Metalloproteinase expression and prognosis in soft tissue sarcomas

Benassi, M. S.; Gamberi, Gabriella; Magagnoli, Giovanna; Molendini, Lara; Ragazzini, Paola; Merli, M.; Chiesa, Fausto; Balladelli, Alba; Manfrini, Marco; Bertoni, Franco; Mercuri, Mario; Picci, Piero

doi:10.1023/a:1008318614461

Cited by 79 publications

(69 citation statements)

References 13 publications

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“…These studies did not investigate other MMPs such as another gelatinase, MMP-2. In soft tissue sarcomas, increased MMP-2 expression and lack of TIMP-2 expression have been reported to be significant factors for poor prognosis (16). The present study analyzed for the first time the expression of not only MMP-9 but also MMP-2, MT1-MMP and TIMP-2 in osteosarcoma tissues immunohistochemically and their correlation to clinical outcome.…”

Section: Discussionmentioning

confidence: 90%

“…Their expressions are associated with tumor invasion and increased metastatic potential (11)(12)(13)(14)(15). In soft tissue sarcomas, MMP-2 reactivity and lack of TIMP-2 expression is correlated with poor prognosis (16). However, although several studies concerning MMP-9 expression in osteosarcoma patients have been conducted (17,18), MMP-2, MT1-MMP and TIMP-2 expression have been described in only a few studies.…”

Section: Increased Expression Of Membrane-type Matrix Metalloproteinamentioning

confidence: 99%

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Increased expression of membrane-type matrix metalloproteinase-1 is correlated with poor prognosis in patients with osteosarcoma

Uchibori¹,

Nishida²,

Nagasaka³

et al. 2006

Int J Oncol

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Abstract. Numerous studies have demonstrated a correlation of matrix metalloproteinase (MMP) overexpression with the prognosis of various kinds of cancer. The current study investigated whether the expression of MMPs is correlated with the prognosis of osteosarcoma. Expression levels of MMP-2, -9, MT1-MMP and TIMP-2 were examined immunohistochemically in samples from 47 patients with osteosarcoma. Correlation of the positivity of staining with prognosis was analyzed with the Kaplan-Meier method, and statistically analyzed with log-rank test. Co-localization of MMP-2, MT1-MMP and TIMP-2 was determined by double staining with fluorescence-conjugated antibodies. Activities of gelatinases in representative tissues were examined with gelatin zymography. MMP-2 was expressed strongly in 60% of cases (28/47), and MMP-9, MT1-MMP and TIMP-2 was strongly positive in 61% (29/47), 45% (21/47), and 91% (43/47), respectively. Increased MT1-MMP expression was associated significantly with poor prognosis in overall survival (P=0.0480). In cases of overexpression for both MMP-2 and MT1-MMP, there was a tendency for poor prognosis (P=0.0969). In 36 cases who underwent neoadjuvant chemotherapy, wide resection of the tumors and post-operative adjuvant chemotherapy, increased expression of MT1-MMP resulted in a significant negative prognostic factor for disease-free survival (P=0.0143). Also, co-overexpression of MT1-MMP and MMP-2 showed a tendency to correlate to the reduced disease-free survival (P=0.0502). Increased gelatinase activity was observed in tissues of co-overexpression of MT1-MMP and MMP-2. The results of this study demonstrate the correlation of MT1-MMP expression and the oncological outcome of osteosarcoma patients, suggesting the prognostic significance of these proteins in osteosarcoma patients. IntroductionOsteosarcoma is the most frequent primary malignant bone tumor in children and adolescents (1-3). In the last two decades, the combination of chemotherapy with surgical treatment dramatically improved the clinical outcome of the patients with osteosarcoma. However, there are still a certain number of patients who do not benefit from these improvements. Attempts have been made to identify prognostic factors to predict outcome, and to determine those patients who should undergo more intensive treatment, however, further work is required.Malignant tumor cell invasion is believed to involve a complex series of integrated events consisting of tumor cell adhesion, extracellular matrix (ECM) proteolysis, and cell migration within the microenvironment (4). Among the proteases contributing to ECM degradation, matrix metalloproteases (MMPs) are thought to play significant roles in tumor invasion and metastasis (5,6). Synthesized as either secreted or membrane-bound latent enzymes, MMPs require proteolytic activation involving cleavage of propeptide domain to exhibit enzymatic activity (7). Cell-mediated pro-MMP-2 activation involves cleavage by MT1-MMP on cell membranes (8,9). The activity of these MMPs is regulated by the...

