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Paul Basset - One of the best experts on this subject based on the ideXlab platform.
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high cancer cell death in syngeneic tumors developed in host mice deficient for the Stromelysin 3 matrix metalloproteinase
Cancer Research, 2001Co-Authors: Anne Boulay, Marie-pierre Chenard, Jean-pierre Bellocq, Regis Masson, Mostapha El Fahime, Lydie Cassard, Catherine Sauteesfridman, Paul BassetAbstract:Matrix metalloproteinases (MMPs) are extracellular enzymes. Some of them are known to be involved in tumor development and/or progression. Several cellular functions have been proposed for MMPs during malignant processes. Notably, they may be involved in tissue-remodeling processes through their ability to digest matrix components or to participate in tumor neoangiogenesis and, subsequently, in cancer cell proliferation. One of these MMPs, Stromelysin-3 (ST3/MMP11), although devoid of enzymatic activity against the matrix components, is associated with human tumor progression and poor patient clinical outcome. Using several in vivo experimental models, it has been demonstrated that ST3 expression by the fibroblastic cells surrounding malignant epithelial cells promotes tumorigenesis in a paracrine manner. The present study was devoted to the identification of the cellular function underlying this ST3-induced tumor promotion using a syngeneic tumorigenesis model in mice. Our results show that ST3 exhibits a new and unexpected role for a MMP, because ST3-increased tumorigenesis does not result from increased neoangiogenesis or cancer cell proliferation but from decreased cancer cell death through apoptosis and necrosis. Thus, during malignancy, the cellular function of ST3 is to favor cancer cell survival in the stromal environment.
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Stromelysin-3 Is Induced in Mouse Ovarian Follicles Undergoing Hormonally Controlled Apoptosis, but This Metalloproteinase Is Not Required for Follicular Atresia
Biology of Reproduction, 2001Co-Authors: Anna-carin Hägglund, Paul Basset, Tor NyAbstract:Apoptotic processes are often associated with an intense proteolytic remodeling of the extracellular matrix (ECM). Proteolytic degradation of the ECM can also be a signal that induces apoptosis. Here, we have investigated the expression pattern and functional role of the matrix metalloproteinase Stromelysin-3 in follicular atresia. Twenty-four hours after the treatment of immature female mice with a low dose of eCG, both apoptosis and the Stromelysin-3 mRNA expression were suppressed approximately threefold. However, the initial suppression of apoptosis and Stromelysin-3 expression was followed by a time-dependent increase, and 96 h after eCG treatment, the levels were similar to those of untreated control mice. In 15- to 16-day-old juvenile mice, the ovary consisted of relatively undeveloped follicles, and almost no apoptosis and only low Stromelysin-3 mRNA expression were observed. However, at the age of 21 days, when several antral follicles were present, a fivefold induction in both apoptosis and Stromelysin-3 mRNA expression was detected. For both models, in situ analysis revealed that the expression of Stromelysin-3 mRNA was localized to the granulosa cells of atretic follicles. To address the functional role of Stromelysin-3 in follicular atresia, Stromelysin-3-deficient mice were studied. However, no difference in the pattern of apoptotic DNA fragmentation and no apparent morphological differences were observed when ovaries from wild-type and Stromelysin-3-deficient mice were compared. Taken together, our data indicate that Stromelysin-3 is induced during follicular atresia, but that this protease is not obligatory for initiation or completion of the atretic process.
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demonstration in vivo that Stromelysin 3 functions through its proteolytic activity
Oncogene, 2000Co-Authors: Agnès Noël, Paul Basset, Anne Boulay, Rama Kannan, F Kebers, Amin Hajitou, C M Calbergbacq, Jean-michel FoidartAbstract:Stromelysin-3 (ST3), a matrix metalloproteinase (MMP) expressed in aggressive carcinomas, has been shown to promote tumor development in different in vivo experimental models. However, the inability of its mature form to degrade extracellular matrix components casts doubt on whether ST3 functions in vivo as a protease. In this study, we evaluated whether the ST3 tumor-promoting effect could be ascribed to its proteolytic activity and whether this putative protease could be targeted with MMP inhibitors. Catalytically inactive mutant cDNA of human (h) ST3 or mouse (m) ST3 were generated and transfected into MCF7 cells. When injected into nude mice in the presence of matrigel, the mutant-bearing cells did not exhibit the enhanced tumorigenicity elicited by MCF7 cells transfected with wild-type ST3 cDNA. In a second approach, TIMP2 overproduction in MCF7 cells expressing hST3 was induced by retroviral infection. The co-expression of ST3 and TIMP2 failed to enhance the tumorigenicity of MCF7 cells. Notably, matrigel depleted of low-molecular-weight proteins and growth factors failed to promote the tumorigenicity of ST3-expressing MCF7 cells. These findings provide the first in vivo evidence that ST3 is indeed a protease that can modulate cancer progression by remodeling extracellular matrix and probably by inducing it to release the necessary microenvironmental factors. Thus, ST3 represents an interesting target for specific MMP inhibition.
