Widespread
asbestos exposure during the past century has been linked to the dramatic increased incidence of
malignant mesothelioma (MM), a
malignancy that was so rare until 1950-1960 that some pathologists questioned its existence. Although
asbestos has been clearly linked to MM pathogenesis, until recently the mechanisms of
asbestos carcinogenesis in humans have remained obscure. Recent results revealed that
asbestos carcinogenesis in humans and in rodents is linked to the activation of the
AP-1 pathway, which induces cell division, and to the secretion of
TNF-alpha (and the expression of its receptor) by mesothelial cells and by nearby macrophages exposed to
asbestos. In mesothelial cells,
TNF-alpha signaling through
NF-kappaB activation prevents apoptosis and cell death, allowing mesothelial cells to survive the genetic damage induced by
asbestos and divide. In addition, mutagenic
oxygen radicals released mainly by lung macrophages may contribute to
asbestos carcinogenesis. Very recent results indicate that
mineral fiber carcinogenesis can be influenced by genetics and microbial
infections.
Genetic susceptibility to the
mineral fiber erionite has been demonstrated in some Turkish families and causes a MM epidemic in Cappadocia, Turkey. In these
mesothelioma families, exposure to minimal amounts of
erionite or
asbestos appears sufficient to cause
mesothelioma. Recent results (Kroczynska B, et al: Proc Natl Acad Sci USA, in press), demonstrate that SV40 and
crocidolite asbestos are cocarcinogens and that, in the presence of SV40, significantly lower amounts of
asbestos suffice to induce MM. These findings indicate that the risk varies among
asbestos- and
erionite-exposed individuals because of their genetic background or because of exposure to other
carcinogens. Moreover, these data provide a rationale for the observation that only a fraction of heavily exposed
asbestos workers developed
mesothelioma, and novel targets for prevention and
therapy.