One of the most exciting areas of current mesothelioma research is the growing body of knowledge that has been discovered about the disease’s molecular and genetic foundations. Even though much of this research is still quite preliminary, doctors and scientists are successfully—albeit, slowly—adding to our understanding of the precise mutations responsible for the development of mesothelioma. A systematic understanding of the relationship between these various mutations has, however, not yet been developed. One of the important precursor steps in creating a cohesive model of human mesothelioma genesis is the development of a mouse model that properly accounts for the disease’s genesis and progression. Not withstanding the significant genetic and biological differences between mice and humans, the fact remains that many of the greatest successes in human medicine have been guided by results obtained from murine testing.

Researchers from the Netherlands have recently published an article that describes their development of a conditional mouse model for mesothelioma carcinogenicity. Their results were obtained through testing of mice bred with specific mutations. Through their analysis of the correlations between individual gene mutations and malignant behavior, they’ve drawn specific conclusions regarding the manner in which individual mutations are responsible for the development, behavior and progression of mesothelioma.

What follows is a summary of their findings.

Overview of the Study

As we have previously covered in these news updates, mesothelioma is one of the most difficult of all forms of cancer to treat effectively. In its most common form, pleural mesothelioma, it typically presents only in the disease’s later stages and almost universally with a poor prognosis. Peritoneal mesothelioma, the second most-common form of the disease, typically presents with a less aggressive behavior pattern and a longer-term median survival range, but neither form responds well to conventional cancer treatments. Because of this, the development of new treatment modalities takes on greater and greater importance. Gene therapy represents one of these promising new strategies, but the lack of specific models regarding the disease’s growth pattern has limited the creation of effective medicine with it. Now that the Dutch researchers have published their findings, many members of the mesothelioma research community will be looking at their results with great interest to see what they reveal about possible treatment targets.

Individual studies have separately reported on a number of genetic mutations that have been implicated in mesothelioma genesis. Mutations and subsequent dysfunction of the tumor suppressor genes INK4A and P14ARF have been previously been reported on, as have loss and mutation of NF2 and TRP53. The authors note that Ink4a/ARF and TRP53 play well-known roles in cell-cycle regulation, while reduced NF2 expression “lowers cell adhesion and induces Schwann cell proliferation, whereas enhanced expression of NF2 leads to growth arrest.” A number of other genes have also been proposed as conducive to mesothelioma development, but the genes mentioned above have received the most attention.

To develop their model, the researchers bred a number of mice families with mesothelial-specific mutations to the Nf2, p53 and Ink4a pathways so they could chart the effects that each of these mutations, both singularly and in combination with the other mutations, had on the development of mesothelioma in these mice. Their findings were indicative of the importance these genes play in mesothelioma carcinogenicity.

One of the first things the researchers studied was the role these mutations had on tumor growth in the first place. They reported that the mice developed a number of individual tumors, but mesothelioma was the single most common development. The most common origin sites for it were the visceral pleuras of the lung and heart, while the most common metastatic developments included the parietal pleura, the diaphragm and the thoracic chest well.

When they looked at the individual relationships between gene mutation and malignant events, they discovered that individual losses of NF2, p53 or Ink4 were all clearly indicative of mesothelioma genesis, but that the loss of all three often led to the development of the most aggressive behavior patterns in their sample. The average latency period (the time between the mice’s first exposure to asbestos and their development of mesothelioma) for mice presenting with NF2;p53 loss was 135 days and for mice with NF2;Ink4a/Arf loss it was 220 days, while the latency period in mice who exhibited loss of NF2;p53;Ink4A was only 80 days. All of the most aggressive epitheloid and sarcomatoid mesotheliomas,i.e., those that were invasive of both the visceral and the parietal pleura, were found in this same NF2;p53;Ink4A group, while mice in the NF2/p53 or NF2;Ink4a/Arf groups did not exhibit the same aggressive behavior. Because of this, the researchers conclude that the loss of Ink4a (especially Ink4a alone-not Ink4a/Arf) leads to the most aggressive malignancies.

The relationship of NF2 and p53 loss to mesothelioma development was also covered extensively in the paper, where the authors conclusively state the importance of these mutations to disease development and progression. The authors propose that exposure to asbestos directly leads to a number of damaging genetic events (“genotoxic effects”), such as loss of both NF2 and Ink4a/Arf, which they see as the origin of asbestos’ carcinogenicity. If their hypothesis is correct, this could be the beginnings of our understanding of the precise physical relationship between asbestos exposure and mesothelioma development.

With NF2 playing such an important role in the development of the disease, the authors wonder if therapies utilizing NF2 re-expression would be effective for the treatment of mesothelioma. They note that recent research on NF2 re-expression has demonstrated some experimental efficacy for inhibiting cell proliferation and impairing the spread and invasive potential of certain types of cells.

The authors discuss a number of other novel findings in the genesis of mesothelioma. We have only covered a small number of their findings in this summary, so we recommend interested readers to read the full article to learn more about this newly developed mouse model.

Conclusion

The development of this mouse model should spur further research into the genetic mutations that underlie mesothelioma development. A greater understanding of the interrelationship between these mutations is sure to shed significant light on the cellular behavior of the disease, which will—hopefully—lead to the development of more targeted and effective therapies.

Labels: mesothelioma