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Re: Analysis of mesothelioma pathogenesis

Dear Editor

Malignant mesothelioma (MM) is a rare, highly aggressive tumor, accounting for less than 1% of all cancer deaths in the world. Although the association between exposure to asbestos and the development of MM is commonly accepted, the exact mechanism whereby asbestos induces MM is unknown. Therefore, we agree with Dr Lange observation that the search for other agents/factors causing this disease should be strengthened.

Our research group is actually investigating the pathogenesis of MM looking both at molecular events and environmental factors. We have a manuscript in press on Thorax showing a possible implication of COX-2 in MM pathogenesis through the effects on cell cycle regulatory proteins.[1] Moreover, our group is collaborating with the Regional Mesothelioma Registry instituted by the Campania Region, and entrusted in convention to the II University of Naples under the direction of Professor Massimo Menegozzo. Finally, in collaboration with the SAFU Dept of Regina Elena Cancer Institute in Rome, we are setting up a canine model of spontaneous MM Spontaneous canine neoplasms have been considered in the recent years a valuable and highly underused resource to characterize several tumor types and to evaluate new experimental therapeutics.[2-4] The advantages of this model system include:
1. similarities between specific types of canine and human cancer with regards to histopathological appearence, biological behavior and response to therapy;
2. significant similarity in drug metabolism between dogs and humans;
3. pet owners’ willingness to enter their tumor bearing dogs in humanely conducted clinical trials due to the absence of a well defined “standard” therapy for many canine cancers;
4. the compressed life-span of dogs, which allows the completion of clinical trials in a timely manner; 5. the fact that dogs share the same environment of their owners but lack their unhealthy habits such as alcohol consumption and cigarette smoking which act as “confounding” in many clinical and epidemiological studies;
6. the larger size of dogs compared to rodents which makes feasible to perform many medical procedures;
7. novel interventional strategies developed in vitro or in laboratory animals studies can be tested in dogs affected by cancer, similar studies might be unacceptable or less feasible in human patients, especially when a standard, yet only partially effective treatment exists.

In conclusion, defining all the factors involved in mesothelioma pathogenesis is a very difficult task, that can be accomplished only by a multidisciplinary approach.

References

1. Baldi A., Santini D., Vasaturo F., Santini M., Vicidomini G., Di Marino M.P., Esposito V., Groeger A.M., Liuzzi G., Vincenzi B., Tonini G., Piccoli M., Baldi F., Scarpa S. Prognostic significance of Cyclooxygenase- 2 (COX-2) and cell cycle inhibitors p21 and p27 expression in human pleural malignant mesothelioma. Thorax 2004 (in press)

2. MacEwen EG. Spontaneous tumors in dogs and cats: models for the study of cancer biology and treatment. Cancer Met Rev 1990; 9: 125-136.

3. Hahn KA, Bravo L, Adams WH, Frazier DL. Naturally occurring tumors in dogs as comparative models for cancer therapy research. In Vivo 1994; 8: 133-144.

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Re: Other non asbestos causes of mesothelioma besides the SV40 virus

Dear Editor

In reviewing the literature on non-asbestos causes of mesothelioma I located the paper by Baldi et al.[1]

This paper provides excellent evidence supporting a molecular mehanism on the pathology of mesothelioma. It is mentioned in passing that there may be other causes of mesothelioma besides asbestos. Certainly this paper suggests the SV40 virus as one of these other agents/factors. When evaluating the literature, there is no current list of the other agents/factors identified, besides asbestos, that have been reported to cause mesothelioma. However, it is commonly discussed that other agents/factors exist in causing this disease with most are not able to mention what they are, which I suggest is because no general list has been published identifying these agents/factors. Table 1 provides a list of these agents/factors along with a reference. Familial mesothelioma has been reported,[2] which is unrelated to any causative agent. Mesothelioma has also been indicated to “naturally” occur with a background level of this disease.[3] It should be mentioned that this list does not include all references and there is likely other agents/factors that I missed in my literature search along with others that have yet to be identified.

Table 1 Agents/Factors reported in causation of mesothelioma

The agents/factors listed exclude SV40 and asbestos. Current investigations on asbestos caused mesothelioma’s suggest that these are a result of amphiboles and a dose-response relationship exist.[11] This indicates that a threshold for amphibole asbestos inducted mesothelioma exist with a suggested threshold level of 5 fiber-years.[12] It has been indicated [13] that chrysotile, a serpentine type of asbestos, is not a causative agent of mesothelioma.

References

1. Baldi A, Groeger AM, Esposito V, Cassandra R, Tonini G, Battista T, Di Marino MP, Vincenzi B, Santini M, Angelini A, Rossiello R, Baldi F, Paggi MG. Expression of p21 in SV40 large T antigen positive human pleural mesothelioma: relationship with survival. Thorax. 2002;57:353-6.

2. Risgerg H, Nickels J, Wagermark J. Familial clustering of malignant mesothelioma. Cancer. 1980;45:2422-7.

3. Price B, Ware A. Mesothelioma trends in the United States: an update based on surveillance, epidemiology, and the end results program data for 1973 through 2003. Am J Epidemiol. 2004;159:107-112.

4. Hoffman J, Mintzer D, Warhol MJ. Malignant mesothelioma following radiation therapy. Am J Med. 1994;94:379-92.

5. Ilgren EB, Wagner JC. Background incidence of mesothelioma: animal and human evidence. Regul Toxicol Pharm. 1991;13:133-49.

6. Health Effects Institute - Asbestos Research (1991) Asbestos in public and commercial buildings: a literature review and synthesis of current knowledge. Cambridge, MA.

7. Hillerdal G, Berg J. Malignant mesothelioma secondary to chronic inflammation and old scars. Cancer. 1985;55:1968-72.

8. Huncharek M. Non-asbestos related difuse malignant mesothelioma. Tumori. 2002;88:1-9.

9. Das PB, Fletcher AG, Deodhare SG. Mesothelioma in an agricultural community of India: a clinicopathological study. Aust New Zealand Journal of Surgery. 1976;46:218-226.

10. Dogan AU. Mesothelioma in Cappadocian villages. Indoor-Built Environ. 2003;12:367-75.

11. Price B, Ware A. Mesothelioma trends in the United States: an update based on surveillance, epidemiology, and the end results program data for 1973 through 2003. Am J Epidemiol. 2004;159:107-112.

12. Lange, JH. Has the World Trade Center tragedy established a new standard for asbestos? Indoor-Built Environ. Editorial. 2001;10: 346-369.