Matrix metalloproteinase (MMP) expression by differentiated thyroid carcinoma of children and adolescents

The factor(s) that control metastasis of thyroid carcinoma are unknown, but the matrix metalloproteinases (MMPs) are excellent candidates. MMP-1, membrane-type-1 MMP (MT1-MMP), and tissue inhibitor of MMP-1 (TIMP-1) have all been implicated, but the site of production and importance are disputed. In vitro, normal thyroid cells secrete TIMP-1, while thyroid cancer cells secrete TIMP-1 and MMP-1. However, previous pathological studies identified MMP-1 and TIMP-1 only in the stroma surrounding thyroid carcinoma. These data suggest that thyroid carcinoma or tumor-associated inflammatory cells might secrete a factor(s) which stimulates MMP-1 or TIMP-1 expression by surrounding tissues. We hypothesized that MMP-1, MT1-MMP, and TIMP-1 would be directly expressed by thyroid carcinoma and might promote invasion or metastasis. We used immunohistochemistry to determine the expression of MMP-1, MT1-MMP, and TIMP-1 in 32 papillary thyroid carcinoma (PTC), 10 follicular thyroid carcinoma (FTC) and 13 benign thyroid lesions from children and adolescents. The intensity of staining was graded from absent (grade 0) to intense (grade 3). Average MMP-1 expression (mean relative intensity units+/-SE) was significantly greater among PTC (1.97+/-0.15; p=0.004) and FTC (2.2+/-0.25; p=0.006) compared to benign lesions (1.30+/-0.15); but there was no relationship between MMP-1 expression and invasion, metastasis, or recurrence. Expression of MT1-MMP and TIMP-1 was similar for benign and malignant lesions; but recurrent PTC expressed lower levels of TIMP-1 when compared to non-recurrent PTC (p=0.049). Only the expression of TIMP-1 correlated with the presence of tumor-associated lymphocytes (r=0.35, p=0.032). We conclude that MMP-1, MT1-MMP and TIMP-1 are all expressed by thyroid carcinoma and could be important in promoting recurrence.     

Enhanced Cell Surface Expression of Matrix Metalloproteinases and Their Inhibitors, and Tumor-Induced Host Response in Progression of Human Gastric Carcinoma

The cell surface and/or intracellular expression of the matrix metalloproteinases (MMP -2, 7, and -9 and MT1-MMP) and their inhibitors (TIMP-2 and -4) were investigated in tumor and tumor-infiltrating lymphocytes (TIL) in gastric carcinoma (n = 15) from the primary locus, metastatic gastric carcinoma (n = 20) from malignant ascites, and benign gastric mucosa (n = 20) for the control. The quantitative analysis was based on the percentage of positive cells by flow cytometry. The results clearly showed increased cell surface expression of MMP-2, -7, and -9, MT1-MMP, and TIMP-2 and -4 in both tumor cells and TIL during the development of invasion and/or metastasis of gastric carcinoma. There were equilateral correlations with cancer progression and frequency of cell surface expression of MMPs and their inhibitors, TIMPs, suggesting not only the aggressive nature of particularly metastatic gastric carcinoma, but also the presence of MMPs complexed with TIMPs on tumor cells and TIL. The enhanced cell surface expression of MMPs and TIMPs on TIL within metastatic carcinoma nests showed the result of a host response induced by tumors. These suggest that the increased cell surface expression of MMPs and TIMPs, and tumor-induced host response play a key role in gastric cancer invasion and/or metastasis.     

Expression of membrane-type matrix metalloproteinases in synovial tissue from patients with rheumatoid arthritis or osteoarthritis

We investigated the expression of membrane-type matrix metalloproteinase (MT-MMP) and matrix metalloproteinase (MMP) mRNAs in synovial tissue from patients with rheumatoid arthritis (RA, n = 5) or osteoarthritis (OA, n = 5) by Northern blot analysis. Northern analysis demonstrated strong expression of MT1-MMP, MT3-MMP, MMP-1, and MMP-3 and weak expression of MT2-MMP and MMP-8 in synovial tissue from patients with RA or OA. MT4-MMP was not detected. No significant difference was shown in the expression of MT-MMP mRNAs between RA and OA. Synovial tissue of RA or OA patients expressed MT-MMPs as well as MMPs. These results indicate that, in addition to MMPs, MT1-MMP, MT3-MMP, and probably MT2-MMP may play a role in the degradation of bone and cartilage matrix in RA and OA. Such information may provide a clue to the development of a novel therapeutic approach targeted on the prevention of joint destruction. Received: April 30, 2000 / Accepted: September 19, 2000     