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Section: Discussionmentioning

confidence: 90%

Section: Increased Expression Of Membrane-type Matrix Metalloproteinamentioning

confidence: 99%

Increased expression of membrane-type matrix metalloproteinase-1 is correlated with poor prognosis in patients with osteosarcoma

Uchibori¹,

Nishida²,

Nagasaka³

et al. 2006

Int J Oncol

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“…Increased levels of matrix metalloproteinase-2 (MMP-2), MMP-9, and urokinase plasminogen activator appear to confer a worse prognosis, whereas increased levels of tissue inhibitor of metalloproteinase-2 (TIMP-2) are associated with improved outcomes. [18][19][20] Several groups have evaluated circulating proangiogenic and antiangiogenic factors in patients with soft-tissue sarcoma. In 1 small series of 46 patients, serum VEGF levels measured by ELISA did not differ between patients with soft-tissue sarcoma and healthy controls.…”

Section: Soft-tissue Sarcomamentioning

confidence: 99%

Markers of angiogenesis and clinical features in patients with sarcoma

DuBois

Demetri

2007

Cancer

129

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Objective: Patient outcome after traumatic brain injury (TBI) is highly variable. The underlying pathophysiology of this is poorly understood, but inflammation is potentially an important factor. Microglia orchestrate many aspects of this response. Their activation can be studied in vivo using the positron emission tomography (PET) ligand [11C](R)PK11195 (PK). In this study, we investigate whether an inflammatory response to TBI persists, and whether this response relates to structural brain abnormalities and cognitive function. Methods: Ten patients, studied at least 11 months after moderate to severe TBI, underwent PK PET and structural magnetic resonance imaging (including diffusion tensor imaging). PK binding potentials were calculated in and around the site of focal brain damage, and in selected distant and subcortical brain regions. Standardized neuropsychological tests were administered. Results: PK binding was significantly raised in the thalami, putamen, occipital cortices, and posterior limb of the internal capsules after TBI. There was no increase in PK binding at the original site of focal brain injury. High PK binding in the thalamus was associated with more severe cognitive impairment, although binding was not correlated with either the time since the injury or the extent of structural brain damage. Interpretation: We demonstrate that increased microglial activation can be present up to 17 years after TBI. This suggests that TBI triggers a chronic inflammatory response particularly in subcortical regions. This highlights the importance of considering the response to TBI as evolving over time and suggests interventions may be beneficial for longer intervals after trauma than previously assumed. ANN NEUROL 2011;

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“…Caudroy et al showed in vitro that EMMPRIN producing tumors can stimulate MMPs both in the stroma and in the tumor cells, thus promoting tumorigenesis and metastasis (26). Another study in ovarian carcinoma showed coexpression of an EMMPRIN and MMP-1, -9 and correlated this with poor survival (27).…”

Section: Discussionmentioning

confidence: 90%

“…Benassi et al studied MMP-2, -9 and TIMP-2 expression as a prognostic indicator in STS using the non-quantitative methods of immunohistochemistry and immunoblotting (27). Their study used frozen and paraffin-embedded tumor samples from 29 liposarcomas, 29 synovial sarcoma cases and 15 malignant peripheral nerve sheath tumors and found a correlation between elevated MMP-2 activity and increased disease-free survival (p=0.0005).…”

Section: Discussionmentioning

confidence: 99%

Matrix metalloproteinase expression in high grade soft tissue sarcomas

et al. 2007

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Abstract. Soft tissue sarcomas comprise a heterogeneous group of mesenchymal tumors with varying biological behavior ranging from indolent tumors with no or minimal metastatic risk to aggressive and frequently metastasizing tumors. Among the more common aggressive adult soft tissue sarcomas are malignant fibrous histiocytoma, synovial sarcoma and liposarcoma. Matrix metalloproteinases are enzymes which perform a homeostatic role in mesenchymal tissue and function in both tumorigenesis and metastasis. The objectives of this study are to determine the presence and relative quantity of matrix metalloproteinases (MMPs) -1, -2, -8, -9, and -13; extracellular matrix metalloproteinase inducer (EMMPRIN); and tissue inhibitors of matrix metalloproteinases (TIMP)-1 and -2 in high grade soft tissue sarcoma tumor specimens using real-time PCR. The second objective is to determine if a relationship exists between quantity of EMMPRIN, MMPs, and TIMPs expressed in tumor tissue and disease-free survival. One hundred and forty patients diagnosed with high grade soft tissue sarcomas between 1995-2003 were identified. Tissue blocks and histologic slides were acquired for 41 specimens. Tumor specimens included 29 malignant fibrous histiocytomas, 3 liposarcomas and 11 synovial sarcomas. RNA was extracted and RT-PCR was performed in triplicate. No significant differences were found between the three types of high grade soft tissue sarcomas studied and the expression of MMPs. Interestingly, no relationship was found between high or low levels of MMPs when compared with disease-free survival. Our data support other research which finds variable correlation between MMP expression in soft tissue sarcomas and disease-free survival. We assert that the difference in correlation between MMP expression in carcinomas and sarcomas and disease-free survival is based on the vast phenotypic and genotypic difference between the cells of origin.

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Metalloproteinase expression and prognosis in soft tissue sarcomas

Abstract: These prognostic markers that influence growth and spread of tumor cells might be useful to define tumor aggressiveness and risk of the metastasic event.

Cited by 79 publications

References 13 publications

Increased expression of membrane-type matrix metalloproteinase-1 is correlated with poor prognosis in patients with osteosarcoma

Increased expression of membrane-type matrix metalloproteinase-1 is correlated with poor prognosis in patients with osteosarcoma

Markers of angiogenesis and clinical features in patients with sarcoma

Matrix metalloproteinase expression in high grade soft tissue sarcomas

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