Details regarding the exact mechanisms by which a normal mesothelial cell is converted to a malignant cell (cancer) by asbestos fiber are largely unknown. Despite this lack of highly-detailed knowledge, researchers have accumulated a treasure of knowledge regarding the basic mechanisms involved in this process. It is not very clear whether asbestos fibers induce mesothelioma by direct interaction with the mesothelial cells or act indirectly via generation of toxic materials that may finally induce cancer. There is some evidence to suggest that generation of reactive oxygen species (ROS) (Ref 1) may be intimately connected with the process of mesothelioma development.
Inhaled asbestos fibers initally cause local irritation and inflammation to the surrounding lung tissue where they get lodged. Local irritation and inflammation leads to the produciton of various body chemical substances called cytokines. Cytokines are the mediators of various body reactions and processes. These newly produced cytokines induces various cellular and intercellular changes to the lung and mesothelial cells. Interaction of asbestos fiber directly or in combination with other factors including these cytokines cause the cell to proceed to the path of malignant transformation.
There are different sets of genes for growth promotion and growth suppression. In normal healthy state the genes that promote growth, and genes that suppresses the growth are in good harmony, so that the cell growth and cell division occur only when it is needed. These growth-related genes can get damaged by internal or external factors. If a growth suppressing gene is damaged the control mechanism suppressing unwanted growth may be lost. If damage occurs in the growth promoting genes, they may lose their ability to promote cell growth, but some types of damage can actually increase the growth promoting ability of these types of genes. This may happen because the part of the gene that senses signals from the growth suppressing genes may be damaged releasing it from the control mechanisms of the growth suppressing genes. As the result of this type of damage, the genes the cell no longer pays attention to the commands of the tumor suppressor genes and continue to multiply. Every cell is programmed to die after certain number of cell divisions. Some times damage can occur to this programmed cell death gene that controls the death of the cell, thereby giving the cell the ability of immortality. If a combination ability to divide without control mechanisms and immortality are achieved that will give the cell very high chance of developing in to cancer. Most of the time only one cell accumulates all the genetic changes that are required to develop a cancer, but it soon will divide to multiple cells. Every time these abnormal cancer cells divide, the traits of lack of control by body growth mechanisms and immortality are passed to each of the daughter cells thereby, perpetuating the process of uncontrolled cell growth.
A tumor suppressor gene located on chromosome 9 called p-16 may have a major role in the ultimate development of malignant mesothelioma. In addition to tumor suppressor genes like p-1, growth-stimulating genes like, c-fos and c-jun also may be involved in the pathogenesis of malignant mesothelioma (Ref 2). Pro-growth genes are turned on by the presence of asbestos or body chemicals (cytokines) induced by asbestos. This growth stimulation may lead to uncontrolled cell division and subsequent development of mutations, which would finally terminate in the development of malignant mesothelioma. Growth stimulation factors like plateletderived growth factors (PDGF) may have some role in the malignant transformation. ((Ref 3).
Various chromosomal abnormalities have been reported in patients with malignant mesothelioma. Abnormalities in chromosomes 1, 3, 6 and 9 are repeatedly observed in patients with this disorder. Occasionally loss of one copy of the chromosome 22 may be observed.
Asbestos by itself is known to be capable of causing DNA damage. Stimulation EGF-receptors (growth promoting regions in cell) in a damaged or mutated cell can eventually lead to activation of growth promoting genes like c-fos and c-jun. Stimulation of these growth promoting genes in turn will result in unchecked cell division and proliferation with increased risk of acquiring another genetic alteration. One of these alterations may involve key cell-cycle regulatory genes, which may confer immortality to the cell, and with increased proliferation, and newly acquired immortality the cell will multiply and eventually lead to malignancy. In other words the combined effects of asbestos and SV40 overcome the cell cycle regulatory mechanisms resulting in un-controlled cell division and proliferation with the subsequent attainment of further genetic alteration finally leading to malignancy.
References:
1. Suzuki K, Hei TK. Induction of heme oxygenase (HO) in mammalian cells by mineral fibers: distinctive effect of reactive oxygen species. Carcinogenesis 1996;17:661.
2. Heintz NH, Janssen YM, Mossman BT. Persistent induction of c-fox and c-jun expression by asbestos. Proc Natl Acad Sci U S A 1993;90:3299.
3. Gerwin BI, Lechner JF, Reddel RR, et al. Comparison of production of transforming growth factor and platelet-derived growth factor by normal human mesothelial cells and mesothelioma cell lines. Cancer Res 1987;47:6180.