Mesothelioma History

The history of the acceptance of mesothelioma as a primary malignancy of the pleura is one of more than 100 years of confusion and frustration. The disease was rare enough that its appearance was only intermittently identified in the medical literature. With less than one case in a thousand being identified as pleural or peritoneal carcinomas, it is little wonder that physicians at first were reluctant to assign it the status of a primary tumor. The medical establishment of the 1800’s was convinced that pleural tumors had to be metastatic cancers from some other primary tumor, regardless of the lack of evidence for this.

In the late 1800’s it was noted that mesothelioma could be found in the lymph nodes and the theory developed that the cancer began in the lymphatic system and spread to the lungs or abdomen. Not until 1891 was consideration given to the opposite theory. As always, research into the nature of mesothelioma was hampered by the lack of a sufficiently large body of evidence. Patients, thankfully, were still few and far between and reaching a consensus with so little clinical data was difficult.

The early 20th century finally brought acceptance that some pleural sarcomas could arise even without a primary cancer elsewhere in the body. From this humble beginning, the realization that the tumor developed from the mesoderm hit home and the term mesothelioma came to be accepted in 1921. Through the ‘30’s and ‘40’s further research and an increasing number of patients established the description of the tumor and began to identify the link to asbestos exposure.

Because of the confusion over whether mesothelioma truly was a separate clinical entity, five different views about causation took hold:
1. The endothelial lining of the lymph nodes was the cause, hence the name endothelioma.
2. Aberrant lung tissue became malignant within the lining of the pleura.
3. The tumor arose in the pleural capillary endothelium.
4. Tumors of epithelial origin always arose from a primary tumor elsewhere. The primary tumors were felt to be too small to be detected in autopsy.
5. The tumor arose from the mesothelial lining of the pleura and peritoneum.

It was Wedler in 1943 who reported a connection too high to be coincidental between asbestosis and pleural malignancy in a population of German asbestos workers. The analysis, which factually reported the connection but made no attempt to stamp the disease with a label, was widely accepted in Germany and ignored in the rest of the world. It wasn’t until the early 1950’s that additional evidence rescued the observations of Wedler and began to build an irrefutable connection between asbestos exposure and mesothelial cancer.

Inhalation- The Primary Path of Exposure:

The primary access path for asbestos fibers is the respiratory system. Fibers released into the air are inhaled by the subjects where they are carried into the deepest recesses of the lungs. Asbestos fibers that are locked into heavier particles of plaster, concrete or paint are often expelled through coughing and rarely reach deeply enough into the lungs. From studies conducted in the early to mid-20th century, most of which were post-mortem examinations, it became apparent that pleural asbestos disease tended to accumulate near the bottom lobes of the lungs, in the gutter of the thoracic cavity and on the surface of the diaphragm.

Microscopic examination of biopsy or autopsy tissue samples revealed that in many cases the asbestos fibers were no longer located in the alveoli of the lungs but rather in the intrapleural space or within the mesothelial lining of that space. This was described by many physicians as a “clearing” of the lungs, but despite the benign sounding label, this process held serious and potentially fatal implications for the subject.

The clearing of the lungs is directly connected to the two primary theories about how injury is caused by asbestos. The first theory postulates that the asbestos fibers pierce the tissue walls of the pleural space (and sometimes the peritoneal space via the stomach or the diaphragm) and cause tissue damage which creates an inflammatory immune response. The second theory states that the asbestos fibers are so small that they begin to interact with mesothelial cells at a molecular level, interrupting cell replication and/or damaging the cellular DNA during mitosis, or cell division.

Inflammatory Immune Response

The migration of the asbestos fibers out of the alveoli is a function of the small size of the fibers. This allows them to pierce the cell walls and migrate between cell boundaries into the mesothelial lining of the pleural cavity or even into the intrapleural space. There, they sometimes penetrate the diaphragm and make their way into the abdomen or the testes.

Whenever these fibers migrate, they leave a trail of damaged or compromised cells behind. The response to this damage varies by individual and invariably involves the immune system. Evidence for the response is found in the irritation and destruction of cells and the creation of scar tissue at the site of the injury. This process can be quite significant in the case of heavy asbestos exposure and can lead to major impairment of the lungs as a crust or plaque of fibrous scar tissue forms over the affected areas. Microscopic examination of this material has often found asbestos fibers entombed in the nodules and layers of tissue and has been used as prima fascia evidence for the asbestos connection as a cause for the injury.

Genetic Damage During Cell Division:

All living cells have a limited ability to renew themselves. This ability confers a specific life span that appears to be pre-programmed into their chromosomes. When cells divide, the ends of the DNA molecules get shorter, truncating a section of the chromosome called the telomeres. The DNA strands get shorter and shorter until the cell can no longer replicate itself.