Induction of membrane-type matrix metalloproteinase-1 stimulates angiogenic activities of bovine aortic endothelial cells

Matrix metalloproteinases (MMPs) have been reported to play critical roles in endothelial cell migration and matrix remodeling during the angiogenic process. Among these MMPs, membrane-type MMP-1 (MT1-MMP) is an important molecule that can trigger the invasion of tumor cells by activating MMP-2 on their plasma membrane. However, the precise involvement of MT1-MMP in the angiogenic process has not been determined. To investigate the roles of the MT1-MMP by the matrix remodeling of endothelial cells, MT1-MMP expression vector was transfected into bovine aortic endothelial cells (BAECs). Increased expression of MT1-MMP in BAECs enhanced the activation of MMP-2, invasion and migration of BAECs. Moreover, the capacity of tube formation was increased in MT1-MMP transfectants. However, cotransfection with antisense MT1-MMP expression vector abolished the effects of MT1-MMP overexpression. These observations indicate that MT1-MMP is involved in the angiogenic process of endothelial cells in vitro. This revised version was published online in June 2006 with corrections to the Cover Date.     

膜型基质金属蛋白酶-1与肝细胞癌侵袭转移性的关系

目的 探索膜型基质金属蛋白酶－１（ｍｅｍｂｒａｎｅ－ｔｙｐｅ１ｍａｔｒｉｘ ｍｅｔａｌｌｏｐｒｏｔｅｉｎａｓｅ,ＭＴ１－ＭＭＰ）与肝细胞癌（ＨＣＣ）侵袭转移性的关系及以ＭＴ１－ＭＭＰ来判断肝细胞癌侵袭转移性的可能性和方法。方法 通过ＲＴ－ＰＣＲ对正常肝、ＨＣＣ及其癌旁组织、癌栓组织,裸鼠人肝癌高、低转移模型中的ＭＴ１－ＭＭＰｍＲＮＡ进行半定量研究,并与ＨＣＣ侵龚转移的病理指标进行统计分析,结果 正     

The prognostic value of metalloproteinases and angiogenic factors in ovarian carcinoma

The objective of this study was to analyze the correlation between matrix metalloproteinases (MMPs) and angiogenic genes and survival in advanced-stage ovarian carcinomas. Primary and metastatic ovarian carcinomas from patients diagnosed with FIGO stage III-IV disease and followed up to 20 years were studied using mRNA in situ hybridization (ISH). Expression of MMP-2, MMP-9, membrane-type 1-MMP (MT1-MMP), the MMP inhibitor TIMP-2, vascular endothelial growth factor (VEGF), interleukin-8 (IL-8) and basic fibroblast growth factor (bFGF) was studied. MMP-2, MMP-9 and TIMP-2 mRNA was detected in both tumor and stromal cells, while MT1-MMP was largely confined to tumor cells. In univariate analysis of primary tumors, TIMP-2 and MMP-9 mRNA expression correlated with poor outcome. In metastatic lesions, mRNA expression of TIMP-2, MMP-2, and MT1-MMP correlated with poor survival. In a multivariate analysis of primary tumors, TIMP-2 expression in stromal cells (P=0.006) and MMP-9 expression in tumor cells (P=0.011) retained their predictive value. Intense expression of bFGF mRNA and weak expression of IL-8 mRNA was detected in both stromal and tumor cells in most cases, while VEGF mRNA expression was limited to a few cases. Angiogenic mRNA expression showed no correlation with disease outcome in survival analysis (P>0.05). We conclude that bFGF is the major angiogenic factor expressed in ovarian carcinoma at the mRNA level. MMP-2, MMP-9, MT1-MMP and TIMP-2 are valid markers of poor survival in advanced-stage ovarian carcinoma.     

