Matrix metalloproteinases participation in the metastatic process and their diagnostic and therapeutic applications in cancer.

Matrix metalloproteinases (MMPs) participate from the initial phases of cancer onset to the settlement of a metastatic niche in a second organ. Their role in cancer progression is related to their involvement in the extracellular matrix (ECM) degradation and in the regulation and processing of adhesion and cytoskeletal proteins, growth factors, chemokines and cytokines. MMPs participation in cancer progression makes them an attractive target for cancer therapy. MMPs have also been used for theranostic purposes in the detection of primary tumor and metastatic tissue in which a particular MMP is overexpressed, to follow up on therapy responses, and in the activation of cancer cytotoxic pro-drugs as part of nano-delivery-systems that increase drug concentration in a specific tumor target. Herein, we review MMPs molecular characteristics, their synthesis regulation and enzymatic activity, their participation in the metastatic process, and how their functions have been used to improve cancer treatment.

Differences in plasma MMPs and TIMPs protein expression and chemotherapy response in patients with tobacco- or wood-smoke-induced lung cancer.

BACKGROUND: One of the risk factors associated with lung cancer in never-smoker patients is wood smoke exposure (WS). However, information about its clinical and molecular characteristics remains scant. OBJECTIVE: This was to analyze--in plasma from patients with tobacco- or wood-smoke-induced lung cancer--whether the enzymatic activity and concentration of matrix metalloproteinases (MMPs) and tissue inhibitors of matrix metalloproteinases (TIMPs) differ, and to determine whether there was a correlation between these indicators of the metastatic potential and the first-line chemotherapy response. METHODS: Patients were classified according to lung cancer associated with: the smoking of tobacco (T), WS and where no association with a known risk factor (N) could be established. The gelatinase activity of plasma MMP was analyzed by radiolabeled substrate degradation and zymography assay. Protein expression of MMPs and TIMPs was evaluated by Western blot densitometry analysis. RESULTS: The 26.9% WS patients had a better response to therapy in comparison with the T group (OR = 4.9, 95% CI = 1.25-20.15; p = 0.019). The lowest gelatinase activity was observed in WS subjects, in comparison with T and N subjects (96.7 ± 15.9, 182.9 ± 31.5 and 163.3 ± 22.7 µg of degraded gelatin/mg of incubated plasma protein, respectively; p < 0.025); this enzymatic activity corresponded to MMP-2. The highest MMP-2, MMP-9, MT1-MMP and TIMP-1 plasma levels were observed in T subjects. CONCLUSION: Tobacco and wood smoke have different effects on MMP and TIMP synthesis and gelatinase activity, directly influencing lung cancer metastatic potential and chemotherapy response.

Gelatinase activity of matrix metalloproteinases during first-line chemotherapy in lung adenocarcinoma patients: an initial approach.

BACKGROUND: The aim of this study was to determine if gelatinase activity of plasma matrix metalloproteinases (MMPs) can be used as a method to assess chemotherapy response and cancer progression in primary lung adenocarcinoma patients. METHODS: A group of 28 patients was divided according to risk factor as follows: lung cancer associated with wood smoke exposure (LCW), lung cancer in tobacco smokers (LCT), and patients with no association to a known risk factor (LCN). Plasma gelatinase activity was measured by zymography and radiolabeled gelatin degradation. RESULTS: The chemotherapy response was better in the LCW group (25%) compared with the LCT (7.1%) patients (P = 0.039). MMP gelatinase activity was increased in all lung cancer subjects. Patients with progression of the disease had a significant increase in gelatinase activity compared with subjects, with a response to treatment (330.3 ± 44.4 and 64.9 ± 8.5 µg of degraded gelatin/mg of incubated plasma protein, respectively, P = 2.972 × 10(-5)). Zymography assay revealed that the increase in gelatinase activity corresponded mainly to MMP-2. CONCLUSIONS: Patients with progression of lung adenocarcinoma, mainly from the LCT group, had an increase in gelatinase activity compared with subjects that responded to chemotherapy. Therefore, plasma gelatinase activity, particularly MMP-2 enzymatic activity, could be used as a way to assess lung adenocarcinoma progression as well as an indicator for the use of MMP-2 inhibitors.