Matrilysin (MMP-7) as a significant determinant of malignant potential of early invasive colorectal carcinomas

Terabe, Masaki; Matsuoka, Hiroaki; Sugiyama, Masanori; Abe, Nobutsugu; Goto, Akiteru; Sakamoto, Atsuhiko

doi:10.1054/bjoc.2001.1790

Cited by 117 publications

(88 citation statements)

References 20 publications

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“…We have also observed a lower basal level sFAS (8.2 ng/mL), but without reaching significance (P = 0.37), in patients with metachronic compared with synchronic disease (10.6 ng/mL), in accordance with the well-known chemoresistance of this group of patients in randomized advanced colorectal cancer trials (2,26). We also noted a higher basal levels of sFAS (12.2 ng/mL) in those patients with serum lactate dehydrogenase >1 upper limit of normal compared with 8.5 ng/mL (P = 0.43), also a well-defined, poor prognosis factor of survival in colorectal cancer (1, 2) and described previously in advanced melanoma (27). These data could explain previous reports associating poor prognosis with sFAS levels in gynecologic malignancies and melanoma (24,25).…”

Section: Discussionsupporting

confidence: 82%

FAS/FAS Ligand Ratio: A Marker of Oxaliplatin-Based Intrinsic and Acquired Resistance in Advanced Colorectal Cancer

Nadal¹,

Maurel²,

Gallego³

et al. 2005

Clinical Cancer Research

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Purpose: Oxaliplatin-5-fluorouracil combinations have increased responses in first-line therapy up to 40% in advanced colorectal cancer. Unfortunately, those patients who will respond are unknown and initially sensitive patients become rapidly resistant to current therapies. FAS (CD95) and FAS ligand (FASL; CD95L) have been implicated in chemosensitivity through leading to apoptosis in response to DNA-damaging drugs.Whereas the proapoptotic role of FAS and FASL is well characterized, the function of their soluble forms as predictors of chemosensitivity remains unknown. Patients and Methods: Blood samples were obtained from 68 patients with advanced colorectal cancer who received oxaliplatin-5-fluorouracil combinations in first-line therapy. Computed tomographic scans were done every 3 months and responses were evaluated by Response Evaluation Criteria in Solid Tumors criteria. ELISA soluble FAS and soluble FASL analysis were done before treatment and every 3 months until disease progression. Ratios between soluble FAS and soluble FASL were established and its values and variations through time were related to treatment responses. Results: We found a significant increase in soluble FAS levels and a significant decrease in FASL at 3 months compared with baseline (13.2 versus 10.02 ng/mL; P = 0.0001; 0.07 versus 0.14 ng/mL; P = 0.007, respectively). A significant increase in the soluble FASL levels up to 9 months (fourth to fifth extractions; 0.26 ng/mL) of therapy compared with first to third extractions (0.11ng/mL; P = 0.003) was also found. A random effect regression statistical model determined that >1.2-fold increase in soluble FAS/soluble FASL ratio was a marker of chemosensitivity (P = 0.001). Conclusions: These data strongly indicate that an increment of soluble FAS/soluble FASL ratio after treatment could be an excellent marker of chemosensitivity in colorectal cancer. On the other hand, a decreased ratio after treatment can be a predictor of chemoresistance despite an initial response.Colorectal cancer is the most common cancer in western Europe, with f70 new cases a year per 100,000 inhabitants. In spite of advances in screening, 15% to 20% of patients show initially advanced disease, and 30% to 50% are destined to metastasize. Recently, oxaliplatin/5-fluorouracil (5-FU)/leucovorin or irinotecan-5-FU/leucovorin have increased responses in first-line therapy up to 40%, with median survival between 16 and 20 months, but 2-year overall survival still remains <20% (1, 2). Unfortunately, those patients who will benefit from first-line chemotherapy are unknown. Furthermore, the initially sensitive patients become rapidly resistant to current therapies.The FAS (CD95) receptor is a cell surface protein that mediates apoptotic cell death on triggering by FAS ligand (FASL). This interaction causes FAS receptor homo-oligomerization and this leads to activation of the caspase cascade (apoptotic extrinsic pathway). A FASL-independent activation of the FAS receptor has also been described (3).Whereas proapopt...

