MATRIX METALLOPROTEINASES - INCREASED INVASIVE BEHAVIOR OF CANCER CELLS

There are more than 25 structurally and functionally related to matrix metalloproteinases (Protein MMPs) may stick different components of the ECM, MMPs are making critical physiological and pathological processes related to the renovation ECM. MMP substrates are numerous, including both ECM and non-ECM molecules, such as growth factors and their receptors, adhesion molecules on cells, cytokines, chemokines, apoptotic ligands and growth factors. Over the past 25 years, a role of MMPs in carcinogenesis is well established and assessed (96-102). MMPs are increased invasive behavior of cancer cells and increases the ability of These cancer cells metastasize in animal models. knockout mice deficient
specific MMPs demonstrate reduced tumor growth, invasion and metastasis in compared to their normal counterparts. In clinical specimens, MMPs are up-regulated almost all human malignancies evaluated, and increased expression of MMP is associated with increased invasion, advanced stage and poor prognosis. In contrast, overexpression of tissue inhibitors of protein MMPs (TIMPs), endogenous inhibitors MMPs proteins, reduces the ability of tumors to grow and metastasize in vitro and in vivo, and antisense depletion of TIMPs results in cells that are carcinogenic, invasive and metastatic. In clinical specimens, increased expression of TIMP was associated with less aggressive tumors and a favorable prognosis. In addition, the degradation of ECM, MMPs are also shown to contribute to carcinogenesis
promoting angiogenesis, stimulating tumor growth, which regulate the innate immunity and have anti-apoptotic properties. MMP-related proteases a disintegrin and metalloproteinase (ADAM) and ADAM with thrombospondin repeats (ADAMTS), have also recently come to the attention of researchers role in promoting cancer progression (99). Despite the encouraging results of basic research and preclinical testing models, large-scale Phase III trials of MMP inhibitors (MMPIs) not to show a statistically significant survival advantage in most of the advanced stage malignancies the respondents. In fact, in some studies where the MMPI treatment compared with placebo, MMPI arm was associated with worse outcomes. main reasons for the collective failure of these large and expensive clinical trials of MMPI early 1990 are many, and There are also revised in 2008 (96-102). In short, the mouse models
can not completely model human diseases, and dose-limiting toxicity is difficult to estimate
in animals. However, the promising activity in animal models clearly link with early stage disease, but most clinical studies were initiated in patients with late stage of the disease. Appropriate dosage MMPI was never achieved, and the optimal biological dose (OBD) was never clearly defined prior to clinical tests. Moreover, the researchers started with the patient in a fraction of the dose was effective in mice, and the dose was reduced or patients taking drugs leave if muscle toxicity develops. Interestingly, the toxicity was probably an indicator
good response. The wide range nature of the MMPIs used in clinical trials were also inappropriate because the MMPs are have different and sometimes opposing effects, depending on micro environmental contexts. We now know that not all MMPs to eliminated to a reaction against the tumor away. The unsuccessful completion of the MMPI clinical trials, there was a Slowly return to the performance evaluation studies of the association and the MMPs are inhibitors in cancer prognosis. There was a similar slow recovery optimism
MMPs that are part of the tumor microenvironment that can successfully therapeutic target. Before then, however, researchers must determine which MMPs are his "good" and "bad" in each histological subtype malignancy during each stage of this malignancy, and clinical
tests should be adapted to the knowledge gained from these studies to adapt. Detailed knowledge of the target MMP, substrate, and the mechanism of activity in vivo is a prerequisite for the most appropriate and effective anti-tumor drugs should be designed. MMP-related research was under investigation last 3-5 years have been informed by the past failures of the research community. "Most researchers attempt to link MMP expression with prognosis is now more aware the expression and the final function of MMP proteases during carcinogenesis are often formed by the microenvironment, MMPs are to diverse and sometimes opposing effects, depending on their source tissues location and stage of disease expressed. Here Recent studies on the expression of MMP clinical outcome in a way that clearly informed by the past failures of the MMP-related cancer treatment. Extracellular matrix metalloproteinase inducer (EMMPRIN? CD147) is a transmembrane