Coordinate cell-surface expression of matrix metalloproteinases and their inhibitors on cancer-associated myofibroblasts from malignant ascites in patients with gastric carcinoma

Purpose:The crucial role of tumor stroma in cancer cell invasion has been described in human carcinoma tissues. However, myofibroblastic invasion remains largely unexplored in malignant ascites. Purpose of this study is to investigate the spatial localization or regulation of matrix metalloproteinases (MMP-2, -7 -9, MT1-MMP) and their inhibitors (TIMP-2 and -4) on myofibroblasts from malignant ascites in 20 patients with gastric carcinoma. Methods: The quantitative flow cytometric analysis of MMPs or TIMPs on myofibroblasts was based on the percentage of double positive cells defined by anti MMPs or anti TIMPs, and anti α-smooth muscle actin (α-SMA) antibodies. Result: The results clearly showed that the coordination of the high level of cell-surface expression of secreted MMPs and TIMPs was noted on the α-SMA⁺ myofibroblasts. The finding suggests the possible formation of ternary complex, MT1-MMP/TIMPs/MMPs on the cells. The events might be a cause and result of activation processing of MMPs on the cells. Conclusion: This study provides the presence of invasive myofibroblasts with activated MMPs in close association with MMPs⁺ and TIMPs⁺ cancer cells and tumor-infiltrating lymphocytes from malignant ascites, emphasizing the importance of molecular cross-talk in tumor-host microenvironment for cancer invasion, metastasis and progression.     

Chronic hypoxia inhibits MMP-2 activation and cellular invasion in human cardiac myofibroblasts

Cardiac myofibroblasts are pivotal to adaptive remodelling after myocardial infarction (MI). These normally quiescent cells invade and proliferate as a wound healing response, facilitated by activation of matrix metalloproteinases, particularly MMP-2. Following MI these reparative events occur under chronically hypoxic conditions yet the mechanisms by which hypoxia might modulate MMP-2 activation and cardiac myofibroblast invasion have not been investigated. Human cardiac myofibroblasts cultured in collagen-supplemented medium were exposed to normoxia (20% O₂) or hypoxia (1% O₂) for up to 48 h. Secreted levels of total and active MMP-2 were quantified using gelatin zymography, TIMP-2 and membrane-associated MT1-MMP were quantified with ELISA, whole cell MT1-MMP by immunoblotting and immunocytochemistry and MT1-MMP mRNA with real-time RT-PCR. Cellular invasion was assessed in modified Boyden chambers and migration by scratch wound assay.In the human cardiac myofibroblast, MT1-MMP was central to MMP-2 activation and activated MMP-2 necessary for invasion, confirmed by gene silencing. MMP-2 activation was substantially attenuated by hypoxia (P < 0.001), paralleled by inhibition of myofibroblast invasion (P < 0.05). In contrast, migration was independent of either MT1-MMP or MMP-2. Reduced membrane expression of MT1-MMP (P < 0.05) was responsible for the hypoxic reduction of MMP-2 activation, with no change in either total MMP-2 or TIMP-2. In conclusion, hypoxia reduces MMP-2 activation and subsequent invasion of human cardiac myofibroblasts by reducing membrane expression of MT1-MMP and may delay healing after MI. Regulation of these MMPs remains an attractive target for therapeutic intervention.     

成纤维细胞与肺癌细胞相互作用对膜型基质金属蛋白酶-1及基质金属蛋白酶-2表达的影响

目的 研究胚肺成纤维细胞对肺癌H460细胞膜型基质金属蛋白酶-1(MTl-MMP)、基质金属蛋白酶-2(MMP-2)表达的影响.方法 采用Western blot方法检测各组MT1-MMP的表达.取其上清,采用酶联免疫吸附法检测各组细胞培养液中活性MMP-2的浓度.结果 H460细胞、胚肺成纤维细胞单独培养时均有MT1-MMP表达,但混合培养后MT1-MMP表达增强(P＜0.05).H460细胞、胚肺成纤维细胞单独培养时MMP-2均有分泌,混合培养MMP-2分泌增强(P＜0.05).结论 胚肺成纤维细胞和肺癌H460细胞相互作用能通过上调MT1-MMP、MMP-2的表达从而促进肺癌的侵袭和转移,这可能为肺癌侵袭转移的一个重要机制.     