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purification of active matrix metalloproteinase catalytic domains and its use for screening of specific Stromelysin 3 inhibitors
Protein Expression and Purification, 1999Co-Authors: Rama Kannan, Agnès Noël, Isabelle Stoll, Vincent Dive, Jean-michel Foidart, Marc Ruff, John G Kochins, Susan P Manly, Mostafa El Fahime, Paul BassetAbstract:Abstract The matrix metalloproteinase (MMP) Stromelysin-3 (ST3) has been shown to be involved in malignant tumor progression and therefore represents an attractive therapeutical target. In order to screen for ST3 synthetic inhibitors, we have produced and purified the catalytic domain of ST3, matrilysin, Stromelysin-2, and membrane type-1 MMP from inclusion bodies in a bacterial system. Our strategy allowed the purification of MMPs directly in the active form, thereby avoidingin vitroactivation. A total of 140,000 synthetic compounds from the Bristol-Myers Pharmaceutical Research Institute chemical deck were tested, using a substrate-based colorimetric enzymatic assay, in which ST3 activity was evaluated through its ability to cleave and inactivate α-1 proteinase inhibitor. One ST3 inhibitor belonging to the cephalosporin family of antibiotics was thereby identified.
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Expression of Stromelysin 3 in keratoacanthoma and squamous cell carcinoma
American Journal of Dermatopathology, 1999Co-Authors: Asch Ph, Edouard Grosshans, Paul Basset, Michel Roos, Jean-pierre Bellocq, Bernard CribierAbstract:Stromelysin 3 (ST3) is a member of the metalloproteinase family, which is expressed in the skin during wound healing and in the stroma of basal cell carcinoma. A high level of expression of ST3 has been observed in carcinomas of poor prognosis. In benign tumors, though, ST3 is not expressed or is at a low level. We have immunohistochemically studied the expression of ST3 in 89 randomly selected cases of squamous cell carcinomas (SCCs), 104 of keratoacanthomas (KA), and 23 cases of metastatic SCC. Stromelysin 3 was expressed only by fibroblasts surrounding the tumors and not by epithelial cells. The proportion of tumors positively stained was 22% of KA, 47% of randomly selected SCC, and 70% of metastatic SCC. In areas of poorly demarcated neoplastic cells, a reinforcement of the staining was observed in the stroma. The intensity and dispersion of staining were used to determine the level of expression. There were significantly more SCC in the groups of high expression levels, and both parameters were significantly higher in SCC than in KA. Expression of ST3 in benign tumors is unusual. Its expression in the the stroma of keratoacanthomas can be related to the high tissue remodeling activity observed in these tumors. It also could be interpreted as in favor of the neoplastic nature of KA. Nevertheless, the level of expression was higher in SCC than in KA and seemed to be related to the prognosis of these tumors. These results correlate well with those obtained in breast cancers and in noncutaneous SCC.
Pierre Chambon - One of the best experts on this subject based on the ideXlab platform.
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Comparative expression of the SPARC and Stromelysin-3 genes in mammary tumours
The Breast, 1996Co-Authors: O.l. Podhajcer, J P Segain, Olivier Lefebvre, Pierre Chambon, Nicolas Rouyer, C. Wolf, I. Stoll, P BassetAbstract:Abstract By differential screening of a human breast cancer cDNA library, we have isolated a cDNA which encodes SPARC (osteonectin/BM40), a secreted glycoprotein which modulates cell-matrix interactions. The SPARC gene was found to be expressed in all invasive human breast carcinomas, metastatic lymph nodes and mouse mammary tumours that were examined. In these tumours SPARC transcripts were specifically detected in fibroblastic cells in the stroma surrounding cancer cell islands. In human carcinomas, but not in mouse mammary tumours, a subset of cells expressing the SPARC gene also expressed the Stromelysin-3 gene, which encodes a matrix metalloproteinase. These observations support the concept that the stromal component of human breast carcinomas is a major source of extracellular proteins and may be involved in the modulation of tumour progression. Future approaches to cancer treatment should include attempts to interfere with the formation and/or functioning of tumour stroma.