protein on the surface of many tumor cells. By stimulating production of MMPs are tumor-adjacent stromal cells, EMMPRIN contributes the accumulation of selected MMPs are tumor microenvironment and therefore associated with invasion and metastasis of cancer, in some institutions. LEINONEN and colleagues analyzed the expression of MMP-2 and inducer, EMMPRIN, a 212 surgical resection specimens of NSCLC (103). Immunohistochemical staining MMP-2 and EMMPRIN was evaluated both cancer and tumoradjacent mattress. High expression of MMP-2 was observed in tumor cells in 44% of cases, with adenocarcinomas with more expression than the other NSCLC cancers. High expression of MMP-2 by tumor cells was associated with increased tumor recurrence (p = 0.001). The layer of the tumor was positive for MMP-2 expression in 98% of cases with 72% of these cases the highest score possible intensity of the spots. High expression of MMP-2 in tumor-adjacent
layer was more often associated with large carcinomas compared with other forms of lung cancer. high expression of EMMPRIN from tumor cells was found in 61% of cases and correlated with high MMP-2 expression by tumor cells (p = 0.006). High tumor cell MMP-2 expression is associated with a reduced general survival and reduced disease-free survival (p = 0.018 and 0.001, respectively) as made large stromal MMP-2 expression (p = 0.010 and 0.045, respectively). By multivariate analysis, however, only increased stromal expression of MMP-2 was independent predictor of poor overall survival and disease-free survival
(P = 0.028 and 0.039, respectively). These data suggest that MMP-2 expression by tumor cells and tumor-adjacent layer is considered separately, MMP-2 has significant predictive value in determining the NSCLC and could be useful in determine which patients have more aggressive disease. resected NSCLC tumors with 150, and colleagues evaluated the Sienel expression of EMMPRIN in association with MMP-2 expression, MMP-9 expression and
overall survival (104). If the team LEINONEN this group rated the intensity size and cellular localization of EMMPRIN staining. of 145 tumors studied 61 of the tumors displayed intense colors and EMMPRIN staining was localized in the tumor cell membrane in 102 volumes. expression of EMMPRIN not associated with MMP-2 and MMP-9 expression in this study. By multivariate analysis, identification of membrane EMMPRIN associated with less survival in patients with adenocarcinoma (p = 0.03), but not squamous cell carcinoma. In fact, the multivariate analysis, the membrane expression of EMMPRIN was independent predictor of patient survival for the group of adenocarcinoma (P = 0.04). The authors suggest that in some institutions, EMMPRIN may play a role the development of NSCLC is independent of its function as an inducer of Proteins MMPs. Generally, studies show that even within LEINONEN Sienel and Non-small cell lung carcinoma, MMP expression patterns and associations with prognosis depends on the histological subtypes. Hakuma and colleagues conducted a similar immunohistochemical evaluation of 208 surgical resection specimens of NSCLC (105). While EMMPRIN expressed by 92% of the samples non-small cell lung cancer, this group found no significant differences in overall survival between patients with high tumor EMMPRIN expression and those with low expression. It should be noted that these study was semi-quantitative, and levels of tumor-adjacent layer EEMPRIN
not evaluated in previous studies. Kim and colleagues examined MMP enzyme activity in normal and cancerous tissues of 34 patients with surgical resection of stage I NSCLC (106). MMP-2 enzyme activity in nontumor tissue was significantly different in patients who later was found with relapse compared with those without recurrence, and this was associated with
the 5-year survival. The authors suggest that MMP-2 enzyme activity in nontumor tissue can be used as a predictive biomarker gives postoperative tumor recurrence and survival in early NSCLC patients. Furthermore, the authors tones that can be used to assist in decision making which patients are most needed postoperative chemotherapy to complete. When considering their micro-marrow involvement and MMP expression in bone aspirates of 57 patients with NSCLC, Hsu and colleagues found that MMP-13 expression by tumor cells is an independent prognostic factor by multivariate Cox Analysis (107). The overall 5-year survival was 36.8%. While the existence Micro involvement of bone marrow did not affect the prognosis, patients
Aspiration of bone marrow, which were positive for MMP-13 expression (n = 34) were
decreased 5-year survival of 26.5% (p = 0.025). The authors suggest that non-small cell lung cancer cells with high MMP-13 expression throw a whole bone marrow leads the worst survival. By examining MMP-7 expression in 147 non-small cell lung cancer samples, Liu and colleagues showed that MMP-7 expression is associated with the spread of cancer and