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Section: Discussionsupporting

confidence: 82%

FAS/FAS Ligand Ratio: A Marker of Oxaliplatin-Based Intrinsic and Acquired Resistance in Advanced Colorectal Cancer

Nadal¹,

Maurel²,

Gallego³

et al. 2005

Clinical Cancer Research

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“…48 MMP-7 expression has also been reported as being associated with distant metastasis and poor outcome. [49][50][51] In the present study, there was an inverse tendency between prognosis and expression of MMP-7 in rectal cancer patients. Like MMP-2 and MMP-9, MMP-7 can degrade type IV collagen and thus it would be expected to correlate with metastasis and poor outcome, but this was not the case in our study.…”

Section: Discussionsupporting

confidence: 57%

Prognostic significance of matrix metalloproteinases‐1, ‐2, ‐7 and ‐13 and tissue inhibitors of metalloproteinases‐1, ‐2, ‐3 and ‐4 in colorectal cancer

Hilska

Roberts

Collan

et al. 2007

Intl Journal of Cancer

133

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Strong expression of many matrix metalloproteinases (MMPs) has been related to poor survival of colorectal cancer (CRC) patients. The expression of tissue inhibitors of metalloproteinases (TIMPs) has been associated with both a beneficial and a poor outcome and there is thus a need to further clarify the significance of MMPs and TIMPs in CRC. The prognostic significance of 4 MMPs and TIMPs in CRC was evaluated. Formalinfixed, paraffin-embedded tissue arrayed samples of 351 patients with primary colon or rectal cancer of Dukes' stages A-D were selected for immunohistochemical staining of MMP-1, -2, -7 and -13, and TIMP-1, -2, -3 and -4. High expression of MMP-2 in the malignant epithelium as well as in the surrounding stroma was associated with reduced survival of colon cancer patients. Strong epithelial and stromal cytoplasmic staining of TIMP-3 was associated with a longer survival in rectal cancer patients, and here the interobserver variation for evaluating the degree of staining was lower than for epithelial staining. Strong stromal cytoplasmic staining of TIMP-4 predicted longer survival of rectal cancer patients. Multivariate analysis showed that stromal cytoplasmic TIMP-3 staining was the only marker of independent prognostic value. MMP-2 might be a useful prognostic marker in colon cancer, and TIMP-3 and TIMP-4 in rectal cancer, but the findings associated with stromal staining should be interpreted with some caution. Different biologic behavior or different genetic development may explain the differences between colon and rectal cancers regarding the expression of MMP-2, TIMP-3 and TIMP-4. ' 2007 Wiley-Liss, Inc.Key words: colorectal cancer; matrix metalloproteinases; tissue inhibitors of metalloproteinases; prognosis; survival Matrix metalloproteinases (MMPs) are a large family of zincdependent neutral endopeptidases that play an important role in the degradation of all matrix components crucial for malignant tumor growth, invasion and metastasis. 1,2 Metalloproteinases are inhibited by tissue inhibitors (TIMPs) which are secreted proteins. These bioactive substances are specific inhibitors of MMPs that bind to enzymatically active MMPs at a 1:1 molar stoichiometry thus inhibiting proteolysis. 3 The role of TIMPs for the homeostasis of the extracellular matrix is critical and may inhibit or stimulate tumorigenesis. 4 Many studies have shown that the expression of several MMPs is enhanced in a number of malignancies, including colorectal cancer (CRC), but the relation between the expression of MMPs and overall patient survival is not clear. 5,6 Enhanced expression of MMP-1, -7 and -13 has been reported to be associated with metastasis and poor survival of patients with CRC. 7-9 Tissue concentrations of MMP-1, MMP-2 and TIMP-1 are increased in CRC compared to healthy colorectal tissue. This has been related to the role of these endogenous substances in cancer progression. 2 Healthy tissue may contain high levels of TIMP-2 10 and the levels of TIMP-3 mRNA are regionally increased in moderately and poorl...

