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See detailIn vivo evidence that the stromelysin-3 metalloproteinase contributes in a paracrine manner to epithelial cell malignancy
Masson, R.; Lefebvre, O.; Noël, Agnès ULg et al

in Journal of Cell Biology (1998), 140

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 ... [more ▼]

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. [less ▲]

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See detailAlteration of Interendothelial Adherens Junctions Following Tumor Cell-Endothelial Cell Interaction in Vitro
Lewalle, J. M.; Bajou, Khalid ULg; Desreux, Joëlle ULg et al

in Experimental Cell Research (1997), 237(2), 347-56

The integrity of the vascular endothelium is mainly dependent upon the organization of interendothelial adherens junctions (AJ). These junctions are formed by the homotypic interaction of a transmembrane ... [more ▼]

The integrity of the vascular endothelium is mainly dependent upon the organization of interendothelial adherens junctions (AJ). These junctions are formed by the homotypic interaction of a transmembrane protein, vascular endothelial cadherin (VE-cadherin), which is complexed to an intracellular protein network including alpha-, beta-, and gamma-catenin. Additional proteins such as vinculin and alpha-actinin have been suggested to link the VE-cadherin/catenin complex to the actin-based cytoskeleton. During the process of hematogenous metastasis, circulating tumor cells must disrupt these intercellular junctions in order to extravasate. In the present study, we have investigated the influence of tumor cell-endothelial cell interaction upon interendothelial AJ. We show that human breast adenocarcinoma cells (MCF-7), but not normal human mammary epithelial cells, induce a rapid endothelial cell (EC) dissociation which correlates with the loss of VE-cadherin expression at the site of tumor cell-EC contact and with profound changes in vinculin distribution and organization. This process could not be inhibited by metalloproteinase nor serine protease inhibitors. Immunoprecipitations and Western blot analysis demonstrate that the overall expression of VE-cadherin and vinculin as well as the composition of the VE-cadherin/catenins complex are not affected by tumor cells while the tyrosine phosphorylation status of proteins within the complex is significantly altered. Our data suggest that tumor cells modulate AJ protein distribution and phosphorylation in EC and may, thereby, facilitate EC dissociation. [less ▲]

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See detailExpression of Stromelysin-3 in the Human Placenta and Placental Bed
Maquoi, Erik ULg; Polette, M.; Nawrocki, B. et al

in Placenta (1997), 18(4), 277-85

Human placentation is mediated by fetal trophoblastic cells which penetrate into the decidualized uterine endometrium. Trophoblast invasion requires the precisely regulated secretion of specific ... [more ▼]

Human placentation is mediated by fetal trophoblastic cells which penetrate into the decidualized uterine endometrium. Trophoblast invasion requires the precisely regulated secretion of specific proteinases able to degrade the endometrial basement membranes and extracellular matrix. To document further the involvement of these proteinases during human placentation, we evaluated in vivo the expression of stromelysin-3, a member of the metalloproteinase family, during the first and third trimesters of pregnancy, by means of immunohistochemistry, in situ hybridization and Northern blot analysis. Human extravillous trophoblasts invading the maternal decidua produced stromelysin-3 during both, the first and third trimesters of pregnancy, but to a lesser extent during the latter. In floating villi, stromelysin-3 expression was restricted to the syncytiotrophoblasts that line intervillous vascular spaces. In conclusion, stromelysin-3 is expressed by differentiated, non-proliferative villous and extravillous trophoblastic cells in early and late placental beds and villi, and its pattern of expression evolves during pregnancy. Our observations suggest that stromelysin-3 could play a role in human placentation. [less ▲]

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See detailInvolvement of Pa/Plasmin System in the Processing of Pro-Mmp-9 and in the Second Step of Pro-Mmp-2 Activation
Baramova, E. N.; Bajou, Khalid ULg; Remacle, A. et al

in FEBS Letters (1997), 405(2), 157-62

Pro-MMP2 activation is a two-step process resulting in (1) an intermediate 64 kDa form generated by the MT1-MMP activity, and (2) a mature 62 kDa form. Addition of plasminogen to HT1080 cells cultured ... [more ▼]

Pro-MMP2 activation is a two-step process resulting in (1) an intermediate 64 kDa form generated by the MT1-MMP activity, and (2) a mature 62 kDa form. Addition of plasminogen to HT1080 cells cultured under various conditions, or to their membrane preparation, induced a complete conversion of the intermediate MMP-2 form to the mature one, and processing of pro-MMP-9. The pro-MMP-2 activation was inhibited by plasmin inhibitors and anti-uPA antibody. These results provide evidence for involvement of the PA/plasmin system in the second step of MMP-2 activation. [less ▲]