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developmental expression of mouse Stromelysin 3 mrna
Development, 1995Co-Authors: Olivier Lefebvre, Pierre Chambon, Marie-pierre Chenard, Catherine H Regnier, Corinne Wendling, Paul BassetAbstract:We have used northern blot analysis and in situ hybridization to study the spatial distribution of Stromelysin-3 (ST3) expression during mouse embryogenesis. ST3 mRNA was observed in trophoblastic cells at the site of embryonic implantation (7.5-8.5 days) and in a variety of developing embryonic tissues. In these tissues, the highest ST3 expression levels were observed during the development of the external features of limb, tail and snout, and during bone and spinal cord morphogenesis. In limb, tail and snout, ST3 expression was specifically detected in mesenchymal cells lining the basement membrane at the junction of primitive dermis and epidermis, and adjacent to epithelial cells undergoing proliferation and/or apoptosis. In bone, ST3 was expressed in invasive mesenchymal cells and, in the spinal cord in neuroepithelial cells of the floor plate, at the time that this structure is crossed by commissural axons. Altogether, these observations suggest a role for ST3 during embryonic morphogenesis, in tissue remodeling processes associated with cell proliferation, death and/or invasion. Moreover, when compared to urokinase and tissue plasminogen activators, the spatiotemporal pattern of ST3 expression shows some similarities, but was not completely superimposable, suggesting that these genes may cooperate in some developing tissues and have specific functions in others.
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neoplastic progression of human colorectal cancer is associated with overexpression of the Stromelysin 3 and bm 40 sparc genes
International Journal of Cancer, 1995Co-Authors: Henri Porte, Paul Basset, Pierre Chambon, Eric Chastre, S Prevot, B Nordlinger, Sylvie Empereur, Christian GespachAbstract:The interaction of neoplastic cells with the extracellular matrix is a critical event for the initiation of cancer invasion and metastasis. This study was designed to evaluate the potential implication of Stromelysin-3 (ST3), a newly identified member of the matrix-degrading metalloproteinase family, and of BM-40/SPARC, a glycoprotein associated with the extracellular matrix, during the progression of human colorectal cancers. We analyzed the relative abundance of ST3 and BM-40/SPARC transcripts by Northern blot, and their distribution by in situ hybridization, in normal mucosa, benign adenomas, and primary colorectal adenocarcinomas and their liver metastases. The ST3 and BM-40/SPARC transcripts were overexpressed in primary colorectal cancers and their liver metastases compared to non-neoplastic mucosa. These transcripts were localized in stromal fibroblasts adjacent to the neoplastic foci. Overexpression of ST3 correlated with the progression of human colorectal tumors toward local invasion and liver metastasis. Induction of these genes also occurred in diverticulitis and digestive neoplasms such as gastric and esophageal carcinomas. © 1995 Wiley-Liss, Inc.
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Neoplastic progression of human colorectal cancer is associated with overexpression of the Stromelysin-3 and BM-40/SPARC genes
International Journal of Cancer, 1995Co-Authors: Henri Porte, Paul Basset, Pierre Chambon, Eric Chastre, S Prevot, B Nordlinger, Sylvie Empereur, Christian GespachAbstract:The interaction of neoplastic cells with the extracellular matrix is a critical event for the initiation of cancer invasion and metastasis. This study was designed to evaluate the potential implication of Stromelysin-3 (ST3), a newly identified member of the matrix-degrading metalloproteinase family, and of BM-40/SPARC, a glycoprotein associated with the extracellular matrix, during the progression of human colorectal cancers. We analyzed the relative abundance of ST3 and BM-40/SPARC transcripts by Northern blot, and their distribution by in situ hybridization, in normal mucosa, benign adenomas, and primary colorectal adenocarcinomas and their liver metastases. The ST3 and BM-40/SPARC transcripts were overexpressed in primary colorectal cancers and their liver metastases compared to non-neoplastic mucosa. These transcripts were localized in stromal fibroblasts adjacent to the neoplastic foci. Overexpression of ST3 correlated with the progression of human colorectal tumors toward local invasion and liver metastasis. Induction of these genes also occurred in diverticulitis and digestive neoplasms such as gastric and esophageal carcinomas. © 1995 Wiley-Liss, Inc.
