Asbestos Lung Cancer - Lung Cancer
Mechanisms of Oncogenesis by Asbestos
The mechanisms of asbestos-induced oncogenesis have not been fully elucidated, but considerable progress has been accomplished in the past few years. There is evidence that depending on the system considered, asbestos can be a complete carcinogen, an initiator, or a promoter.23 The tumor-promoting model can be best applied to lung cancer, where synergistic interaction between asbestos and cigarette smoke occurs. Compared with nonsmokers not exposed to asbestos, the death rate from lung cancer is multiplied five times in nonsmokers exposed to asbestos, by 11 in smokers not exposed to asbestos, and by 53 in smokers exposed to asbestos.237
Such an effect has been shown experimentally by exposing tracheal epithelial cells to polycyclic aromatic hydrocarbons and asbestos in various schedules;23 however, asbestos alone may produce these changes as well,23 and lung cancer occurs in nonsmokers exposed to asbestos, although to a much lesser degree than in smokers exposed to asbestos. Other changes observed in target tissues compatible with a promoter effect of asbestos include hyperplasia, metaplasia, DNA synthesis, and increased production of oxygen free radicals.
Activation of diacylglycerol, protein kinase C, and ornithine decarboxylase also has been reported in a pathway similar to classic tumor promoters, such as phorbol esters.23,168,183 Evidence that asbestos can also be a complete oncogen and an initiator lies in the fact that it can produce mesothelioma in humans without interaction with other known carcinogens, such as cigarette smoke, and that a single instillation of asbestos in the celomic cavities or the trachea can produce mesotheliomas in rodents.23,130,185
Although asbestos is weakly or not at all mutagenic in the classic sense of the word,23,183 it can induce heritable changes in the growth properties of normal mammalian cells in culture, leading to transformation and immortalization and to chromosomal mutations (aneuploidy and aberrations), which are dependent on fiber size.23 These changes may occur by physical interference of the mitotic process in the cell by penetrating asbestos fibers,23,183 or through other mechanisms, such as formation of active oxygen species.183
The changes provide a rational growth factor (EGF) was detected in mesothelioma cell lines,103 whereas in paraffin-embedded human mesothelioma specimens EGF was expressed more commonly in the epithelial cell type.80 Both normal human mesothelial and human mesothelioma cell lines were shown to express insulin-like growth factor-1 (IGF-1), IGF-binding protein 3, and IGF-1 receptor mRNA, suggesting that IGF-1 may also be an autocrine growth factor.154 In addition, immunologic factors play a possible role, which is described below.
Other Etiologic Factors
Since about 20% of patients have no demonstrable or anamnestic exposure to asbestos, and some have an asbestos lung burden similar to that of controls, alternative factors are presumably involved. Other etiologic factors are rarely found, however. The role of various other fibers, such as zeolites (erionite type) from volcanic rocks, has been incriminated in Turkey,21,22 and a few deposits have been found in Oregon in the United States.294 The potential of zeolites to produce mesotheliomas has been confirmed experimentally after intraperitoneal injection.261 After inhalation, the mesothelioma yield from zeolites exceeds that of any other fiber.294Workers in the fiberglass industry are being closely monitored, but so far there is no evidence that they have a higher risk for cancer or mesothelioma.127
Mesotheliomas have occurred within or in proximity to prior radiotherapy fields. In a cumulative review of 23 cases of possible radiationinduced mesothelioma, including 2 after extravasation of thorium dioxide (Thorotrast), the interval between radiation and mesothelioma ranged from 5 to 41 years (median 13.5 years).128 Radiation has also been shown to induce mesothelioma in animal experiments.197
A few cases of mesothelioma have been described 15 to 33 years following collapsotherapy (the induction of artificial pneumothorax) for tuberculosis, a technique used before effective drugs were available. 66,224 It is speculated that chronic irritation and inflammation may play a role in such cases. A similar mechanism has been postulated in a patient without known asbestos exposure who developed peritoneal mesothelioma associated with severe persistent diverticulitis and peritonitis and showed histologic evidence of benign mesothelial proliferation, atypical mesothelial proliferation, and malignant mesothelioma.