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See detailIntratumoral heterogeneity for hsp90 mRNA levels in a breast cancer cell line
Luparello, C.; Noël, Agnès ULg; Pucci-Minafra, I.

in DNA & Cell Biology (1997), 16

BC-3A and BC-61 are two breast cancer cell lines that have been cloned from parental 8701-BC cells and exhibit different biosynthetic, proliferative, and invasive properties in vitro. In the attempt to ... [more ▼]

BC-3A and BC-61 are two breast cancer cell lines that have been cloned from parental 8701-BC cells and exhibit different biosynthetic, proliferative, and invasive properties in vitro. In the attempt to search whether alterations in the profiles of gene expression could be detected, we have submitted both cytotypes to identification of differentially expressed cDNAs. In addition, steroid hormone receptor mRNA arrays and in vivo tumorigenesis of the two lines have been checked. The technique used allowed identification of changes in the expression of the 90-kD heat shock protein-beta (hsp90beta) which is prominently down-regulated in BC-61 cells. Because we have also found that these cells, which lack estrogen receptor mRNA synthesis, display a more invasive behavior in vitro and increased tumorigenesis in vivo, we propose that evaluation of hsp903 transcript levels may be taken into consideration for screening as a novel molecular marker of breast cancer progression. [less ▲]

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See detailProduction and activation of matrix metalloprotease-9 (MMP-9) by HL-60 promyelocytic leukemia cells
Devy, L.; Noël, Agnès ULg; Baramova, E. et al

in Biochemical and Biophysical Research Communications (1997), 238

Human promyelocytic HL-60 cells have been used as a model of acute leukemia to investigate the expression and the regulation of matrix metalloproteases (MMPs), known to contribute to the degradation of ... [more ▼]

Human promyelocytic HL-60 cells have been used as a model of acute leukemia to investigate the expression and the regulation of matrix metalloproteases (MMPs), known to contribute to the degradation of extracellular matrix components. As shown by gelatin zymography, HL-60 cells constitutively released significant amounts of proMMP-9 (92 kDa) and moderate amounts of proMMP-2 (72 kDa). Furthermore, casein zymography confirmed the presence of serine proteases in the form of pro-urokinase. Activation of proMMP-9 was dependent on the plasminogen activator/plasmin (PA/plasmin) system and was inhibited by aprotinin. MMP-9 was only detected in cellular extracts or conditioned media incubated with HL-60 cells, indicating that cells are essential to the activation process. Addition of plasminogen increased by 3-fold the basal invasive rate of these cells across a matrigel layer (2.1%versus0.7% in control cells after 4 h of incubation). Taken together, these results indicate that HL-60 cells exhibit an autocrine activation mechanism of proMMP-9 via the PA/plasmin system and that activation of proMMP-9 increases their invasive potential [less ▲]

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See detailMatrix metalloproteinases in choriocarcinoma cell lines: a potential regulatory role of extracellular matrix components
Maquoi, Erik ULg; Noël, Agnès ULg; Foidart, Jean-Michel ULg

in Foidart, Jean-Michel; Aplin, J.; Kaufmann, P. (Eds.) et al Trophoblast Research. Early Pregnancy (1997)

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See detailLoss of type IV collagen alpha 5 and alpha 6 chains in human invasive prostate carcinomas
Dehan, Pierre ULg; Waltregny, David ULg; Beschin, Alain et al

in American Journal of Pathology (1997), 151(4), 1097-104

Type IV collagen, a major component of basement membranes, is organized in a network responsible for the mechanical resistance of the basement membranes. It also plays a key role in epithelial cell ... [more ▼]

Type IV collagen, a major component of basement membranes, is organized in a network responsible for the mechanical resistance of the basement membranes. It also plays a key role in epithelial cell adhesion to basement membranes. This study was designed to investigate the distribution of type IV collagen alpha-chains in normal, preneoplastic, and malignant prostate basement membranes. For this purpose, immunohistochemistry using specific antibodies raised against the different alpha-chains of type IV collagen was performed in eight normal samples, six prostatic intraepithelial neoplasia, and 20 malignant lesions of the prostate. Our results demonstrate the presence of the "novel" alpha 5 (IV) and alpha 6 (IV) chains along with the "classical" alpha 1 (IV)/alpha 2 (IV) chains in the basement membrane of the normal prostate gland. The alpha 3 (IV) chain was never detected in any prostate specimen. Prostatic intraepithelial neoplasia showed a similar immunostaining pattern to that found in normal glands. In cancer gland basement membranes, we demonstrate for the first time a specific loss of the alpha 5 (IV) and alpha 6 (IV) chains, whereas the classical alpha 1 (IV) and alpha 2 (IV) chains were consistently exhibited. Additionally, type VII collagen colocalized with alpha 5 (IV) collagen chain, and these two proteins, which were always observed in normal and prostatic intraepithelial neoplasia gland basement membranes, were lost in invasive carcinoma basement membranes. This observation raises questions about the possible association or cooperation between alpha 5 (IV)/alpha 6 (IV) chains and anchoring fibrils in prostate glands basement membrane. [less ▲]