poor prognosis in NSCLC, possibly through regulation of Wnt1 expression in tumor cells
MMP-7 (108). Overall survival was significantly lower in patients with MMP-7- positive tumor cells, compared to those with MMP-7-negative tumor cells (p = 0.0018). By multivariate analysis, MMP-7 status was significant prognostic factor (hazard radio 2187? p = 0.0023). Mino and colleagues examined 143 resected NSCLC samples, the evaluation
TIMP-3 expression in combination with a large number of clinical parameters including prognosis (109). TIMP-3 is an endogenous protein inhibitor of MMPs to select including MMP-2. TIMP-3 expression was higher in squamous cell carcinoma in adenocarcinoma, and low levels of TIMP-3 expression significantly correlated with nodal involvement (p = 0.016) and stage (p = 0.036). MMP-2 expression was also reduced compared with TIMP-3 expression (p = 0.010). By multivariate analysis, high expression of TIMP-3 when an independent indicator of favorable prognosis (p = 0.037). Reversion-inducing cysteine-rich protein with Kazal motifs (PER) is a endogenous MMP inhibitor demonstrated that angiogenesis, invasion and metastasis inhibiting in association with the inhibition of MMP-2, MMP-9, and MTP-1/MMP-14 (110). Takemoto and colleagues analyzed PER expression of MMP-2, MMP-9 and MMP-14 expression in 83 NSCLC resection specimens and 20 matched normal tissue samples from the lung (111). Expression of PER in tumor samples was significantly lower than in control tissues. In addition, PER was higher in adenocarcinomas than stage IA adenocarcinoma stage IB-IIIA. By multivariate Cox analysis, the low expression of PER (p = 0.036) was significant negative prognostic predictors of relapse-free survival. No one has between the expression of PER and survival rate for squamous cell carcinoma. This suggests that the repression of expression PER contributes to the development adenocarcinoma histological subtype of NSCLC and that the expression
the PER is a good predictor of prognosis. studies suggest that they also indicated
NSCLC in different patterns of expression of MMPs are MMP inhibitors and In the histological subtype and stage of disease. Taken together, these studies also show that the partition (volume in relation to low), and even the type of cells expression of MMP or MMP inhibitor should be considered as strong correlations going to be a clinically relevant parameters such as survival. Overexpression of Treatment of normal tissue remains to be assessed PER preclinical and the effect of PER on the development direction established vascular system still considered. interest, HDAC inhibitors (Trichostatini A) increased levels of AT by minimizing the suspension supporter of PER (112). Moreover, NSAIDs PER
expression, perhaps due to inhibition of the path ras/ERK/Sp1. This action seems to be regulated by PER, which is independent of NSAID action cyclooxygenase by concomitant administration of PGE2, or overexpression COX-2 in lung cancer cells does not affect the level of PER (112). This makes it HDAC inhibitors an instrument for increasing levels of PER in tumor microenvironment. In the future MMPs associated with cancer treatments can take the form of antisense oligonucleotides, siRNA, shRNA, or recombinant antibodies, small molecular inhibitors of the weight will likely remain cheaper and easier to manufacture,
manufacture and supply. As assessed by Konstantinopoulos et al. (98), a wide range MMPIs will probably be replaced with more specific MMPIs that a goal or several MMPs are expressed in specific cancers at certain stages of the disease, which can eliminate a number of musculoskeletal toxicity associated with the use of broad spectrum MMPIs. Next-generation MMPIs probably first be evaluated in acute settings and Stokes, for clinical use in the definition of chronic diseases such as cancer. As suggested in a review of the general and Kleifeld (102), validating MMPs as therapeutic targets and understanding the role of targets and nontargets requires the use of surrogate markers that dose escalation could lead. Determination molecular markers to predict the response is also helpful. The auditors
show that the generation of additional MMP-knockout mice crossed with models
spontaneous cancers is essential if we want to study and MMP-related layoffs preclinical studies of drug resistance. Furthermore, combinations with other MMPIs chemotherapy or molecular targeted agents have preclinical evaluation. If these proposals are implemented in future clinical trials carefully selected patient populations with very specific malignancies at predetermined stages justified, despite the disappointing past MMPIs in cancer therapy.