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“…MMP-7 overexpression has been correlated with invasion and to liver metastasis formation in CRC nonmetastatic disease. [29][30][31][32][33][34][35] As noted earlier, MMP-7 is secreted to the media. Both soluble MMP-7 forms, active and proactive, can be measured in serum by a commercial ELISA Kit.…”

mentioning

confidence: 99%

Serum matrix metalloproteinase 7 levels identifies poor prognosis advanced colorectal cancer patients

Maurel

Nadal

García-Albéniz

et al. 2007

Intl Journal of Cancer

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Metalloproteinase 7 (MMP-7) plays an important role in tumor growth, invasion and dissemination, and is secreted to the media. Because of the close implication of MMP-7 in cancer biology, we sought to define the prognostic significance of serum levels of MMP-7 in metastatic colorectal cancer (CRC) and explore its possible impact in the daily clinical practice. MMP-7 expression was determined by enzyme-linked immunoabsorbent assay. We assessed serum MMP-7 levels in 87 healthy controls, 96 patients with nonmetastatic CRC and 120 patients with advanced CRC. Clinical information was gathered from patient files. Cox proportional hazards model was used to assess survival. MMP-7 and the variables associated with prognosis were entered and a backward elimination method was employed to adjust the model. Inclusion criteria was p 0.05 and exclusion criteria was p 0.10. Advanced CRC patients have a significant higher mean serum MMP-7 levels (13.4 ng/ml) than those in nonmetastatic CRC (5.5 ng/ml; p < 0.001) and healthy controls (4.2 ng/ml; p < 0.001). In metastatic patients, after adjusting for other prognostic variables, MMP-7 (entered as a continuous variable) is associated with decreased survival (HR 1.016, IC 95% 1.002-1.031). Serum MMP-7 levels are significantly elevated in patients with advanced CRC. In conclusion, MMP-7 is an independent prognostic factor for survival in advanced CRC. In our sample, the risk of death associated to MMP-7 increase is much higher than the risk of death associated to lactate dehydrogenase elevation. ' 2007 Wiley-Liss, Inc.Key words: colorectal cancer; prognosis; matrix metalloproteinases Widely accepted prognostic factors in advanced colorectal cancer (CRC) are performance status (PS), serum lactate dehydrogenase (LDH) and alkaline phosphatase (ALP) levels. 1-4 Despite of it, novel markers and useful prognostic indexes are needed to better classify these patients for clinical practice.Matrylisin (MMP-7) is a proteolytic enzyme belonging to Matrix Metalloproteinase (MMPs) family. [5][6][7] It is constitutively expressed in the ductal and glandular epithelium of many tissues. 8 In the lung and intestine it plays a role activating antibacterial peptides such as prodefensins. 9 MMP-7 is synthesized and secreted by tumor epithelial cells as a 28-KDa proenzyme that can be activated through proteolytic removal of a 9-KDa prodomain from the N-terminus. The soluble activated form binds to the tumor epithelial cell surface. Both active forms, the soluble and the membranebounded, have proteolytic activity. Its expression is regulated by transcription factors such as AP-1, PEA3 and b-catenin/ tcf4 complex. [10][11][12] By degrading elastin, laminin, proteoglycans, osteopontin, fibronectin and type IV collagen, MMP-7 gains the capacity to invade. Matrilysin can also promote tumor invasion by activating other MMPs (MMP-2 and MMP-9), through ectodomain shedding of E-cadherin. 13 and receptor activator of nuclear factor-kappa B ligand (RANKL) 14 or through cleavage of adhesion molecules, such as integri...

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Matrilysin (MMP-7) as a significant determinant of malignant potential of early invasive colorectal carcinomas

Cited by 117 publications

References 20 publications

FAS/FAS Ligand Ratio: A Marker of Oxaliplatin-Based Intrinsic and Acquired Resistance in Advanced Colorectal Cancer

FAS/FAS Ligand Ratio: A Marker of Oxaliplatin-Based Intrinsic and Acquired Resistance in Advanced Colorectal Cancer

Prognostic significance of matrix metalloproteinases‐1, ‐2, ‐7 and ‐13 and tissue inhibitors of metalloproteinases‐1, ‐2, ‐3 and ‐4 in colorectal cancer

Serum matrix metalloproteinase 7 levels identifies poor prognosis advanced colorectal cancer patients

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