Survivin gene expression in endometriosis

Survivin is a novel inhibitor of apoptosis and is expressed during fetal development and in cancer tissues, but its expression has not been reported in normal adult tissues or benign diseases. We investigated survivin gene and protein expression in a tumor-like benign disease, endometriosis, and correlated them with apoptosis and invasive phenotype of endometriotic tissues. Gene expression levels of survivin, matrix metalloproteinase (MMP)-2, MMP-9, and membrane type 1 (MT1)-MMP in 63 pigmented or nonpigmented endometriotic tissues surgically obtained from 35 women with endometriosis were compared with those in normal eutopic endometrium obtained from 12 women without endometriosis. Survivin, MMP-2, MMP-9, and MT1-MMP mRNA expression levels in clinically aggressive pigmented lesions were significantly higher than those in normal eutopic endometrium, and survivin gene expression in pigmented lesions was also higher than that in nonpigmented lesions (P < 0.05). There was a close correlation between survivin and MMP-2, MMP-9, or MT1-MMP gene expression levels in 63 endometriotic tissues examined (P < 0.01). Apoptotic cells detected by the dUTP nick-end labeling were rare in 11 ovarian endometriotic tissues, which showed positive immunohistochemical expression for survivin and MMPs. Our findings suggest that up-regulation of survivin and MMPs may cooperatively contribute to survival and invasion of endometriosis.     

The role of heat shock protein 27 expression in hepatocellular carcinoma in Japan: special reference to the difference between hepatitis B and C.

BACKGROUND: A recent report showed that heat shock protein (HSP)-27 expression was related to histological grade and survival of patients with hepatocellular carcinoma (HCC). AIMS: The aim of this study was to examine the effect of expression of HSP-27 on clinicopathological variables in Japanese patients with HCC. METHODS: An immunohistochemical study for HSP-27 was performed on 60 HCC cases using a monoclonal anti-HSP-27 antibody. We divided 60 patients into two groups, patients with a low expression of HSP-27 (n = 34) and those with a high expression of HSP-27 (n = 26). Forty patients tested positive for the hepatitis C virus (HCV) antibody and 20 tested positive for the hepatitis B surface antigen. RESULTS: There appeared to be no relationship between HSP expression and clinicopathologic factors and no differences were observed between the high expression group and the low expression group. In the hepatitis B virus (HBV) group (n = 20), HSP-27 expression correlated significantly with prognosis, disease-free survival (DFS) and overall survival. High expression was significantly associated with poor prognosis in the HBV group. In contrast, patients with a high expression tended to have a good prognosis in the HCV group (n = 40): DFS and overall survival. CONCLUSIONS: This study showed the possibility that HSP-27 plays different roles in HBV- and HCV-associated HCCs.     

Expression of membrane type 1 matrix metalloproteinase, matrix metalloproteinase 2 and tissue inhibitor of metalloproteinase 2 in human cartilaginous tumors with special emphasis on mesenchymal and dedifferentiated chondrosarcoma

Membrane type 1 matrix metalloproteinase (MT1-MMP) has been identified as an activator of the proenzyme of matrix metalloproteinase 2 (MMP-2: gelatinase A), and has also been shown to play a crucial role in tumor invasion by activating proMMP2 in both lung and gastric carcinoma. The tissue inhibitor of metalloproteinase 2 (TIMP-2) plus the MT1-MMP complex also plays an important role in the activation of proMMP-2. In this study, the expressions of MT1-MMP, MMP-2 and TIMP-2 were evaluated in 10 enchondromas, 34 conventional chondrosarcomas, 5 clear-cell chondrosarcomas, 7 mesenchymal chondrosarcomas and 8 dedifferentiated chondrosarcomas. The expressions were immunohistochemically visualized on paraffin sections and the levels of expression were assessed semiquantitatively. The extent of staining was assessed by the extent score in order to determine the overall level of expression. The extent scores of MT1-MMP, MMP-2 and TIMP-2 in grade 2 chondrosarcoma were significantly higher than those in either enchondroma or grade 1 chondrosarcoma (P < 0.05). In conventional chondrosarcoma, significant correlations were found between the extent scores of MT1-MMP and MMP-2 (P < 0.001), MT1-MMP and TIMP-2 (P < 0.01), and MMP-2 and TIMP-2 (P < 0.01). The undifferentiated small round tumor cells of mesenchymal chondrosarcoma showed lower positive rates and extent scores for MT1-MMP (2/7, 0.7 ± 0.5) and MMP-2 (3/7, 0.7 ± 0.4) than for cartilaginous components of mesenchymal chondrosarcoma [MT1-MMP (4/7, 1.3 ± 0.5) and MMP-2 (7/7, 1.9 ± 0.3)] or conventional chondrosarcoma. In dedifferentiated chondrosarcoma, the extent scores of MT1-MMP, MMP-2 and TIMP-2 in low-grade cartilaginous components were not significantly different from those in conventional chondrosarcoma; however, the high-grade anaplastic components showed high extent scores for MT1-MMP, MMP-2 and TIMP-2, compared with the low-grade cartilaginous components of dedifferentiated chondrosarcoma or conventional chondrosarcoma. According to our results, the expression of MT1-MMP as well as that of MMP-2 or TIMP-2 demonstrated a significant correlation with the tumor grade in human cartilaginous tumors. Furthermore, the expressions of MT1-MMP, MMP-2 and TIMP-2 were also found to play a crucial role in invasion in the high-grade components of dedifferentiated chondrosarcoma. Received: 17 February 1999 / Accepted: 21 April 1999     