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See detailEmerging Roles for Proteinases in Cancer
Noël, Agnès ULg; Gilles, Christine ULg; Bajou, Khalid ULg et al

in Invasion & Metastasis (1997), 17(5), 221-39

Metalloproteinases and serine proteinases have been associated with tumor invasion and formation of metastasis which represent the major obstacles to cancer cure. The contribution of proteinases in these ... [more ▼]

Metalloproteinases and serine proteinases have been associated with tumor invasion and formation of metastasis which represent the major obstacles to cancer cure. The contribution of proteinases in these processes was initially thought to be the destruction of extracellular matrices. However, recent evidence suggests that they mainly affect tumor growth rather than invasion. Proteinases can indeed generate active matrix protein fragments, influence the release, the activation and the bioavailability of growth factors, and consequently modulate tumor cell growth, apoptosis and angiogenesis. Additionally, proteinases, their receptors and/or inhibitors can be directly involved in cell migration and in the processing or shedding of cell surface proteins. Further elucidation of the functions of proteinases is essential for the development of novel anticancer strategies. [less ▲]

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See detailLa prééclampsie est la conséquence d'un déficit de placentation: de la biologie aux considérations cliniques
Maquoi, Erik ULg; Schaaps, Jean-Pierre ULg; Jacobs, J. L. et al

in Revue Médicale de Liège (1997), 52(7), 478-84

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See detailStromelysin-3: a paradigm for stroma-derived factors implicated in carcinoma progression."
Basset, P.; Bellocq, J. P.; Lefebvre, O. et al

in Critical Reviews in Oncology/Hematology (1997)

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See detailStromelysin-3 in the biology of normal and tumoral mammary gland.
Rio, M. C.; Lefebvre, O.; Santavicca, M. et al

in Journal of Mammary Gland Biology & Neoplasia (1996), 1(2), 231-240

Stromelysin-3 (ST3) is an extracellular proteinase predominantly expressed in fibroblasts. The particular structural features andin vitro functions of this molecule suggest it could be the first member of ... [more ▼]

Stromelysin-3 (ST3) is an extracellular proteinase predominantly expressed in fibroblasts. The particular structural features andin vitro functions of this molecule suggest it could be the first member of a new subgroup of the matrix metalloproteinase family. ST3 is transiently expressed during mammary gland post-weaning involution, embryonic implantation, various organogeneses, and during amphibian metamorphosis. Moreover, ST3 is expressed in a panel of human invasive carcinomas including breast, colon, and head and neck carcinomas. Almost all ST3-expressing tissues show intense extracellular matrix remodeling activities including the loss of basement membrane integrity. Thus, either directly, or indirectly in association with other proteinases, ST3 might be involved in tissue remodeling processes occurring in both physiological and pathological processes.In vitro andin vivo studies using malignant cells stably transfected in such a way as to modulate their ST3 expression levels indicate that ST3 modifies neither cell proliferation nor invasive properties, but rather favors tumor cell survival in host tissues. This hypothesis is consistent with clinical data showing that ST3 expression could be predictive of tumor progression leading to metastases. [less ▲]

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See detailCharacterisation of structural determinants and molecular mechanisms involved in Stromelysin-3 activation by 4-aminophenylmercuric acetate and furin-type convertases.
Santavicca, M.; Noël, Agnès ULg; Stoll, I. et al

in Biochemical Journal (1996), 315

Stromelysin-3 (ST3) is a matrix metalloproteinase (MMP) which has been implicated in cancer progression and in a number of conditions involving tissue remodelling. In contrast to other MMPs which are ... [more ▼]

