**7. Conclusions**

MM is a fatal form of cancer derived from pleural mesothelial cells. Its etiology usually involves professional and/or environmental exposure to asbestos. Unluckily, early symptoms of this pathology are commonly nonspecific, and this generally entails a diagnosis of the disease at an advanced stage. There are several studies in literature dealing with potential biomarkers for MM early diagnosis and its differentiation from secondary pleural metastases, benign exudative forms and pleural plaques typical of subjects previously exposed to asbestos. If one considers what said so far, it appears clear that the use of reliable biomarkers (sensitive and specific) might be decisive for MM patients' diagnosis, lengthening their life expectations.

The results of the various studies suggest that Fb3 may have a role in developing neoplastic as well as non-neoplastic diseases of the respiratory tract in subjects exposed to asbestos and/or asbestiform fibers. Moreover, some surveys are looking into the hypothesis that Fb-3 might be accounted for the malignant mutation of mesothelial cells after exposure to asbestos fibers.

In fact, chronic inflammation may induce cancer through the production of several cytokines and growth factors, which, as a consequence, may cause the apoptosis and cell proliferation process to alter. About this, it has been observed that p27, an onco-suppressor gene, often deactivated in tumors, gets downregulated in mesothelial cells after exposure to asbestiform fibers. In the same way, Fb-3 has been seen as significantly decreasing in several cancers, this suggesting its potential role as oncosuppressor gene and as antagonist to angiogenesis. However, conflicting scientific data point out a different role for Fb-3, like a "Dr Jekyll and Mr. Hyde" pattern, and suggest that Fb-3 may rather act as promoter of tumor invasion and survival, as in malignant gliomas, fostering angiogenesis. A reasonable interpretation of such pattern may be due to the aberrant methylation of Fb-3 promoter, since the Fb-3 expression is regulated by the hypermethylation of the promoter and/or by the interference of Fb-3 with the activation of kinase B protein (AKT).

In conclusion, circulating Fb-3 seems to be able to tell healthy asbestos-exposed subjects from MM patients. Fb-3 in the pleural liquid is thought to further differentiate MM subjects from those with benign and/or malignant effusions.

To validate present results and test the effectiveness of Fb-3 combination with other possible biomarkers, it will be necessary to recruit larger numbers of patients. The combined use of more biomarkers seems likely to guarantee more reliable results in terms of sensitivity and specificity so as to allow to tell, already at an early stage, MM from other pathologies of various nature. In the same way, using several biomarkers together with clinical-diagnostic exams, might contribute to carrying out the screening of populations exposed to asbestos/asbestiform fibers like in the abovementioned case of subjects living in Biancavilla (CT), exposed to FE fibers released in the surrounding area.
