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Biomedical subjects

A Noel

Publications and source records attributed to A Noel.

At least 19 recordsLinked to original sources
PubMed2003

Membrane type-1 matrix metalloproteinase and TIMP-2 in tumor angiogenesis.

The matrix metalloproteinases (MMPs) constitute a multigene family of over 23 secreted and cell-surface associated enzymes that cleave or degrade various pericellular substrates. In addition to virtually all extracellular matrix (ECM) compounds, their targets include other proteinases, chemotactic molecules, latent growth factors, growth factor-binding proteins and cell surface molecules. The MMP activity is controlled by the physiological tissue inhibitors of MMPs (TIMPs). There is much evidence that MMPs and their inhibitors play a key role during extracellular remodeling in physiological situations and in cancer progression. They have other functions that promoting tumor invasion. Indeed, they regulate early stages of tumor progression such as tumor growth and angiogenesis. Membrane type MMPs (MT-MMPs) constitute a new subset of cell surface-associated MMPs. The present review will focus on MT1-MMP which plays a major role at least, in the ECM remodeling, directly by degrading several of its components, and indirectly by activating pro-MMP2. As our knowledge on the field of MT1-MMP biology has grown, the unforeseen complexities of this enzyme and its interaction with its inhibitor TIMP-2 have emerged, often revealing unexpected mechanisms of action.

Animals↗
PubMed2002

MT1-MMP expression promotes tumor growth and angiogenesis through an up-regulation of vascular endothelial growth factor expression.

Membrane type 1 metalloprotease (MT1-MMP) is a transmembrane metalloprotease that plays a major role in the extracellular matrix remodeling, directly by degrading several of its components and indirectly by activating pro-MMP2. We investigated the effects of MT1-MMP overexpression on in vitro and in vivo properties of human breast adenocarcinoma MCF7 cells, which do not express MT1-MMP or MMP-2. MT1-MMP and MMP-2 cDNAs were either transfected alone or cotransfected. All clones overexpressing MT1-MMP 1) were able to activate endogenous or exogenous pro-MMP-2, 2) displayed an enhanced in vitro invasiveness through matrigel-coated filters independent of MMP-2 transfection, 3) induced the rapid development of highly vascularized tumors when injected subcutaneously in nude mice, and 4) promoted blood vessels sprouting in the rat aortic ring assay. These effects were observed in all clones overexpressing MT1-MMP regardless of MMP-2 expression levels, suggesting that the production of MMP-2 by tumor cells themselves does not play a critical role in these events. The angiogenic phenotype of MT1-MMP-producing cells was associated with an up-regulation of VEGF expression. These results emphasize the importance of MT1-MMP during tumor angiogenesis and open new opportunities for the development of anti-angiogenic strategies combining inhibitors of MT1-MMP and VEGF antagonists.

Animals↗
PubMed2001

Synergism between vascular endothelial growth factor and placental growth factor contributes to angiogenesis and plasma extravasation in pathological conditions.

Vascular endothelial growth factor (VEGF) stimulates angiogenesis by activating VEGF receptor-2 (VEGFR-2). The role of its homolog, placental growth factor (PlGF), remains unknown. Both VEGF and PlGF bind to VEGF receptor-1 (VEGFR-1), but it is unknown whether VEGFR-1, which exists as a soluble or a membrane-bound type, is an inert decoy or a signaling receptor for PlGF during angiogenesis. Here, we report that embryonic angiogenesis in mice was not affected by deficiency of PlGF (Pgf-/-). VEGF-B, another ligand of VEGFR-1, did not rescue development in Pgf-/- mice. However, loss of PlGF impaired angiogenesis, plasma extravasation and collateral growth during ischemia, inflammation, wound healing and cancer. Transplantation of wild-type bone marrow rescued the impaired angiogenesis and collateral growth in Pgf-/- mice, indicating that PlGF might have contributed to vessel growth in the adult by mobilizing bone-marrow-derived cells. The synergism between PlGF and VEGF was specific, as PlGF deficiency impaired the response to VEGF, but not to bFGF or histamine. VEGFR-1 was activated by PlGF, given that anti-VEGFR-1 antibodies and a Src-kinase inhibitor blocked the endothelial response to PlGF or VEGF/PlGF. By upregulating PlGF and the signaling subtype of VEGFR-1, endothelial cells amplify their responsiveness to VEGF during the 'angiogenic switch' in many pathological disorders.

Animals↗
PubMed2001

Down-Regulation of MT1-MMP expression by the alpha3 chain of type IV collagen inhibits bronchial tumor cell line invasion.

The basement membrane (BM) is the first barrier encountered by tumor cells when they become invasive. Moreover, some invasive tumor clusters are surrounded by a remnant or neosynthetized BM material. We have previously reported the presence of a particular alpha chain of type IV collagen, the alpha3(IV) chain, in bronchopulmonary carcinomas. This chain was not detected in the normal bronchial epithelium, but was found around some invasive tumor cluster BM. In the present study, we examined the effects of the alpha3(IV) chain on the invasive properties of bronchial tumor cell lines, with special emphasis on their expression of matrix metalloproteinase-2 (MMP-2) and its activator, membrane type 1-matrix metalloproteinase (MT1-MMP), which is largely involved in tumor progression. Two epithelial bronchial cell lines (16HBE14o- and BZR), showing different invasive abilities, were evaluated. Using the Boyden chamber invasion assay, we demonstrated that the alpha3(IV) chain inhibits the invasive properties of BZR cells and modifies their morphology by inducing an epithelial cell shape. In the presence of the recombinant NC1 domain of the alpha3(IV) chain, the expression of MMP-2 and tissue inhibitor of metalloproteinase-2 (TIMP-2) was not modified in either cell line. The NC1 alpha3(IV) domain did not modulate the MT1-MMP expression of noninvasive 16HBE14o- cells, whereas a 50% decrease of MT1-MMP mRNA was observed in invasive BZR cells. Accordingly, Western blot analyses showed a disappearance of the 45-kd MT1-MMP form when BZR cells were treated with the recombinant NC1 alpha3(IV) domain. These findings suggest that the alpha3 chain of type IV collagen may play a role in tumor invasion, at least by decreasing the expression and synthesis of MT1-MMP.

