The mesothelium consists of a single layer of avascular flat nucleated cells that lines serosal cavities and the majority of internal organs, playing important roles in maintaining normal serosal integrity and function. The exact mechanism of mesothelioma development – a highly aggressive tumor with a dismal prognosis – is still unclear.
The pathophysiological mechanism has been linked to asbestos fibers such as curly, serpentine fibers (white asbestos) or long chain-like fibers such as amosite (brown asbestos), crocidolite (blue asbestos), anthophyllite, tremolite and actinolite. The pleura represents the target for the carcinogenic activity of asbestos due to the fact that asbestos can efficiently move from the lung to the pleural space, concentrating in the parietal pleura at the sites of lymphatic drainage.
Mechanisms of asbestos pathogenesis
During the long latency period of malignant mesothelioma, a myriad of pathogenic events may occur that can contribute to the development of the disease. After asbestos fibers are inhaled deeply into the lung and penetrate pleural space, prolonged cycles of tissue damage, repair and local inflammation are initiated, following the interaction of asbestos fibers with mesothelial cells. That in turn leads to carcinogenesis.
Reactive oxygen species induced by asbestos fibers with their exposed surface lead to DNA damage and stimulate a signal transduction cascade. Macrophages phagocytize asbestos fibers, but are unable to digest them, producing in turn abundant reactive oxygen species. These events activate MAP-kinase signaling pathways through the epithelial growth factor (EGF) receptor, and several of the induced transcription factors are highly expressed in mesothelioma.
Asbestos fibers can absorb different proteins and chemicals to the broad surface of asbestos, with the accumulation of hazardous molecules (including carcinogens) as a consequence. Once inside, asbestos fibers bind important cellular proteins, thus their subsequent deficiency can also be detrimental for normal mesothelial cells.
Macrophages and asbestos-exposed mesothelial cells produce a panoply of different growth factors and cytokines which induce inflammation and promote tumor development. Those include tumor necrosis factor-α, insulin-derived growth factor-1, interleukin-1β, transforming growth factor-β, granulocyte/macrophage colony-stimulating factors and platelet-derived growth factor.
Tumor necrosis factor-α has been shown to activate nuclear factor-κB, which seriously contribute to tumor formation and progression in mesothelioma. High-mobility group box 1 protein has also been shown to be released from mesothelial cells, promoting an inflammatory response by establishing an autocrine circuit in mesothelial cells that influences their proliferation and survival.
Long latency period (up to 40 years) suggest that multiple genetic alterations are important in the conversion from normal to malignant mesothelial cell. Comprehensive karyotypic analysis has revealed that malignant mesotheliomas display multiple clonal chromosomal abnormalities (more than 10 of them in most mesotheliomas).
Asbestos fibers are also engulfed by mesothelial cells, which can then disrupt mitotic spindles and influence the cell cycle process. Tangling of asbestos fibers with mitotic spindles may result in chromosomal structural abnormalities and aneuploidy of mesothelial cells.
Loss of one copy of chromosome 22 represents the single most consistent chromosomal change in patients with mesothelioma. Specific deletions of chromosomal sites involve the short arm (p) of chromosomes 1, 3 and 9, as well as the long arm (q) of chromosome 6. Other nonrandom cytogenetic alterations can be found on other chromosomes as well.
Certain tumor suppressor genes located in aforementioned chromosomal regions have also been implicated in the disease, including CDKN2A/ARF at chromosome band 9p21 and NF2 at 22q12. Mutations of the p53 gene (one of the most frequent genetic changes seen in the cancer cells) are occasionally observed in malignant mesothelioma as well.
It has also been postulated that simian virus 40 (SV40) can bind and inactivate wild-type p53 in mesothelioma, interfering with DNA repair, as well as apoptotic and growth inhibitory functions. Although it is a DNA monkey virus, the probable route of transmission to humans was through the SV40 contaminated polio vaccines distributed between 1955 and 1978.