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Stromelysin-3 gene expression in human cancer: an overview.
Invasion & Metastasis, 1994Co-Authors: Nicolas Rouyer, Pierre Chambon, Marie-pierre Chenard, Jean-pierre Bellocq, Catherine Wolf, Basset PAbstract:Stromelysin-3 (ST3) belongs to the family of matrix metalloproteinases, a group of proteolytic enzymes which are believed to play a role in tumor invasion and metastasis. In the present study, we report that the ST3 gene, which was initially identified in invasive breast carcinoma, is expressed in most other invasive human carcinomas, but rarely in sarcomas and other nonepithelial tumors. In carcinomas, both ST3 RNA and protein were specifically detected in fibroblastic cells immediately surrounding the cancer cells. In agreement with this observation, the carcinomas which are known to progress without inducing a prominent tumor stroma are also those which usually do not express the ST3 gene. ST3 gene expression was also observed in noninvasive carcinomas of the breast, uterus cervix and bladder, where the probability of detecting ST3 RNA and protein positively correlated with the known risk of these lesions evolving towards invasion. Taken together, these observations further support the hypothesis that ST3 may contribute to tissue-remodeling processes associated with carcinoma progression, and may represent a new prognostic factor to define populations of aggressive tumors.
Christian Gespach - One of the best experts on this subject based on the ideXlab platform.
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overexpression of Stromelysin 3 bm 40 sparc and met genes in human esophageal carcinoma implications for prognosis
Clinical Cancer Research, 1998Co-Authors: H Porte, S Prevot, B Nordlinger, A Wurtz, J P Triboulet, Larissa Kotelevets, Fabrice Carrat, Y Digioia, Paolo M Comoglio, Christian GespachAbstract:Molecular markers can improve staging and predict aggressive clinical behavior in esophageal cancer, thus helping to define appropriate therapeutic protocols and to identify patients who will benefit from surgery. We therefore characterized, by Northern blot and/or immunohistochemistry, the relative expression of three effectors involved in the invasion, angiogenesis, and dissemination of tumor cells in esophageal cancer versus nontumoral mucosae: (a) Stromelysin-3 (ST3), a member of the metalloproteinase family; (b) basement membrane 40/secreted protein acidic and rich in cysteine (BM-40/SPARC), an extracellular matrix-associated protein involved in angiogenesis; and (c) the hepatocyte growth factor receptor MET, which triggers the scattering of epithelial cells. Results were analyzed in relation to clinicopathological parameters (cpTNE) including tumor size (T), lymph node status (N), periesophageal tissue invasion (E), disease recurrence, and overall survival. The ST3, BM-40/SPARC, and MET genes were found to be overexpressed in tumor samples compared to control mucosa. BM-40/SPARC and MET mRNA levels were not linked to any one of the cpTNE, indicating that this overexpression occurs at an early stage of neoplastic progression. In contrast, ST3 expression, identified by immunohistochemistry in fibroblastic cells surrounding neoplastic islets, correlated with tumor size and periesophageal tissue invasion. Of the 36 patients studied, those with high ST3 levels had shorter disease-free survival than those with low levels, but there was no relationship between the cpTNE and disease recurrence or survival. Our study demonstrates that ST3, BM-40/SPARC, and MET are involved in different steps of esophageal carcinogenesis and that ST3 overexpression is a marker of aggressive clinical behavior. We conclude that in esophageal cancer, ST3 might help to assess survival and the risk of recurrence after surgical resection.
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Overexpression of Stromelysin-3, BM-40/SPARC, and MET genes in human esophageal carcinoma: implications for prognosis.
