Help mesothelioma

Malignant pleural mesothelioma is a relatively uncommon and yet incurable tumor that is aggressive and highly lethal. After the occurrence of mesothelioma was first reported in 1960 in workers exposed to blue asbestos crocidolite, (1) a huge, number of experimental and epidemiologic studies has proved causality between asbestos mineral fibers and mesothelioma, (2) whereas relatively few efforts have been made to understand the mechanisms underlying the pathogenesis of and the susceptibility to this tumor. Yet, in the last 2 decades geographic clusters of mesothelioma have been reported in populations with nonprofessional environmental exposure to asbestos, (3-6) and other mineral fibers including zeolite (7) and fluoro-edenite, (8) a new amphibole end-member, which is chemically different from known asbestos types. (9)

According to current knowledge, mesothelioma derives from multipotent mesothelial stem cells, which differentiate into malignant epithelial or mesenchymal elements. (10) However, the mechanisms determining this differentiation as well as the local invasiveness of mesothelioma, despite extensive investigation, still remain poorly understood. Mesotheliomas with a predominantly epithelial growth pattern have a better prognosis than the sarcomatoid mesothelioma and the mixed or biphasic types, consisting of both epithelial and sarcomatous foci. (10) Thus, the phenotype appears to be highly important for the biological behavior of the tumor, but little is known about the mechanisms and genetic determinants of different phenotypes. The mesothelioma occurs in selected individuals among population groups with known exposure to asbestos, either in the workplace or in the Community. Interestingly, the evidence of a background incidence of this tumor, (11) along with the description of familial clustering, (12) suggest that the occurrence of asbestos-induced mesothelioma in some individuals, but not in others, may not be a matter of chance and points to the existence of genetic predisposition. (11-13) Furthermore, although malignant mesothelioma has received much attention, benign pleural diseases, including pleural plaques, pleural effusion, diffuse pleural thickening, and rounded atelectasis, induced by asbestos and nonasbestos fibers, are also common in clinical practice and often produce difficulties in the differential diagnosis. (14) Hence, an understanding of the genetic profiling of malignant mesothelioma and other asbestos-induced pleural diseases is of pivotal importance and can be viewed from the perspective of how normal mesothelial cells respond to injury, how they transform into malignant cells, and how they proliferate so aggressively.

In this issue of CHEST (see page 1843), Hoang and coworkers explore the expression of matriptase, at trypsin-like protease, in freshly dissected human malignant mesothelioma and cultured mesothelioma cell lines, and find a mean 826-fold overexpression of this enzyme in mesothelioma epithelial cells. Matriptase messenger RNA, which has been detected in tissues rich in epithelial cells, and cancerous breast, ovarian, and colon tissues, but not in cancers of a mesenchymal origin, has been characterized as an extracellular matrix-degrading protease system that may function as an epithelial membrane activator for other proteases and latent growth factors involved in cancer cell growth, invasion, and metastasis. (15) In addition, the article by Hoang and associates describes the up-regulation of insulin-like growth factor (IGF) exon I. According to previous studies, IGF-I acts as an autocrine growth factor stimulus in normal mesothelial and mesothelioma cells, (16) and the production of IGF-I is not only implicated in regulating the carcinogenic process and the growth rate of simian virus 40-induced mesotheliomas, but can also be targeted for carcino-genesis inhibition,. (17) Yet IGF-I has been shown to be able to induce the differentiation of mesothelioma cells toward a fibroblast-like morphology. (18) Interestingly, Hoang and coworkers also found an underexpression of IGF binding protein 5, a family of transmembrane ligands whose controversial functional role may be cell type-specific; they speculated that the underexpression of IGF binding protein 5 could act as an inhibitor of IGF-I expression, thus contributing to uncontrolled cell proliferation via an IGF-mediated autocrine growth loop. Taken together, these results represent an interesting advance in that they could explain why mesothelioma is a predominantly local or regional disease, although it grows aggressively, and rapidly invades the pleural spaces and surrounding organs. Yet these results implicate multiple cell-signaling cascades in the process of mesothelial cell proliferation and suggest that a focus on blocking common downstream events or points of convergence of these pathways might be important for the treatment of mesothelioma. A central question remains, however, whether matriptase up-regulation and other gene expression identified in mesothelioma play only direct causative role in mesothelial cell transformation.

Recently, microarray technology has been successfully applied in a number of studies (19-21) to identify specific gene expression changes in mesothelioma compared with normal mesothelial cells. These studies (19-21) have identified the expression of a variety of genes that could explain many of the biological characteristics exhibited by mesotheliomas.

Abnormal karyotypes are common in mesothelioma cell lines, and abnormalities in chromosome 6 have been frequently described. The present evidence suggests that chromosome arm 6q harbors at least three tumor suppressor genes involved in the pathogenesis of mesothelioma. (20) By doing simple segregation analysis of the occurrence of mesothelioma among nuclear families (parents and children) in Cappadocia, Turkey, an autosomal-dominant pattern of inheritance was postulated. (12) More recently, by using gene expression-profiling data that had been previously collected from 17 mesothelioma patients with different overall survival times, Gordon and colleagues (21) have been able to define two outcome-related groups of patients and to evaluate an expression ratio-based outcome predictor model. This approach could allow the preoperative identification of" patients with widely divergent prognoses and could enhance the allocation of therapeutic resources.

Although experimental and circumstantial evidence clearly indicate that a number of genes may influence the malignant transformation of human mesothelial cells and the biological behavior of mesothelioma, we know relatively little about the way genes expressed by mesothelioma cells interact with each other or how this interaction is influenced by environmental risk factors. Similarly to other complex disorders, malignant pleural mesothelioma does not follow a clear Mendelian mode of inheritance, and it is likely to involve several low-penetrance genes, each with only' weak-to-moderate effects. Thus, identification of these genes has proven difficult so far. Two main approaches to identify, disease genes in complex disorders are the positional candidate and the functional candidate gene approach. The first approach is based on the choice of candidate genes according to their chromosomal position, whereas the other approach is to choose candidates based on a gene's function mad how that gene might fit into disease pathophysiology. Both of these approaches have limitations, but, most often, investigators rely on the retrospective case-control study design, which appears to be powerful enough to study the relationship between genetic susceptibility and environmental risk factors, to determine whether a candidate gene is associated with a disease.