Stromelysin-3 (ST3) is a matrix metalloproteinase (MMP) which has been implicated in cancer progression and in a number of conditions involving tissue remodelling. In contrast to other MMPs which are secreted as zymogens requiring extracellular activation, ST3 is found in the extracellular space as a potentially active mature form, suggesting that the activation of the ST3 proform differs from that of other MMPs. We show in the present study that the ST3 proform is not autocatalytically processed in the presence of 4-aminophenylmercuric acetate (APMA). By using ST3/ST2 chimeras, we demonstrate that resistance to APMA is due to properties associated with both the ST3 pro- and catalytic domains. In agreement with the observation made by Pei and Weiss [Pei and Weiss (1995) Nature (London) 375, 244-247], we find that the requirement for activation of the ST3 proform by the furin convertase is entirely contained within a stretch of 10 amino acids located at the junction between the ST3 pro- and catalytic domains. Furin cleaves human and mouse ST3 equally well. However, PACE-4, a furin-like convertase, is much more efficient on the mouse enzyme, suggesting that ST3 protein determinants other than the conserved Ala-Arg-Asn-Arg-Gln-Lys-Arg sequence preceding the furin cleavage site are implicated in PACE-4 action. Finally, we show that processing of the ST3 proform is inhibited by a furin inhibitor in human MCF7 breast cancer cells stably transfected to constitutively express a full-length human ST3 cDNA. Using brefeldin A, we demonstrate that, in these MCF7 cells, the 56 kDa precursor form of ST3 is post-translationally modified in the cis- or media-Golgi into a 62 kDa proform. Thereafter, its processing into the 47 kDa mature form occurs in the trans-Golgi network and is followed by secretion into the extracellular space. [less ▲]

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See detailStromelysin-3 expression promotes tumor take in nude mice
Noël, Agnès ULg; Lefebvre, O.; Maquoi, Erik ULg et al

in Journal of Clinical Investigation (1996), 97

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 ... [more ▼]

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<10(-4)). However, once established, the ST3 expressing tumors did not grow faster than those obtained with the parental MCF7 cell line. In addition, tumors obtained after sub-cutaneous injection of ST3-expressing or nonexpressing cells did not exhibit obvious histological differences, and careful examination did not reveal any local invasive tissue areas nor systemic metastases. These in vivo observations were in agreement with those obtained in vitro showing that ST3 expression did not modify proliferative nor invasive properties of transfected cells. Altogether, these results indicate that ST3 expression promotes tumor take in nude mice, presumably by favoring cancer cell survival in a tissue environment initially not permissive for tumor growth. These findings represent the first experimental evidence showing that ST3 can modulate cancer progression. [less ▲]

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See detailCloning of choriocarcinoma cells shows that invasion correlates with expression and activation of gelatinase A
Crescimanno, C.; Foidart, Jean-Michel ULg; Noël, Agnès ULg et al

in Experimental Cell Research (1996), 227

Implantation and placental development are dependent upon trophoblast invasion of the endometrium. While the villous trophoblast does not display invasive behavior, the extravillous cytotrophoblast is ... [more ▼]

Implantation and placental development are dependent upon trophoblast invasion of the endometrium. While the villous trophoblast does not display invasive behavior, the extravillous cytotrophoblast is highly invasive. By cloning BeWo choriocarcinoma cells, we have isolated two distinct clones that share similarities with villous and extravillous cytotrophoblasts. When cultured at the surface of a type I collagen gel, BeWo MC-1 cells were not invasive, whereas BeWo MC-2 cells rapidly invaded this matrix. When injected subcutaneously in nude mice, BeWo MC-1 cells developed a localized tumor and BeWo MC-2 cells developed larger tumors with micrometastases. Gelatinase A expression and minute amounts of gelatinase B were detected in the parental cell line and in both clones. However, the parental and the BeWo MC-2 cells secreted 5- to 10-fold more gelatinase A than the BeWo MC-1 cells. Laminin and matrigel stimulated the production of gelatinase A in BeWo MC-2 cells. Type I collagen promoted the conversion of the 72-kDa progelatinase A in an active enzyme only in parental BeWo and in BeWo MC-2 cells. These clones provide an interesting model for studying the complex mechanisms regulating implantation as well as the controlled invasiveness during implantation compared to tumor invasion. [less ▲]

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See detailStromelysin-3 and other stromelysins in breast cancer : importance of epithelial-stromal interactions during tumor progression.
Basset, P.; Bellocq, J. P.; Anglard, P. et al

in Lippman, M. E.; Dickinson, R. D. (Eds.) Breast Cancer: Cellular and Molecular Biology (1996)