Clinical Cancer Research, 1998Co-Authors: H Porte, S Prevot, A Wurtz, J P Triboulet, Larissa Kotelevets, Fabrice Carrat, Y Digioia, Paolo M Comoglio, B Nordlinger, Christian GespachAbstract:Molecular markers can improve staging and predict aggressive clinical behavior in esophageal cancer, thus helping to define appropriate therapeutic protocols and to identify patients who will benefit from surgery. We therefore characterized, by Northern blot and/or immunohistochemistry, the relative expression of three effectors involved in the invasion, angiogenesis, and dissemination of tumor cells in esophageal cancer versus nontumoral mucosae: (a) Stromelysin-3 (ST3), a member of the metalloproteinase family; (b) basement membrane 40/secreted protein acidic and rich in cysteine (BM-40/SPARC), an extracellular matrix-associated protein involved in angiogenesis; and (c) the hepatocyte growth factor receptor MET, which triggers the scattering of epithelial cells. Results were analyzed in relation to clinicopathological parameters (cpTNE) including tumor size (T), lymph node status (N), periesophageal tissue invasion (E), disease recurrence, and overall survival. The ST3, BM-40/SPARC, and MET genes were found to be overexpressed in tumor samples compared to control mucosa. BM-40/SPARC and MET mRNA levels were not linked to any one of the cpTNE, indicating that this overexpression occurs at an early stage of neoplastic progression. In contrast, ST3 expression, identified by immunohistochemistry in fibroblastic cells surrounding neoplastic islets, correlated with tumor size and periesophageal tissue invasion. Of the 36 patients studied, those with high ST3 levels had shorter disease-free survival than those with low levels, but there was no relationship between the cpTNE and disease recurrence or survival. Our study demonstrates that ST3, BM-40/SPARC, and MET are involved in different steps of esophageal carcinogenesis and that ST3 overexpression is a marker of aggressive clinical behavior. We conclude that in esophageal cancer, ST3 might help to assess survival and the risk of recurrence after surgical resection.
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neoplastic progression of human colorectal cancer is associated with overexpression of the Stromelysin 3 and bm 40 sparc genes
International Journal of Cancer, 1995Co-Authors: Henri Porte, Paul Basset, Pierre Chambon, Eric Chastre, S Prevot, B Nordlinger, Sylvie Empereur, Christian GespachAbstract:The interaction of neoplastic cells with the extracellular matrix is a critical event for the initiation of cancer invasion and metastasis. This study was designed to evaluate the potential implication of Stromelysin-3 (ST3), a newly identified member of the matrix-degrading metalloproteinase family, and of BM-40/SPARC, a glycoprotein associated with the extracellular matrix, during the progression of human colorectal cancers. We analyzed the relative abundance of ST3 and BM-40/SPARC transcripts by Northern blot, and their distribution by in situ hybridization, in normal mucosa, benign adenomas, and primary colorectal adenocarcinomas and their liver metastases. The ST3 and BM-40/SPARC transcripts were overexpressed in primary colorectal cancers and their liver metastases compared to non-neoplastic mucosa. These transcripts were localized in stromal fibroblasts adjacent to the neoplastic foci. Overexpression of ST3 correlated with the progression of human colorectal tumors toward local invasion and liver metastasis. Induction of these genes also occurred in diverticulitis and digestive neoplasms such as gastric and esophageal carcinomas. © 1995 Wiley-Liss, Inc.
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Neoplastic progression of human colorectal cancer is associated with overexpression of the Stromelysin-3 and BM-40/SPARC genes
International Journal of Cancer, 1995Co-Authors: Henri Porte, Paul Basset, Pierre Chambon, Eric Chastre, S Prevot, B Nordlinger, Sylvie Empereur, Christian GespachAbstract:The interaction of neoplastic cells with the extracellular matrix is a critical event for the initiation of cancer invasion and metastasis. This study was designed to evaluate the potential implication of Stromelysin-3 (ST3), a newly identified member of the matrix-degrading metalloproteinase family, and of BM-40/SPARC, a glycoprotein associated with the extracellular matrix, during the progression of human colorectal cancers. We analyzed the relative abundance of ST3 and BM-40/SPARC transcripts by Northern blot, and their distribution by in situ hybridization, in normal mucosa, benign adenomas, and primary colorectal adenocarcinomas and their liver metastases. The ST3 and BM-40/SPARC transcripts were overexpressed in primary colorectal cancers and their liver metastases compared to non-neoplastic mucosa. These transcripts were localized in stromal fibroblasts adjacent to the neoplastic foci. Overexpression of ST3 correlated with the progression of human colorectal tumors toward local invasion and liver metastasis. Induction of these genes also occurred in diverticulitis and digestive neoplasms such as gastric and esophageal carcinomas. © 1995 Wiley-Liss, Inc.
Marie-pierre Chenard - One of the best experts on this subject based on the ideXlab platform.