221 A case of peritoneal mesothelioma has also been reported in a patient with familial Mediterranean fever with recurrent peritonitis.63
Beryllium has been incriminated in a patient with a mesothelioma of the rectovaginal septum after she repeatedly douched with water containing that element.110 Beryllium was demonstrated in the tumor itself, but the patient was also environmentally exposed to asbestos.
Two observed associations with mesothelioma are of importance. Various immunoproliferative disorders, particularly of B-cell origin, have been reported, including myeloma, plasmacytoma, lymphocytic lymphoma, and chronic lymphocytic leukemia in patients with asbestosis or mesothelioma. 63,89,106,133 A case-control study showed an association between occupational exposure to asbestos and large cell lymphomas of the gastrointestinal tract and oral cavity.222 These observations provide further significance to immunologic abnormalities related to asbestos exposure and mesothelioma. Asbestos fibers can disseminate by lymphatic and even hematogeneous routes and can be found in various organs, including lymph nodes and bone marrow.
141 Interestingly, plasmacytomas with frequent C particles have been produced in mice after intraperitoneal injection of asbestos or zeolite fibers.261 Administration of carrageenan, which depresses lymphocyte and macrophage functions, has tripled the rate of asbestosinduced mesothelioma in rats.292 It has been shown that asbestos fibers suppress natural killer (NK) cell activity in vitro in a dosedependent fashion for both human peripheral blood lymphocytes and lung mononuclear cells obtained by bronchoalveolar lavage (BAL).215
Pre-exposure of cells to interleukin-2 (IL-2) restores NK activity.215 Human mesothelioma cells in vitro are resistant to NK cell lysis but susceptible to lymphokine-activated killer (LAK) cells, thereby providing a rationale for immunotherapy with IL-2/LAK cells.164 The absolute number of total peripheral T cells and T helper cells was found to be normal in asbestos workers but reduced in mesotheliom patients, whereas suppressor T cells were elevated in asbestos workers and unchanged in mesothelioma patients.157 NK activity was depressed in 70% of mesothelioma cases and was partially restored by co-incubation with human interferon-alpha (IFN-‡).157 No clear pattern emerged when histocompatibility antigens (human leukocyte antigens [HLA] A and B) were studied in mesothelioma patients.296
Clinical observations also strongly suggest a genetic susceptibility to mesothelioma. Clusters of cases have been reported in some families, often by household exposure to asbestos, and also in identical twins.7,63,134,171,212,281 The growing knowledge of the genetic changes associated with mesothelioma will better explain these observations and shed more light on the pathogenesis of the disease.
Strain MC 29 avian leukosis virus, an agent which ususally induces myelocytomas in chickens, has also produced mesotheliomas in chickens after injection into the coelomic cavity.50 Recently, SV40-like DNA sequences were found in 60% (29 of 48) of human mesotheliomas, and the SV large T antigen was expressed in 13 of 16 specimens.
46 SV40 is a DNA tumor virus which can immortalize human mesothelial cells in vitro and also produce mesotheliomas in hamsters when injected intrapleurally. These provocative findings are intriguing and their significance is as yet unknown. It should be noted that the early polio vaccines (both oral and inactivated) were contaminated by SV40 from 1954 until 1960.46 A number of laboratories have now confirmed that at least 60% of human mesotheliomas contain and express SV40.195a,265a In these tumor cells, the SV40 tumor antigen binds and inhibits the cellular tumor suppressors p53 and Rb.46a,80a These findings suggest that SV40 may contribute to the development of those human mesotheliomas that occur in people not exposed to asbestos.
SV40 may also facilitate asbestos-mediated carcinogenicity. The epidemiologic data available are insufficient to address the role that SV40 may have played in contributing to the increased incidence of mesothelioma in the second half of this century.254a The use of vaccination therapy against SV40 tumor antigen is presently under investigation in preclinical studies.39a,309a Although many other agents have produced mesothelioma in animal experiments,197 the disease in humans is overwhelmingly linked to fiber oncogenesis, particularly asbestos, in industrialized countries. Whether cases are due to a genetic susceptibility to background levels of asbestos or to some other etiologic factor(s) in patients with no unusual exposure to asbestos or in those with low asbestos lung burden remains to be determined.