**3. Potential roles of MMPs as biomarkers for MM**

#### **3.1 Pathological markers**

To date, MM is still difficult to diagnose in early stages due to our limited knowledge of its molecular pathogenesis. Indeed, pathological examination techniques to diagnose MM and distinguish MM from other diseases must be improved [44]. However, more molecular markers are required to distinguish benign from malignant mesothelial disease or other tumors. In addition, effective pathologic predictors of prognosis and therapeutic response are urgently needed. Since MMPs are involved in tumor pathogenesis, some MMPs may be potential pathological markers.

*Potential Roles of Matrix Metalloproteinases in Malignant Mesothelioma DOI: http://dx.doi.org/10.5772/intechopen.88783*

In general, MMP expression and activation are very low and tightly regulated during normal tissue homeostasis. MMP production and activation are rapidly induced during active tissue remodeling and in pathological conditions such as cancer [37]. MMP-7 and MMP-14 are potential diagnostic and prognostic biomarkers of mesothelioma, respectively. MMP-7 is a highly specific negative biomarker to distinguish MM from other high-grade serous carcinomas with 100% specificity and moderate sensitivity, but it cannot distinguish mesothelial cells from reactive mesothelial cells in serous effusion due to uniformly negative expression of MMP-7 in reactive mesothelial cells [45]. It is intriguing that MMP-14 is a potential biomarker for the differential diagnosis of MPM and reactive mesothelial hyperplasia (MH). A group from Italy found that MMP-14 expression is markedly increased in MPM patient specimens compared with MH specimens based on polymerase chain reaction array and immunohistochemistry analyses [46]. MMP-14 levels have been reported to be elevated in all tissue samples from MM patients compared to those from normal individuals, but more evidence is needed to substantiate MMP-14 as a diagnostic biomarker for MM [47]. MMP-14 expression has prognostic value for MM. Clinically high MMP-14 expression in MM patients is significantly correlated with poor prognosis [47].

#### **3.2 Genetic biomarkers**

Although most mesotheliomas are attributable to asbestos exposure, genetic factors are also important causes of carcinogenesis. Gene mutations influence the prognosis of MM. For example, heritable mutations in BRCA1-associated protein-1 (BAP1), a tumor suppressor gene, may predispose individuals to asbestos-related MM [48, 49]. Moreover, Baumann et al. reported that mesothelioma patients with germline BAP1 mutations have a seven-fold improvement in long-term survival [50].

More recently, some MMP single-nucleotide polymorphisms (SNPs) have been found to have potential as genetic biomarkers for MM. For instance, Štrbac et al. reported that patients carrying a polymorphic MMP-9 rs2250889 allele had a negative outcome, with a shorter time to progression (TTP) (6.07 vs. 10.03 months, HR = 2.45, 95% CI = 1.45–4.14, p = 0.001) and worse overall survival (OS) (9.23 vs. 19.2 months, HR = 2.39, 95% CI = 1.37–4.18, p = 0.002) than those with the reference allele [51]. However, patients harboring at least one polymorphic MMP-9 rs20544 allele had a positive outcome, with a longer TTP (10.93 vs. 9.40 months, HR = 0.57, 95% CI = 0.38–0.86, p = 0.007) and improved OS (20.67 vs. 13.50 months, HR = 0.56, 95% CI = 0.37–0.85, p = 0.007) [51]. These researchers also found that the MMP-2 rs243865 polymorphism plays a protective role in MM; carriers of this polymorphism have a decreased risk for MM (OR = 0.66, 95% CI = 0.44–1.00, p = 0.050) [52]. Interestingly, the decreased risk for MM is more pronounced in people exposed to asbestos [52]. These findings provide insight into some MMP SNPs that are considered genetic biomarkers, indicate the prognosis of MM patients, and predict susceptibility to MM. In the future, appropriate genetic counseling and clinical management should be considered for MM patients who are carriers of MMP-2/MMP-9 susceptibility SNPs.

#### **4. Conclusion**

In this chapter, we provide an overview of recent findings on MMP function in MM and the mechanisms by which MMPs may induce both phenotypic and genotypic alterations that facilitate MM progression and invasion. Accumulating evidence indicates that tumor-associated MMPs can stimulate processes associated with EMT, a developmental event that is activated in MM cells during invasion and metastasis. Meanwhile, future investigations on extracellular targets and intracellular signaling pathways through which MMPs can induce EMT of MM cells will provide insight into novel therapeutic targets. We also describe possible roles of MMPs as pathological markers or genetic biomarkers in MM. Certainly, the underlying mechanisms of secreted MMPs, including their function and circulation, are complex in MM and remain to be elucidated in the future.