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dual Stromelysin 3 function during natural mouse mammary tumor virus ras tumor progression
Cancer Research, 2003Co-Authors: Kumari L Andarawewa, Isabelle Stoll, Anne Boulay, Marie-pierre Chenard, Regis Masson, C Mathelin, Catherine Tomasetto, Martine Gintz, Jean-pierre BellocqAbstract:In human carcinomas, Stromelysin-3/matrix metalloproteinase 11 (ST3, MMP11) expression by nonmalignant fibroblastic cells located in the immediate vicinity of cancer cells is a bad prognostic factor. Using mouse models of primary tumors, it has been demonstrated that ST3 is a key player during local invasion, favoring cancer cell survival in connective tissue through an antiapoptotic function. To investigate the ST3 impact on additional phases of cancer cell invasion, we developed mammary gland cancer prone MMTV-ras transgenic mice in wild-type (ras+/+;ST3+/+) or ST3-deficient (ras+/+;ST3−/−) genotype and studied their whole natural cancer history. The tumor-free survival and delay between the first ras oncogenic hit and primary tumor appearance increased in ras+/+;ST3−/− mice ( P P P
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high cancer cell death in syngeneic tumors developed in host mice deficient for the Stromelysin 3 matrix metalloproteinase
Cancer Research, 2001Co-Authors: Anne Boulay, Marie-pierre Chenard, Jean-pierre Bellocq, Regis Masson, Mostapha El Fahime, Lydie Cassard, Catherine Sauteesfridman, Paul BassetAbstract:Matrix metalloproteinases (MMPs) are extracellular enzymes. Some of them are known to be involved in tumor development and/or progression. Several cellular functions have been proposed for MMPs during malignant processes. Notably, they may be involved in tissue-remodeling processes through their ability to digest matrix components or to participate in tumor neoangiogenesis and, subsequently, in cancer cell proliferation. One of these MMPs, Stromelysin-3 (ST3/MMP11), although devoid of enzymatic activity against the matrix components, is associated with human tumor progression and poor patient clinical outcome. Using several in vivo experimental models, it has been demonstrated that ST3 expression by the fibroblastic cells surrounding malignant epithelial cells promotes tumorigenesis in a paracrine manner. The present study was devoted to the identification of the cellular function underlying this ST3-induced tumor promotion using a syngeneic tumorigenesis model in mice. Our results show that ST3 exhibits a new and unexpected role for a MMP, because ST3-increased tumorigenesis does not result from increased neoangiogenesis or cancer cell proliferation but from decreased cancer cell death through apoptosis and necrosis. Thus, during malignancy, the cellular function of ST3 is to favor cancer cell survival in the stromal environment.
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in vivo evidence that the Stromelysin 3 metalloproteinase contributes in a paracrine manner to epithelial cell malignancy
Journal of Cell Biology, 1998Co-Authors: Regis Masson, Agnès Noël, Olivier Lefebvre, Marie-pierre Chenard, Corinne Wendling, F Kebers, Marianne Lemeur, Mostapha El Fahime, Andree Dierich, Jean-michel FoidartAbstract:Stromelysin-3 (ST3; Basset, P., J.P. Bellocq, C. Wolf, I. Stoll, P. Hutin, J.M. Limacher, O.L. Podhajcer, M.P. Chenard, M.C. Rio, P. Chambon. 1990. Nature. 348:699–704) is a matrix metalloproteinase (MMP) expressed in mesenchymal cells located close to epithelial cells, during physiological and pathological tissue remodeling processes. In human carcinomas, high ST3 levels are associated with a poor clinical outcome, suggesting that ST3 plays a role during malignant processes. In this study we report the ST3 gene inactivation by homologous recombination. Although ST3 null mice (ST3−/−) were fertile and did not exhibit obvious alterations in appearance and behavior, the lack of ST3 altered malignant processes. Thus, the suppression of ST3 results in a decreased 7,12-dimethylbenzanthracene-induced tumorigenesis in ST3−/− mice. Moreover, ST3−/− fibroblasts have lost the capacity to promote implantation of MCF7 human malignant epithelial cells in nude mice (P < 0.008). Finally, we show that this ST3 paracrine function requires extracellular matrix (ECM)-associated growth factors. Altogether, these findings give evidence that ST3 promotes, in a paracrine manner, homing of malignant epithelial cells, a key process for both primary tumors and metastases. Therefore, ST3 represents an appropriate target for specific MMP inhibitor(s) in future therapeutical approaches directed against the stromal compartment of human carcinomas.
