GPCRs IN CANCER

| In Cappadocia, Turkey, an unprecedented mesothelioma epidemic causes 50% of all deaths in three small villages. Initially linked solely to the exposure to a fibrous mineral, erionite, recent studies by scientists from Turkey and the United States have shown that erionite causes mesothelioma mostly in families that are genetically predisposed to mineral fibre carcinogenesis. This manuscript reports, through the eyes of one of the researchers, the resulting scientific advances that have come from these studies and the social improvements that were brought about by both the scientists and members of the Turkish Government. P E R S P E C T I V E S NATURE REVIEWS | CANCER VOLUME 7 | FEBRUARY 2007 | 147 © 2007 Nature Publishing Group exposure8. Crocidolite induces cell lysis and apoptosis9, however, asbestos-induced TNFα secretion activates nuclear factor-κB (NF-κB) that protects mesothelial and other cells from crocidolite-induced cell lysis7. Therefore, asbestos-damaged mesothelial cells divide rather than die and can propagate the genetic damage7 that is induced by mutagenic oxygen radicals released by mononuclear phagocytes that have ingested asbestos10–13. Moreover, asbestos induces the phosphorylation of extracellular signalregulated kinases 1 and 2 (ERK1 and ERK2), which leads to the activation of the transcription factor AP1 and stimulates cell division10. Activation of this pathway can also promote cell invasion by causing the induction and release of cellular metalloproteinases14. Whether other types of asbestos and mineral fibres are carcinogenic owing to the same mechanisms is under investigation. Mesothelioma is rare between cohorts that are not exposed to asbestos, but it is frequent in workers who are exposed to it. For example, 4.6% of South African crocidolite asbestos miners who had been exposed to asbestos for more than 10 years developed and died of mesothelioma15. This finding highlights the risk of this disease among asbestos workers, and at the same time shows that only a fraction of heavily exposed individuals develop mesothelioma. In contrast to other carcinogens there is no linear dose–response relationship between asbestos exposure and the incidence of mesothelioma2. Above a certain threshold additional exposure does not seem to proportionally increase the risk of developing mesothelioma. Instead, some people seem more susceptible than others2. Most studies report that about 80% of mesotheliomas develop in asbestos-exposed individuals5. However, the association of exposure with the development of mesothelioma varies from about 10% to 100% depending on the article and on the criteria used to establish whether exposure has occurred5. The obvious question that arises from these studies is whether there are cofactors that make some individuals more susceptible to asbestos carcinogenesis. We found that genetic predisposition to mineral fibre carcinogenesis has led to an epidemic of this disease in Cappadocia, Turkey, and also in some US families16,17. We also found that simian virus 40 (SV40) functions as a co-carcinogen with crocidolite asbestos in causing meso thelial cell transformation18. SV40 can also induce the development of mesothelioma in hamsters exposed to crocidolite, and it lowers the amount of crocidolite that is required to cause the disease14. Crocidolite–SV40 co-carcinogenesis has been independently verified19–22. Experiments are in progress in our laboratory to investigate whether co-carcinogenesis extends to other mineral fibres. So far, our studies indicate that genetics and viral infection influence mineral fibre carcinogenesis and that the risk of mesothelioma in individuals exposed to asbestos and erionite varies depending on their genetic background and possible exposure to other carcinogens. In this Science and Society article M.C. discusses the sequence of events, obtained with his co-authors, that have linked genetic predisposition to mineral fibre carcinogenesis in some villages in Cappadocia, Turkey. In addition to the scientific results, some social issues concerning this work are also discussed. Box 1 | Asbestos and mesothelioma Mesothelioma was rare until the second half of the twentieth century47. In 1960, C. Wagner reported a mesothelioma epidemic among crocidolite asbestos miners in South Africa48. After the report from Wagner, the link between asbestos exposure and mesothelioma remained controversial over the following decade. Epidemiological data (reviewed in REF. 34) and experiments in animals supported this association (reviewed in REF. 49). Eventually, the argument was settled in the scientific community, and the idea that people exposed to asbestos had an unusually high incidence of mesothelioma was accepted50–52. However, the debate still persists on whether all types of asbestos cause mesothelioma. There are, in fact, two main types of asbestos. The first type, amphibole asbestos, includes the minerals crocidolite, amosite, tremolite, anthophyllite and actinolite. The second type, serpentine asbestos, is also called chrysotile. According to some experts, only amphibole asbestos, particularly crocidolite and amosite (which were mostly mined in South Africa), causes mesothelioma. Chrysotile (which is still mined in some countries) does not cause the disease, and mesotheliomas associated with chrysotile exposure are probably caused by the frequent contamination with tremolite3. Other experts, however, argue that chrysotile is as dangerous as amphibole asbestos and consider chrysotile the main cause of mesothelioma in the developed world, because it accounts for about 90% of all exposures4 (BOX2). A review of the literature on this topic revealed that the data were so diametrically different that it was not possible to reconcile these contradictory findings5. The median latency from time of asbestos exposure to disease development is about 32 years and ranges from 20 to about 50 years1,2,34. Early diagnosis (stage 1A) and surgical treatment are often associated with prolonged survival of ≥5 years, but less than 5% of mesotheliomas are diagnosed at this early stage1. By the time patients develop clinical symptoms, usually dyspnoea (difficulty in breathing) and pain, and seek medical attention, the disease is well advanced and incurable1,53. Box 2 | Economic issues related to asbestos and mesothelioma research After 40 years of research on whether chrysotile does or does not cause mesothelioma, the issue is still unresolved, and the controversy is stronger than ever6. The argument is not purely scientific: the economic implications of linking chrysotile or any other agent to mesothelioma are enormous because of litigation54, and chrysotile production is a major source of revenue for some countries. The most prominent example of economic versus scientific argument is seen in the United States, where, up until 2002, defendants had paid out US$54 billion in asbestos-related claims and the estimated future liability ranges from $145 to $210 billion54. Asbestos victims, however, have received less than half this money, because over 50% of the money is spent in transaction costs, mostly attorney fees54. Because most asbestos-containing products were banned from the marketplace in the 1970s, it had been predicted that the incidence of asbestos-related diseases would decrease and the claims would decline. However, the volume of new asbestos cases and the costs of litigation continue to increase54. Because of this, any research that seems to link any factor other than asbestos to mesothelioma pathogenesis becomes invariably controversial, like chrysotile, which some experts believe was erroneously included in the asbestos family because it has significant mineralogical and biological differences compared with amphibole asbestos. Recently, the research linking simian virus 40 (SV40) to mesothelioma has also caused problems because SV40 contaminated early polio vaccines; therefore vaccine manufacturers have been dragged into litigation. The published literature reflects these conflicts of interest and it is difficult to identify articles that might have some bias from those that do not. Our studies on erionite and genetic predisposition to mineral fibre carcinogenesis have not been controversial, probably because the problem seems localized in Cappadocia where litigation is not a factor. P E R S P E C T I V E S 148 | FEBRUARY 2007 | VOLUME 7 www.nature.com/reviews/cancer © 2007 Nature Publishing Group