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

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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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Primary Mesothelial Cell Lines

Primary cultures of mesothelial cells have been established from rats, rabbits,
mice, and humans (Table 5.1). Mesothelial cell lines provide several advantages
for experimental studies: they provide a large number of cells isolated from a
single donor, cell lines can be isolated from genetically engineered mice, and
primary cell lines limit the number of animals required for experiments.
However, cell lines have several disadvantages: variability among donors,
variability in culture conditions in different laboratories, potential
phenotypic and genetic instability, and a limited life span in vitro (reviewed
in ref. 1). Some of these disadvantages can be overcome by quality control
procedures. For example, cell lines should not be passaged indefinitely; frozen
stocks should be maintained and thawed at regular intervals to prevent
phenotypic and genetic instability (reviewed in ref. 2). As in all cell cul¬ture
models, precautions are required to prevent cross-contamination and
contamination with bacteria or viruses. DNA profiles could be use¬ful to
identify cell lines; for example Manning et al (3) established initial genetic
profiles for their panel of human malignant mesothelioma cell lines. All
cultures should be screened for Mycoplasma and other pathogens (2).

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In Vivo Models of Mesothelioma, Their Purposes, and
Roles

Knowledge of the factors and mechanisms responsible for cancer induc¬tion rests
largely on the development of animal models. In these models, both benign and
malignant tumors, as well as preneoplastic lesions, can be induced by proper
experimental designs and with appropriate con¬trols, and their analogy to human
pathology can be determined. The animal models can be used to test and identify
agents (chemical, physi¬cal, or biologic) that are capable of carcinogenic
activity, and to investi¬gate their mechanisms. In addition, species and strains
of laboratory animals with specific genetic susceptibility to specific types of
sponta¬neous or induced tumors can be identified. Recently, genetic
manipula¬tion has given rise to transgenic or gene-deleted (knockout) animals,
which can reveal selective molecular pathways to carcinogenesis.

The study of in vivo animal models of carcinogenesis has sometimes followed the
indications of the evidence derived from studies of human epidemiology,
especially for occupational and environmental carcino¬gens. On the other hand,
with the systematic development of animal bioassays, many experimentally
identified active carcinogens have been subsequently shown to be human
carcinogens in epidemiologic studies.
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