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high levels of Stromelysin 3 correlate with poor prognosis in patients with breast carcinoma
International Journal of Cancer, 1996Co-Authors: Marie-pierre Chenard, Paul Basset, Yves Lutz, Nicolas Rouyer, Catherine Wolf, L Osiorain, S G Shering, Jeanpierre Belloco, M J DuffyAbstract:Stromelysin 3 (ST3) is a matrix metalloprotease (MMP) expressed in fibroblast-like cells of most human invasive carcinomas. In this investigation, ST3 was measured by semiquantitative immunohistochemistry in III primary breast cancers. ST3 levels showed no correlation with tumor size, axillary-node status or tumor grade (Scarff-Bloom-Richardson system; SBR) but were significantly associated with higher nuclear grade (modified SBR). In addition, ST3 levels were significantly higher in ductal than in lobular cancers. Patients with high scores of ST3 staining had a shorter disease-free interval and shorter overall survival than patients with low scores. ST3 is thus one of the first MMPs to correlate with patient outcome in breast cancer. These findings are consistent with earlier clinical and experimental observations suggesting that ST3 contributes to breast-cancer progression. © 1996 Wiley-Liss, Inc.
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Stromelysin-3 expression promotes tumor take in nude mice.
Journal of Clinical Investigation, 1996Co-Authors: Agnès Noël, Erik Maquoi, Olivier Lefebvre, L. Vanhoorde, Marie-pierre Chenard, Marcus Mareel, Jean-michel Foidart, Paul BassetAbstract:Stromelysin-3 (ST3) is a matrix metalloproteinase expressed in human carcinomas in ways suggesting that it may play a role in tumor progression. To test this possibility, we have performed gene transfer experiments using both anti-sense and sense ST3 expression vectors, and malignant cells either expressing (NIH 3T3 fibroblasts) or not (MCF7 epithelial cells) endogenous ST3. We have compared the ability of parental and transfected cells to cause subcutaneous tumor development in nude mice. 3T3 cells expressing anti-sense ST3 RNA showed reduced tumorigenicity, and MCF7 cells expressing mouse or human ST3 were associated with reduced tumor-free period leading to a significant increased tumor incidence(P
Catherine Wolf - One of the best experts on this subject based on the ideXlab platform.
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high levels of Stromelysin 3 correlate with poor prognosis in patients with breast carcinoma
International Journal of Cancer, 1996Co-Authors: Marie-pierre Chenard, Paul Basset, Yves Lutz, Nicolas Rouyer, Catherine Wolf, L Osiorain, S G Shering, Jeanpierre Belloco, M J DuffyAbstract:Stromelysin 3 (ST3) is a matrix metalloprotease (MMP) expressed in fibroblast-like cells of most human invasive carcinomas. In this investigation, ST3 was measured by semiquantitative immunohistochemistry in III primary breast cancers. ST3 levels showed no correlation with tumor size, axillary-node status or tumor grade (Scarff-Bloom-Richardson system; SBR) but were significantly associated with higher nuclear grade (modified SBR). In addition, ST3 levels were significantly higher in ductal than in lobular cancers. Patients with high scores of ST3 staining had a shorter disease-free interval and shorter overall survival than patients with low scores. ST3 is thus one of the first MMPs to correlate with patient outcome in breast cancer. These findings are consistent with earlier clinical and experimental observations suggesting that ST3 contributes to breast-cancer progression. © 1996 Wiley-Liss, Inc.
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characterization of monoclonal antibodies against Stromelysin 3 and their use to evaluate Stromelysin 3 levels in breast carcinoma by semi quantitative immunohistochemistry
International Journal of Cancer, 1995Co-Authors: Maria Santavicca, Agnès Noël, Isabelle Stoll, Marie-pierre Chenard, Jean-pierre Bellocq, Yves Lutz, Jeanpierre Segain, Nicolas Rouyer, Catherine Wolf, Paul BassetAbstract:Stromelysin-3 (ST3) is a matrix metalloproteinase which is expressed in fibroblastic cells of most human invasive carcinomas and represents a potential new prognostic indicator. Expression of recombinant ST3 forms in Escherichia coli from cDNA constructs indicated that high levels of expression were achieved when the ST3 pro-domain was deleted. The putative mature form of ST3 thus produced and recovered from bacterial inclusion bodies was used to prepare monoclonal antibodies (MAbs) against ST3 by immunization of BALB/C mice. Ten hybridomas producing MAbs against ST3 were obtained and analyzed for their ability to detect endogenous ST3 in breast cancer and in conditioned media from human fibroblasts. One of these MAbs (5ST-4A9) was found to be suitable for the routine detection of ST3 on breast cancer tissue sections, thus opening the possibility to evaluate ST3 prognostic value in breast cancer using semi-quantitative immunohistochemistry. © 1995 Wiley-Liss, Inc.
