**4. ECM remodeling and matrix metalloproteinases**

Each tissue has an ECM with a unique composition, which is formed by biochemical and biophysical interaction between the various cellular components (e.g., fibroblast and endothelial elements) and the evolving cellular and protein microenvironment [1]. There is a constant turnover of ECM in the body and it is being regulated with either enzymatically or nonenzymatically which makes ECM a dynamic structure.

Matrix metalloproteinases (MMPs) are a large family of endopeptidases, which are calciumdependent zinc-containing enzymes. They are responsible for the degradation of the ECM in which they assist the tissue remodeling and they play a central role in tissue homeostasis [8]. They are present in both pathologic and normal tissues performing proteolytic action [9]. The main cell types excreting MMPs are macrophages, fibroblasts, osteoblasts, endothelial cells, neutrophils and lymphocytes [8].

MMPs have been studied in many conditions. It has been found that they have an impact on tumor cell behavior as a result of their ability to make alterations on cell surface receptors, growth factors, cell adhesion molecules and cytokines. Furthermore, MMPs are able to produce apoptosis-resistant cells, which leads to generation of an aggressive phenotype. MMPs may also regulate angiogenesis positively or negatively in cancer depending on activation of proangiogenic factors or generation of angiogenesis inhibitors, respectively [10].

In bladder cancer, it has been shown that there is a correlation with the levels of MMP-2 and MMP-9 and tumor grade and invasiveness [11]. MMP-2 levels were also found to be strongly associated with tumor stage and prognosis [12]. In a study, serum level of MMP-7 was also found to be associated with the prognosis of the patient. It is reported that in bladder cancer patients treated with radical surgery high MMP-7 plasma levels were significantly associated with poor overall- and disease-specific survival [13].