Catechins prevent vascular smooth muscle cell invasion by inhibiting MT1-MMP activity and MMP-2 expression

OBJECTIVE: Regular consumption of green tea is associated with a reduced risk of mortality due to coronary diseases and cancer. The present study examined whether a green tea extract (GTE) inhibits activation of matrix metalloproteinase-2 (MMP-2), a major collagenase involved in vascular remodeling of atherosclerotic plaques, in vascular smooth muscle cells (VSMCs). METHODS AND RESULTS: The expression of MMP-2 was assessed by Northern and Western blot analyses in human aortic VSMCs. MMP-2 activity was evaluated by zymography, membrane-type1-MMP (MT1-MMP, MMP-14) activity by an enzymatic assay, and cell invasion by a modified Boyden chamber assay. The thrombin-induced activation of secreted MMP-2 was abolished by GTE and the green tea polyphenols (-)-epigallocatechin-3-gallate (EGCG) and (-)-epicatechin-3-gallate (ECG). GTE reduced the expression of MMP-2 mRNA and protein. GTE, EGCG and ECG directly inhibited cell-associated MT1-MMP activity, the physiological activator of MMP-2, in a reversible manner. Thrombin-stimulated VSMCs invasion was abolished by EGCG and ECG, and reduced by GTE. CONCLUSIONS: GTE inhibits thrombin-induced VSMCs invasion most likely by preventing MMP-2 expression and its activation by a direct inhibition of MT1-MMP. The ability of green tea to prevent cell invasion and matrix degradation might contribute to its protective effect on atherosclerosis and cancer.     

Regulation of matrix metalloproteinase MT1-MMP/MMP-2 in cardiac fibroblasts by TGF-beta1 involves furin-convertase

OBJECTIVE: Heart failure is characterized by an imbalance of matrix synthesis/turnover, finally resulting in fibrosis. Cardiac myocytes and fibroblasts play a pivotal role in the remodeling process. Cardiac remodeling involves the expression of TGF-beta1 and matrix metalloproteinases (MMPs) in cardiac fibroblasts (CFBs). Furin, a subtilisin/kexin-like proprotein convertase (PC), activates TGF-beta1 and membrane-bound MT1-MMP, which facilitates pro-gelatinase A (MMP-2) activation. Even though several reports identified TGF-beta1 as a pro-fibrotic cytokine in the heart, it increases MMP-activity and cell migration/invasion in several cell types. The present study was done to investigate the contribution of TGF-beta1 and furin to CFBs MMP-activity and motility. METHODS AND RESULTS: Stimulation of CFBs from adult Sprague-Dawley rats with TGF-beta1 (20 ng/ml) induced furin, but had no effect on the closely related PC5. Inhibition of furin inhibited angiotensin II-induced TGF-beta1 activation, indicating that TGF-beta1 amplifies its activating convertase in CFBs. Pretreatment of CFBs with TGF-beta1 (20 ng/ml, 24 h) increased their migration by about two-fold (p<0.05), which was accompanied by an enhanced expression and activity of MT1-MMP and MMP-2. Brefeldin A (BFA), a Golgi-disturbing agent, inhibited MT1-MMP activation, indicating that it occurs in the trans-Golgi network (TGN), where furin is concentrated and colocalized with MT1-MMP. Inhibition of furin significantly inhibited TGF-beta1-induced MT1-MMP/MMP-2 activation. Furthermore, inhibition of furin attenuated TGF-beta1-enhanced migration on gelatin-coated membranes (p<0.05). This was comparable to the effects of the MMP-inhibitor GM6001, pointing out that MMPs are major mediators of TGF-beta1-enhanced CFB motility. CONCLUSION: We demonstrate that TGF-beta1 induces MMP-activity in CFBs, thereby facilitating CFBs motility. Furthermore, TGF-beta1 amplifies its activating convertase furin, which is also required for MT1-MMP/MMP-2 activation in CFBs. Thus, furin is central for TGF-beta1 and MT1-MMP activation and might be a novel target in cardiac remodeling.     