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Characterization of monoclonal antibodies against Stromelysin‐3 and their use to evaluate Stromelysin‐3 levels in breast carcinoma by semi‐quantitative immunohistochemistry
International Journal of Cancer, 1995Co-Authors: Maria Santavicca, Agnès Noël, Isabelle Stoll, Marie-pierre Chenard, Yves Lutz, Jeanpierre Segain, Nicolas Rouyer, Catherine Wolf, Jean-pierre BellocqAbstract:Stromelysin-3 (ST3) is a matrix metalloproteinase which is expressed in fibroblastic cells of most human invasive carcinomas and represents a potential new prognostic indicator. Expression of recombinant ST3 forms in Escherichia coli from cDNA constructs indicated that high levels of expression were achieved when the ST3 pro-domain was deleted. The putative mature form of ST3 thus produced and recovered from bacterial inclusion bodies was used to prepare monoclonal antibodies (MAbs) against ST3 by immunization of BALB/C mice. Ten hybridomas producing MAbs against ST3 were obtained and analyzed for their ability to detect endogenous ST3 in breast cancer and in conditioned media from human fibroblasts. One of these MAbs (5ST-4A9) was found to be suitable for the routine detection of ST3 on breast cancer tissue sections, thus opening the possibility to evaluate ST3 prognostic value in breast cancer using semi-quantitative immunohistochemistry. © 1995 Wiley-Liss, Inc.
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Stromelysin-3 gene expression in human cancer: an overview.
Invasion & Metastasis, 1994Co-Authors: Nicolas Rouyer, Pierre Chambon, Marie-pierre Chenard, Jean-pierre Bellocq, Catherine Wolf, Basset PAbstract:Stromelysin-3 (ST3) belongs to the family of matrix metalloproteinases, a group of proteolytic enzymes which are believed to play a role in tumor invasion and metastasis. In the present study, we report that the ST3 gene, which was initially identified in invasive breast carcinoma, is expressed in most other invasive human carcinomas, but rarely in sarcomas and other nonepithelial tumors. In carcinomas, both ST3 RNA and protein were specifically detected in fibroblastic cells immediately surrounding the cancer cells. In agreement with this observation, the carcinomas which are known to progress without inducing a prominent tumor stroma are also those which usually do not express the ST3 gene. ST3 gene expression was also observed in noninvasive carcinomas of the breast, uterus cervix and bladder, where the probability of detecting ST3 RNA and protein positively correlated with the known risk of these lesions evolving towards invasion. Taken together, these observations further support the hypothesis that ST3 may contribute to tissue-remodeling processes associated with carcinoma progression, and may represent a new prognostic factor to define populations of aggressive tumors.
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Stromelysin 3 belongs to a subgroup of proteinases expressed in breast carcinoma fibroblastic cells and possibly implicated in tumor progression
Proceedings of the National Academy of Sciences of the United States of America, 1993Co-Authors: Catherine Wolf, Pierre Chambon, Jean-pierre Bellocq, N Rouyer, Y Lutz, C Adida, M Loriot, P BassetAbstract:Abstract The expression of the Stromelysin 3 (ST3) gene, which encodes a putative matrix metalloproteinase, was studied during breast cancer progression. The ST3 gene is expressed in all invasive breast carcinomas, in a number of their metastases, and in some in situ carcinomas where the probability of detecting ST3 transcripts correlates with the known risk of these carcinomas to become invasive. ST3 RNA and protein were specifically detected in fibroblastic cells immediately surrounding the neoplastic cells in both primary and metastatic tumors. This expression pattern distinguishes the ST3 gene from other matrix metalloproteinase genes, most notably from the 72-kDa type IV collagenase gene, which can be expressed in fibroblastic cells distributed throughout the stroma of primary breast carcinomas. Furthermore, high levels of 72-kDa type IV collagenase, but not of ST3 transcripts, are detected in benign breast fibroadenomas. Interestingly, the urokinase and ST3 genes exhibit very similar patterns of expression in breast carcinomas, which suggests that their products may cooperate during cancer progression.
