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Assessment of Biomarkers in asbestos-exposed workers as indicators of cancer risk

Monday, August 11, 2008

Source: Mutation Research

That exposure to asbestos is the cause of all forms of mesothelioma has been definitively known for many years. Evidence for this relationship was uncovered as early as the 1920s, but the asbestos companies hid this information for as long as they could, so it wasn’t until the 1960s that the carcinogenic aspects of asbestos became true public knowledge. In the wake of the incontrovertible evidence of the mineral’s disastrous health effects, the United States—and nearly all other developed nations—enacted stringent regulations regarding the use of asbestos or outright bans on it. However, these regulations came too little and too late for workers with previous exposures to the fibers. To this day, the United States sees approximately 2500 yearly deaths from mesothelioma and international health organizations estimate that, worldwide, asbestos-related diseases claim 15,000–20,000 lives each year.

Pleural mesothelioma is the most common form of mesothelioma and is commonly associated with a poor prognosis. Mesothelioma treatments are not effective for the long-term management of the disease and most people who are diagnosed will die within 16 months. One of the major reasons for this poor prognosis is that the disease is often misdiagnosed or not diagnosed at all until it hits the later stages, when pleural tissue structures feature significant infiltration and tumor spread that make effective treatment impossible. Studies have shown that earlier diagnoses often correlate with better prognosis and treatability, so there is a great attempt to develop tests that can return a mesothelioma diagnosis earlier than current methodologies allow.

One such research project is actively investigating what, if any, biomarkers are indicative of mesothelioma. A biomarker is a biochemically-expressed substance, such as a protein, that can be used to identify a cancer before its regular symptoms assert themselves. The hope among mesothelioma specialists is that the development of effective biomarker tests will lead to much earlier diagnoses of the disease. Researchers from Italy have recently released the results of a study they commissioned on the use of biomarkers in the diagnosis of mesothelioma and lung cancer. Their data suggests that a combination of elements can be used together to identify the malignancy in high-risk populations.

Overview of the Study

Previous research into the biochemical and genetic foundations of mesothelioma has revealed that a number of specific proteins, growth factors and other substances are significantly over-expressed in mesothelioma patients. These studies have indicated that some of these substances, either singularly or in combination, could be effective for the early diagnosis of asbestos-related diseases (ARDs). The identified substances include 8-hydroxy-2 -deoxyguanosine (8OHdG), interleukine-6 (IL-6), platelet-derived growth factor (PDGF-BB), hepatocyte growth factor (HGF), basic fibroblast growth factor (bFGF), vascular endothelial growth factor (VEGF) and soluble mesothelin-related peptides (SMRPs).

To investigate the efficacy of these substances for marker purposes, the authors enrolled 119 subjects with a history of asbestos exposure into their study. This group was analyzed according to occupational exposures to the fibers, including total exposure burden and duration of exposure. This information was used to develop a risk factor analysis for asbestos-disease and mesothelioma development. They also enrolled a control sample of 54 age-matched individuals who did not have a history of asbestos exposure.

The asbestos workers underwent clinical examination, chest radiography and high-resolution CT, while the control group received chest x-rays that all returned normal results. Both groups had blood drawn that was analyzed for the presence of the identified markers using the standard tests for each substance.

Results

The authors analyzed the presence and distribution of the various markers by sex, smoking history, age, gender and asbestos-group vs. control-group membership. Within the asbestos group they created a job risk assessment that showed that some occupations, such as hands-on work related to pipe fitting, maintenance work and other shipbuilding functions, carried the highest levels of exposures, while office work in environments surrounding areas that featured direct exposures was associated with a significantly less fiber burden.

They found that risk of malignant mesothelioma increased according to cumulative asbestos exposure. 80HdG and IL-6 levels correlated with high levels of SMRPs, which were associated with workers demonstrating the highest asbestos burden. They also found that these groups were most likely to have other asbestos-related diseases (ARDs), such as pleural plaques and fibrosis. The maintenance worker subgroup presented with a 71% of ARDs, pipe fitters with a 57% ARD rate and 50% of electricians were found with ARDs. This is a strong indication of the risks associated with direct exposure, especially when compared to the office worker subgroup which only demonstrated a 10% ARD rate.

Workers demonstrating the highest risk for mesothelioma due to occupational exposure to asbestos also demonstrated higher levels of angiogenic growth factors, such as platelet-derived growth factor (PDGF-BB), hepatocyte growth factor (HGF), basic fibroblast growth factor (bFGF) and vascular endothelial growth factor (VEGF). Angiogenesis is the process by which new blood vessels are formed within tissue structures and it is directed through growth factor signaling pathways. While angiogenesis and growth factor expression are necessary processes for many aspects of tissue growth and are not directly representative of malignant developments, they are absolutely essential for tumor growth, as tumors need blood to fuel their growth and spread.

The authors indicate that prevoiusly-identified “preclinical and clinical evidence suggests that angiogenesis may be a critical step in the pathogenesis of mesothelioma.” Several studies have previously reported on the high levels of VEGF, bFGF, HGF and PDGF found in mesothelioma cells. There is even evidence to suggest that these growth factors form autocrine growth loops in mesothelioma, which means that aside from their facilitation of blood vessel development to mesothelioma tumors, these growth factors may also stimulate the proliferation of mesothelioma cells themselves.

Conclusion

The authors conclude that combination analytics using both growth factor levels and SMRP levels in high-risk populations could be used for mesothelioma diagnoses. Growth factor expression can be indicative of underlying tumor genesis, but these proteins are not specific to mesothelioma, while SMRP levels can be used to separate healthy individuals from mesothelioma patients, but haven’t had the same success in screening out potential mesothelioma patients from other high-risk, asbestos-exposed populations. Thus, screening methodologies that take both elements into account could possibly function as an early diagnostic marker for pleural mesothelioma.

Labels: diagnosis, mesothelioma

posted by Belluck & Fox at 4:24 PM
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