Asbestos Exposure as a Risk Factor For Malignant Mesothelioma
The exact way mesothelioma develops is still not completely understood. The pleura, which is the fluid-filled sac that lines either lung and the chest cavity, is the focus of the carcinogenic activity of asbestos. This is because asbestos fibers can penetrate the lung and enter the part of either pleura that lines the chest cavity and settle in the sites where the lymph nodes drain. This results in changes to certain chromosomes.
These chromosomal changes were investigated in a study titledMalignant Pleural Mesotheliomapublished May 12, 2009 in Future Oncology. According to the researchers, the most consistent change occurs in chromosome 22, which contains the neurofibromatosis type 2 gene (NF2). The protein called merlin is encoded in this gene, and this protein acts as a tumor suppressor in humans. Mesothelioma causes mutations to this gene.
The researchers noted that a 2003 study examining the association between NF2 and asbestos-induced tumors of the abdominal cavity suggested that mesothelioma developed at a greater frequency in mice with only one NF2 allele compared with wild mice that had more than one when they were exposed to asbestos fibers. An allele is one of two or more versions of a particular gene. They also found that the remaining NF2 allele was lost once the tumor developed, which makes the NF2 gene a “gatekeeper in asbestos-induced mesothelioma”.
When they continued to assess the mouse model, the scientists found that the loss of the remaining NF2 allele was followed by the loss of INK4a/ARF, located on chromosome 22 that encodes the p16 and ARF proteins. The p16 protein plays a role in cell division and ARF prevents the destruction of the protein called p53that acts a s a tumor suppressor.
Mesothelioma patients don’t have the p16 and ARF proteins either because the NF2 gene in all its forms is completely removed, or it becomes methylated. This is a process in which a methyl group is added to the gene, which decreases its output. In other words, the NF2 gene gets the addition of the methyl group, which decreases the amount of tumor-suppressing merlin that is produced, which allows the mesothelioma cells to develop.
Furthermore, when the researchers deliberately tried to inactivate the NF2 gene in the mouse models by infecting the mesothelial cells lining the thoracic cavity, the disease rarely developed. However, when the other part of the equation was added, meaning the loss ofINK4a/ARF, the development of the disease was accelerated. The conclusion they drew from this was that making NF2 functionally inactive only leads to tumor development when INK4a/ARF is missing.
The next question the researchers investigated was how the genes acted as gatekeepers. They reasoned that NF2/merlin was only necessary for the assembly of the junctures where two of the different types of membrane that make up epithelial cells met, but not the maintenance of these junctures. Consequently, the loss of the NF2 gene was only important when it happened in dividing cells during tissue repair.
This they believed was the reason why merlin production is interrupted in mesothelioma, which occurs because of constant injury to mesothelial cells caused by asbestos fibers.
Cells that cannot create those necessary junctures will be unable to create well-formed tissues, making them resistant to any substance that controls their growth that depends on actual contact to work. So the chronic injury to the mesothelial cells activates the stem cells that try to repair the tissue; however, because of the way normal cells develop into mesothelioma cells by disrupting NF2, new tissue is not properly formed and the body’s repair mechanisms don’t know how to fix the improperly formed ones.