK) cells, NK T cells, and gd T cells (7). All are derived from
a common lymphoid precursor but differentiate along separate pathways. Whereas
NK cells are CD56+ but lack the CD3 and T-cell receptor markers, NK T cells and
gd T cells coexpress CD3 as well as differing forms of the T-cell receptor.
Unlike conventional T cells,

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Malignant mesothelioma (MM) is a primary tumor of the pleura and
peritoneum. Malignant mesotheliomas that are limited to other organs are
extremely rare, though several cases of pericardial MM have been reported (1). A
unique feature of MM is its strong relationship with asbestos exposure (2,3),
which has recently led to great public concern in view of the ubiquitous
presence of that mineral. Insulation, construction, shipyard industries, and
automobile brakes are among the many sources of occupational exposure (4).
Exposure can be not only occupational but also environmental, or even familial
by household contamination (5).

The mechanisms of MM pathogenesis have not been fully elucidated. Asbestos
fibers could work their way through the lung tissues to damage pleura and
produce adhesions and plaques. Changes observed in target tissues exposed to
asbestos include hyperplasia, metaplasia, DNA synthesis, and increased
production of oxygen free radicals. Acti¬vation of diacylglycerol, protein
kinase C, and ornithine decarboxylase also has been reported in a pathway
similar to classic tumor promot¬ers, such as phorbol esters (6–8). Moreover,
crocidolite fibers, which are the major tumorigenic asbestos fibers, induce
angiogenesis in the peri¬toneal lining of MM animal models (9). Thus, ingrowth
of new blood vessels around clusters of asbestos fibers may also facilitate the
later emergence of MM at these sites.

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Malignant mesothelioma is a disease strongly associated with carcino¬gen
exposure (1). As has been observed in a wide variety of other
carcinogen-associated solid cancers, mesothelioma tumors accumulate a spectrum
of acquired genetic lesions during the molecular patho-genesis leading to overt
cancer. Perhaps reflecting the unique history of carcinogen exposure routinely
seen in mesothelioma, many of the well-characterized mutations found in other
cancers such as p53 and ras family alterations are not a common feature in
malignant mesothe-lioma (1). Nonetheless, a variety of well-defined molecular
abnormal¬ities have been identified in the majority of cases of mesothelioma. As
has often been the case in cancer genetics, the first information regard¬ing
genetic alterations in mesothelioma came from tumor karyotypic or family
studies.

Although generally observed to be a disease strongly associated with asbestos
exposure, familial clustering of mesothelioma independent of asbestos exposure
has been reported (2–6). Epidemiologic data suggest that there may be a possible
familial predisposition to mesothelioma, but the molecular basis for this
remains unclear (7). Examples of chro¬mosome 9p or 22 abnormalities have been
reported in single cases or families with early-onset mesothelioma, but
observations such as these have occurred infrequently and largely have confirmed
known genetic loci that are involved in mesothelioma pathogenesis (2,6). The
lack of a heritable model of mesothelioma, such as defined in breast cancer or
colon cancer, has concentrated studies on the genetics of asbestos-induced
mesothelioma. In these more common cases of sporadic mesothelioma with no
obvious familial clustering or early onset, both of which are ultimately rare in
mesothelioma, the most frequent cyto-genetic abnormality in tumors reported has
been the loss of chromo¬some 22 (8). As will be seen, this marks one of the most
common somatic genetic targets, NF2, identified to date in mesothelioma. Other
frequently observed karyotypic abnormalities include loss of the short arm (p)
of chromosomes 1, 3, and 9 (8–10). Again, one of these recur¬ring molecular
lesions, loss of the 9p21 locus, has been correlated with corresponding loss of
multiple well-characterized tumor suppressor
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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

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Pleural malignant mesotheliomas (MMs) are aggressive tumors that generally
affect individuals older than 50 years of age and occur more frequently in men
than in women (1). They are derived from mesothe-lial cells lining the pleural,
pericardial, and peritoneal cavities. Approx¬imately 3000 patients are diagnosed
with MM in the United States each year. Its frequency is increasing worldwide,
and this trend is expected to continue until the year 2020 (2). The increasing
incidence of MM over the past 40 years is a reflection of exposure to asbestos
fibers in industrialized countries, particularly in connection with the mining
and shipyard industries (2). Epidemiologic studies have established that
exposure to asbestos fibers is associated with about 80% of the cases (3);
however, recent studies have implicated simian virus 40 (SV40) in the etiology
of some MMs (reviewed in refs. 4–6).

Malignant mesothelioma is characterized by a long latency of 20 to 40 years
between exposure to asbestos and tumor development, indicating that multiple
somatic genetic alterations may be required for tumori-genic conversion of a
normal mesothelial cell. Early evidence to support this idea was provided by
karyotypic analyses, which revealed multiple cytogenetic alterations in most
human MMs (reviewed in ref. 7). Specific chromosomal changes are not shared by
all MMs; however, several prominent sites of chromosomal loss have been
identified in this malig¬nancy. Tumor suppressor genes (TSGs) located in these
deleted chromo¬somal regions may be responsible for the tumorigenic conversion
of mesothelial cells, and recent studies have begun to identify the specific
TSGs that contribute to the development and progression of MM. This chapter
presents an overview of recurrent chromosomal imbalances and molecular genetic
alterations characteristic of this malignancy.

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