Potential Biomarkers for Malignant Mesothelioma (MM) in Asbestos Exposure and MM Patients

by | Jan 4, 2016 | 2014, Cancer, Mesothelioma, Pollution

Written by Joyce Smith, BS. Study shows RANTES has the potential to be a critical biomarker for MM prognosis.

Asbestos exposure and its association with mesothelioma is well documented. While Crocidolite asbestos is considered the asbestos type most pathogenic in the development MM, the Word Health Organization maintains that all types of asbestos fibers can cause cancers in humans (1-4). A genetic predisposition to MM and the SV40 virus have also been implicated in asbestos related malignancies (5-7). Studies have also shown that insulin-like growth factor-1 enhances the growth and tumor development of mesothelial cells in the presence of the SV40 virus, thus contributing greatly to a shorter survival of MM patients (8, 9).

Unfortunately, the long and unpredictable latent period of MM and its low incidence in individuals exposed to asbestos makes the diagnosis of MM very challenging. In fact, it is often in the late stages of the disease when diagnosis is finally established and treatment can begin.

Because asbestos-induced mesothelial inflammatory processes are thought to be the basic mechanism underlying MM development, researchers in this study set out to explore the inflammatory process that occurs in the body following asbestos exposure and to detect any immunological biomarkers that might be useful in the early diagnosis of asbestos-related MM.

To achieve this goal, researchers took serum samples from 43 subjects and studied their immunological profiles using a large panel of analytes that included 47 cytokines and growth factors. The 43 study participants were divided into 3 groups:

  • Workers previously exposed to asbestos but free from MM disease (Asb-workers) (n=15)
  • Asbestos patients with MM (n=15)
  • Healthy individuals (control group, n=13)

All 43 participants were from an Italian hyperendemic area where massive use of asbestos in dockyards and shipyards had occurred. Because SV40 virus is considered a cofactor in MM development (10), (11-13), researchers also tested all participants for the presence of this virus and calculated its influence when they analyzed their results.

Polymerase chain reaction was performed to detect the presence of SV40 and immune assays were done to determine the presence of inflammation and the concentration of cytokines and growth factors.

Results:

A variety of 25 cytokines linked to pulmonary inflammation and tumor development were significantly associated with Asb-workers and MM patients compared to healthy controls.

  • In Asb-workers, the following pattern of cytokines were found highly expressed:

IFN-alpha (p<0.05), EOTAXIN (p<0.01), RANTES (p<0.001)

  • In MM patients the following pattern was expressed:

IL-12(p40), IL-3, IL-1 alpha, MCP, beta-NGF, TNF-beta, RANTES (p<0.001).

  • The C-C chemokine RANTES measured the highest serum level, and increased in concentration from 0.52 pg/ml in healthy subjects to 23004 pg/ml in Asb-workers and 34539 pg/ml in MM patients (p<0.001) suggesting a strong association of this growth factor with exposure to asbestos fibers. An ELISA assay further verified these results.
  • A cytokine profile of 8 inflammatory molecules, not including RANTES, were significantly associated with SV40 infection in MM patients (n=5) compared to MM patients who were not infected with SV40 (n=10).
  • In SV40 –positive MM patients compared to SV40 –negative MM patients the following pattern was expressed: IL-15, EOTAXIN, MIP-1ß, IL-18, IFN-α2, and HGF were unregulated (p <0.01) while MCP-3 and MIF (p<0.01) were found at lower levels.
  • RANTES, although not significantly higher, was higher in SV40- negative MM patients (34,000 pg/ml) compared to SV40- positive patients (18,000 pg/ml) thus reinforcing the association of RANTES with asbestos.
  • The growth factor HGF was, for the first time, shown to be significantly associated with SV40 infection in the sera of patients with MM.

Conclusion:

Even though the number of study subjects was small, this pilot study demonstrated a significant increase in the level of RANTES both in workers chronically exposed to asbestos and in asbestos-induced MM. It showed for the first time that C-C Chemokine RANTES is significantly associated with asbestos exposure, inflammation, and an increased risk for malignant mesothelioma.

If larger studies validate these results, RANTES could have the potential to be a critical biomarker for MM prognosis.

Source: Comar, Manola, Nunzia Zanotta, Alessandra Bonotti, Mauro Tognon, Corrado Negro, Alfonso Cristaudo, and Massimo Bovenzi. “Increased levels of CC chemokine RANTES in asbestos exposed workers and in malignant mesothelioma patients from an hyperendemic area.” PloS one 9, no. 8 (2014): e104848. 

© 2014 Comar et al. Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Click here to read the full text study.

Posted September 3, 2015.

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