Metastatic tumor antigen 1 is closely associated with frequent postoperative recurrence and poor survival in patients with hepatocellular carcinoma

Metastatic tumor antigen 1 (MTA1) is known to play a role in angiogenic processes as a stabilizer of hypoxia-inducible factor 1-alpha (HIF1-alpha). In this study, we examined whether overexpression of MTA1 affects the recurrence of hepatocellular carcinoma (HCC) after surgical resection and the survival of the patients. A total of 506 HCC patients who underwent hepatic resection were included in the study. They were followed up for a median of 43 months (range, 1-96 months) after hepatectomy. MTA1 expression levels were determined by the proportion of immunopositive cells (none, all negative; +, <50%; ++, >50%). The relationships between MTA1 expression and the HCC histological features, the appearance of recurrent HCC after surgical resection, and the survival of the patients were examined. Eighty-eight cases (17%) of the HCCs were positive for MTA1, although the surrounding liver tissues were all negative for MTA1; 62 cases were + and 26 cases were ++. Increased MTA1 expression levels in HCC were correlated with larger tumors (P = 0.04), perinodal extension (P = 0.03), and microvascular invasion (P = 0.008). Histological differentiation had marginal significance (P = 0.056). However, there was no association between MTA1 expression and age, sex, Child-Pugh class, and capsule invasion of HCC. Interestingly, MTA1 expression levels were significantly greater in hepatitis B virus (HBV)-associated HCC compared with hepatitis C virus (HCV)-associated HCC (P = 0.017). The cumulative recurrence rates of MTA1-positive HCCs were markedly greater than those of MTA1-negative HCCs (P < 0.0001). The cumulative survival rates of patients with MTA1-positive HCCs were significantly shorter than those of patients with MTA1-negative HCCs (P < 0.0001). In conclusion, our data indicate that MTA1 is closely associated with microvascular invasion, frequent postoperative recurrence, and poor survival of HCC patients, especially in those with HBV-associated HCC.     

Mechanism of metastasis by membrane type 1-matrix metalloproteinase in hepatocellular carcinoma

AIM: To investigate the precise role of membrane type1-matrix metalloproteinase (MT1-MMP) in hepatocellular carcinoma (HCC) metastasis.METHODS: Human HCC cells Hep3B with overexpression of MT1-MMP were established by stable transfection, and compared with control cells carrying the empty vector.Cells were examined in vivo for their differences in the metastatic ability of athymic nude mice, and analyzed in vitro for their differences in invasion ability by invasion chamber coated with Matrigel, adhesion towards collagen I and migration through culture chamber. Cell proliferation and apoptosis in adherent and suspension status were evaluated by MTT and flow cytometry analysis.RESULTS: We found that overexpression of MT1-MMP could increase intrahepatic metastasis in nude mice with orthotopic implantation of HCC cells (incidence of 100%[MT1-MMP transfectants] vs 40% [vector control transfectants], P＜0.05). MT1-MMP could also enhance cell invasion through Matrigel (107.7 vs 39.3 cells/field,P＜0.001), adhesion towards matrix (0.30 vs 0.12absorbance unit at 540 nm, P＜0.001), cell migration(89.3 vs 39.0 cells/field, P＜0.001), and cell proliferation(24.3 vs 40.5 h/doubling, P＜0.001). We also observed that MT1-MMP supported cell survival (71.4% vs 23.9%,P＜0.001) with reduced apoptosis (43.7% vs51.0%, P＜0.05)in an attachment-free environment.CONCLUSION: MT1-MMP overexpression could enhance metastasis. In addition to its active role in matrix degradation during tumor invasion, MT1-MMP enhances tumor cell survival upon challenge of detachment, which is important during metastasis when cells enter the circulation.