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See detailIdentification of structural determinants controlling human and mouse stromelysin-3 proteolytic activities
Noël, Agnès ULg; Santavicca, M.; Stoll, I. et al

in Journal of Biological Chemistry (1995), 270

Matrix metalloproteinases (matrixins) constitute a group of extracellular proteinases belonging to the metzincin superfamily. They are involved in both physiological and pathological tissue remodeling ... [more ▼]

Matrix metalloproteinases (matrixins) constitute a group of extracellular proteinases belonging to the metzincin superfamily. They are involved in both physiological and pathological tissue remodeling processes, including those associated with cancer progression. Stromelysin-3, which is expressed in most invasive human carcinomas, is a matrix metalloproteinase with unusual functional properties. In particular, its mature form does not cleave any of the major extracellular matrix components. To define critical structural determinants involved in controlling stromelysin-3 proteolytic activity, we have used site-directed mutagenesis. We show that the deletion of at least 175 C-terminal amino-acids is sufficient to endow mouse stromelysin-3 with activities against casein, laminin, and type IV collagen. In the case of the human enzyme, however, a further and single Ala-235 Pro substitution is necessary to observe similar activities. Ala-235, which characterizes human stromelysin-3 among matrixins, is located immediately after the C terminus of the “Met-turn,” which forms a hydrophobic basis for the catalytic zinc atom in the metzincin family. We conclude that human stromelysin-3 has gained specific functional properties during evolution by amino acid substitution in the catalytic zinc environment, and that it represents an attractive target for specific inhibitors that may be used to prevent cancer progression. [less ▲]

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See detailStromelysin-3 - a paradigm of extracellular proteinase expressed in stromal cells of human carcinomas.
Basset, P.; Rouyer, N.; Wolf, C. et al

in Cell Biology International (1995), 19(3), 242-242

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See detailHeterotransplantation of Primary and Established Human Tumour Cells in Nude Mice
Noël, Agnès ULg; Borcy, V.; Bracke, M. et al

in Anticancer Research (1995), 15(1, Jan-Feb), 1-7

Previous successful transplantations of human tumour cells into athymic nude mice have been described when cells were injected with a reconstituted basement membrane (matrigel). We have compared the ... [more ▼]

Previous successful transplantations of human tumour cells into athymic nude mice have been described when cells were injected with a reconstituted basement membrane (matrigel). We have compared the development and the histology of tumours following injection with matrigel or with culture medium of a panel of tumour cells exhibiting different degrees of tumorigenicity. Two cell lines (MCF7 and MCF7/6) required matrigel in order to form tumours. When inoculated with matrigel, all the other cell lines tested [MCF7 gpt, MCF7ras, MCF7(AZ), MCF7(AZ)TD5, MDA-MB 231, HT1080] showed increased tumour take and reduced latency period. Human primary tumours (melanoma, breast and colon cancers) were transplanted successfully into nude mice, in the presence of matrigel. Breast primary tumours or cell lines gave rise to poorly differentiated carcinomas. The other tumours presented histopathological patterns typical of differentiated human cancers. [less ▲]

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See detailModulation of the Expression of Interstitial and Type-Iv Collagenases in Coculture of Ht1080 Fibrosarcoma Cells and Fibroblasts
Munaut, Carine ULg; Noël, Agnès ULg; Weidle, U. H. et al

in Invasion & Metastasis (1995), 15(5-6), 169-78

Members of the metalloproteinase family (MMPs) are known to play a crucial role in the metastatic cascade. Here, we report some investigations about the synthesis of interstitial and type-IV collagenases ... [more ▼]

Members of the metalloproteinase family (MMPs) are known to play a crucial role in the metastatic cascade. Here, we report some investigations about the synthesis of interstitial and type-IV collagenases (gelatinases A and B) in a model of coculture of human fibroblasts and HT 1080 fibrosarcoma cells. The interstitial collagenase activity, mainly found in the conditioned medium of fibroblasts, and its mRNA level were increased in the in vitro coculture model. In contrast, gelatinase A was produced by both cell types. The HT 1080 cells additionally synthesised gelatinase B. In coculture, an enhancement of gelatinase A and the presence of its activated form were observed. Northern blot analysis demonstrated that this enzymatic enhancement occurred at a pretranslational level. The stimulation of the interstitial collagenase activity was partially mediated through soluble factor(s), whereas increased gelatinase A appeared to require direct cell-cell interactions. The extracellular matrix component, type-I collagen, stimulated the enzymatic activities released by the individual cells, but it did not modulate the synthesis of interstitial collagenase in coculture. Our results demonstrate that distinct MMPs are modulated by distinct mechanisms, all depending on specific interactions between tumour cells and host fibroblasts. [less ▲]

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