Almost all of the cells in our body, including mesothelial skin cells, will grow old and die. The only exceptions are bone marrow cells (making blood cells) and the sperm producing cells of the testes. These cells are called immortal cells since they never lose the ability to reproduce themselves. They are assisted during cell division by an enzyme called telomerase that allows them to keep dividing endlessly without degrading. Before regular cells get old and die they divide, and new cells, (daughter cells) take their place. This process, called mitosis, can be repeated roughly 60 to 100 times during the human lifespan before the cells lose their ability to divide. Once that happens, our tissues and organs begin to fail and we reach the end of our lifespan.

It is during mitosis of respiratory tissue cells that asbestos fibers are thought to do the damage that eventually leads to mesothelioma. During mitosis, the DNA in the parent cell is split into two haves and each half is drawn towards an opposite end of the cell. There, new amino acids replace the missing halves of the DNA by using the original halves as templates. Assuming nothing goes wrong, the cell now contains two identical sets of DNA and a barrier forms that divides the cell into two identical halves.

During mitosis, asbestos fibers that have penetrated the cell are thought to physically interfere with the replication of the DNA. This may break the DNA chains, causing the cell to fail, or damage the functioning of its genes, making it become cancerous. The majority of cells whose genetic machinery is non-functional will die and be cleaned up by the immune system but not all of them will. Some cells whose genetic machinery wasn't fatally damaged will continue to live on in a diminished or damaged state. Those malfunctions which cause a regular cell to reproduce endlessly are termed cancer.

Molecular Details

As cells proceed through mitosis they are monitored by a system of chemical controls that check for DNA damage and look for the inability to perform essential cellular processes. If this system detects damage or errant functions, RNA message molecules are used to cause the cells to stop dividing. These controls cause damaged cells to either repair themselves or self-destruct. The latter process is called apoptosis or programmed cell death.

Recent research has uncovered a protein, called p53, (ad) which identifies chemical messages caused by genetic damage to the cellular DNA. P53 is produced by a gene that oversees tumor suppression. Once activated, p53 then stimulates the production of proteins that stop the DNA replication process. Without this valuable intervention, damage in the genetic machinery of the cell can accumulate unchecked. A direct consequence of failure to produce p53 is that damaged cells progress into a cancerous state. Today, defects in the functioning of p53 are associated with a variety of cancers, including some breast and colon cancers. A more detailed explanation of gene activation and suppression is provided below.

Cell Methylation and Cancer:

Recent developments in the field of biology have studied the functional processes of genes at the molecular level. Scientists have known for some time that certain sections of the chromosome, called genes, serve essential functions for the health and welfare of the cell and the host organism. There are large areas of the chromosome that were previously regarded as non-functional or “junk” DNA that are now known to have a role in the control of which genes are active (expressed) and which are not. The process of controlling genes through protein molecule messengers is called methylation.

Some genes control the replication of, and also the longevity of the cells that contain them. While we haven’t identified all of these genes, we have learned that, when growth regulating genes are blocked from doing their functions, cells can grow without restraint, causing cancer.

We have now discovered some of the proteins that appear to be responsible for interfering with the balanced and normal functions of a wide variety of regulatory genes. The excessive presence of such proteins in blood or urine (called over-expression) can be used as a measure of the presence of cancer. We still don’t know exactly what causes these proteins to be produced in excessive amounts, nor have we uncovered all the connections between the production of these molecules and the genetic damage caused by asbestos.

However, studies of this area would seem to imply that damage to a cell isn’t automatically a cause for cancer and that other factors come into play.

Simian Virus SV40

One new and highly contentious issue is the role of simian virus 40 (SV40) in the development of mesothelioma tumors. Animal experiments have established that SV40 is a potent tumor inducing virus, however, clinical studies still have not conclusively linked SV40 to human mesothelioma cases. Many studies and publications have demonstrated the presence of SV40 in human mesothelioma tissue samples.

There is some evidence, however, that the SV40 presence in the samples may be due to pervasive laboratory contamination. The source of this contamination was the original monkey cell cultures used as a medium in which to grow smallpox vaccines. The SV40 remnants were felt to be benign and were therefore ignored by laboratories. it was only later that the tentative connection to cancer was noted.

It is also interesting that the presence of SV40 in pathology samples is statistically indicative of a poor outcome, suggesting that asbestos and SV40 may interact in the spread and aggressiveness of mesothelioma tumors. More research is necessary before we can claim to have a causal link between SV40 and human malignant mesothelioma.