mesothelioma cancer

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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