Mesothelioma epidemiology, carcinogenesis, and pathogenesis

Abstract

The incidence of mesothelioma has gone from almost none to the current 2500-3000 cases per year in the USA. This estimate is an extrapolation based on information available from the Surveillance, Epidemiology and End Results (SEER) Program that collects information on approximately 12% of the US population. Mesothelioma is a cancer that is linked to exposure to carcinogenic mineral fibers. Asbestos and erionite have a proven causative role; the possible role of other mineral fibers in causing mesothelioma is being investigated. Asbestos is considered the main cause of mesothelioma in the US and in the Western world. The capacity of asbestos to induce mesothelioma has been linked to its ability to cause the release of TNF-alpha (that promotes mesothelial cells survival), other cytokines and growth factors, and of mutagenic oxygen radicals from exposed mesothelial cells and nearby macrophages. Some investigators proposed that as a consequence of the regulations to prevent exposure and to forbid and/or limit the use of asbestos, the incidence of mesothelioma in the US (and in some European countries) should have started to decline before or around the year 2000, and sharply decline thereafter. Unfortunately, there are no data available yet to support this optimistic hypothesis. Simian virus 40 (SV40) infection and radiation exposure are additional causes, although their contribution to the overall incidence of mesothelioma is unknown. Recent data from several laboratories indicate that asbestos exposure and SV40 infection are co-carcinogens in causing mesothelioma in rodents and in causing malignant transformation of human mesothelial cells in tissue culture. An exciting new development comes from the discovery that genetic susceptibility to mineral fiber carcinogenesis plays a critical role in the incidence of this cancer in certain families. It is hoped that the identification of this putative mesothelioma gene will lead to novel mechanistically driven preventive and therapeutic approaches.

Figure 1

TNF-α inhibits asbestos induced cytotoxicity via a NF-κB dependent pathway: a possible mechanism for asbestos induced oncogenesis. In tissue culture, crocidolite is very cytotoxic to human mesothelial cells (HM), causing extensive cell death. Crocidolite causes the accumulation of macrophages in the pleura and lung. These macrophages or some other cells release TNF-α when they encounter asbestos. At the same time, asbestos induces HM to secrete TNF-α, with paracrine and autocrine effects. TNF-α induces translocation of the NF-κB subunit, and activation of NF-κB increases HM survival. This allows HM with asbestos-induced DNA damage to divide rather than die and, if key genetic alterations accumulate, to eventually develop into a MM.

Figure 2

Family 1: Pedigree from the now abandoned village of “Old” Sarihidir showing a family of 30 in which 17 died of MM (black symbols), 4 died of other cancers [osteosarcomas (B), leukemia (D), prostate cancer (F), and pancreatic cancer (G)], 4 died of reasons other than cancer [2 traffic accidents (A), 1 intestinal occlusion (C), 1 congestive heart failure (E), and 1 unknown reason (first generation, female; F)], and 4 are alive (white symbols). Five MM developed in individuals who married into the family. They were also from MM families. Bottom, representative examples. Family 9: Pedigree of the family of origin of 65-year-old male (+) who married into family 1. Seven of the 17 people of this two-generation pedigree died of MM, 1 of liver cancer (H), and 5 unknown. The deaths from MM include a 46-year-old female (^) who married into family 9. The family of origin of this woman (family 10) has a very high incidence of MM: 5 of the 7 family members died of MM and 1 of lung cancer (K); the remaining cause of death is unknown. Family 3: When members of family 1 (*) marry into a non–MM family, the cancer appeared in the descendents. A, traffic accident; C, intestinal occlusion; the other causes of death were not cancer-related, but they could not be established with certainty.