Bronchi↗
PubMed2001

New functions of stromal proteases and their inhibitors in tumor progression.

Acquisition of invasive metastatic potential through protease expression is a key event in tumor progression. In carcinomas, the production of metalloproteinases and serine proteinases is regulated by a cross talk between stromal cells and cancer cells. Paradoxically, high rather than low levels of their inhibitors predict poor survival of patients suffering from a variety of cancers. Recent observations suggest a much more complex role of these inhibitors in tumor progression than expected initially.

Disease Progression↗
PubMed2000

In vivo gene transfer of endothelial nitric oxide synthase to carotid arteries from hypercholesterolemic rabbits enhances endothelium-dependent relaxations.

BACKGROUND AND PURPOSE: Hypercholesterolemia is associated with abnormal endothelium-dependent vasorelaxation due to decreased nitric oxide bioavailability. Our aim was to examine the effect of adenovirus-mediated gene transfer of endothelial nitric oxide synthase (eNOS) to the hypercholesterolemic rabbit carotid artery in vivo. In addition, we examined whether adenovirus-mediated gene transfer was associated with vascular dysfunction. METHODS: Rabbits were fed a 1% cholesterol diet for 4 weeks followed by a 0.5% cholesterol diet for 6 weeks. Vascular reactivity was assessed in nontransduced carotid arteries from chow- and cholesterol-fed animals. In addition, carotid arteries were surgically isolated, and 2 separate doses of adenoviral vectors encoding eNOS or beta-galactosidase (AdbetaGal) on the contralateral side were delivered to the lumen (1x10(10) and 5x10(10) pfu/mL). RESULTS: Abnormal acetylcholine-mediated endothelium-dependent vasorelaxation was detected in the carotid artery from cholesterol-fed animals, whereas responses to calcium ionophore A23187 and diethylamine NONOate were normal. Vascular reactivity was similar in nontransduced and AdbetaGal-transduced hypercholesterolemic vessels. In vessels transduced with eNOS, transgene expression was demonstrated by immunostaining in both the endothelium and the adventitia and by Western blot analysis. High-dose but not low-dose eNOS gene transfer enhanced endothelium-dependent relaxation in vessels from cholesterol-fed rabbits. CONCLUSIONS: Adenovirus-mediated gene transfer of eNOS to carotid arteries of cholesterol-fed animals improves endothelium-dependent relaxation when an optimal viral titer is administered.

Animals↗
PubMed1999

Cyclooxygenase dependent release of heme from microsomal hemeproteins correlates with induction of heme oxygenase 1 transcription in human fibroblasts.

Induction of heme oxygenase 1 transcription and enzymatic activity is a common response after exposure of cells to various forms of oxidative stress including ultraviolet A radiation (UVA) and hydrogen peroxide. We now show that UVA irradiation or hydrogen peroxide treatment of human skin fibroblasts leads to an immediate release of the heme oxygenase substrate, heme, from microsomal hemeproteins. The release of heme by UVA apparently involves cyclooxygenase activity because it is inhibited by the cyclooxygenase inhibitor indomethacin. We also demonstrate a high degree of correlation between the amount of heme released and the degree of subsequent induction of heme oxygenase 1 transcription following UVA and hydrogen peroxide treatment. We propose that release of heme from microsomal hemeproteins determines the degree of induction of heme oxygenase 1 transcription in human fibroblasts after oxidative stress.

Butylated Hydroxytoluene↗
PubMed1999

[Tumor-host interactions in the progression of breast cancer].

Breast carcinomas are composed of different compartments: tumor epithelial cells and host cells such as fibroblasts. Cancer progression and metastasis formation depend on complex interactions occurring between these two cell types. In response to the presence of tumour cells, fibroblasts secrete proteases able to degrade the extracellular matrix and to promote tumor invasion. These proteases are potential targets for anti-cancer agents.

Breast Neoplasms↗
PubMed1997

Involvement of PA/plasmin system in the processing of pro-MMP-9 and in the second step of pro-MMP-2 activation.

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.

Enzyme Activation↗
PubMed1997

Loss of type IV collagen alpha 5 and alpha 6 chains in human invasive prostate carcinomas.

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.

Adenocarcinoma↗
PubMed1996

Characterization of structural determinants and molecular mechanisms involved in pro-stromelysin-3 activation by 4-aminophenylmercuric acetate and furin-type convertases.

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.

Amino Acid Sequence↗
PubMed1995

Characterization of monoclonal antibodies against stromelysin-3 and their use to evaluate stromelysin-3 levels in breast carcinoma by semi-quantitative immunohistochemistry.

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.

Animals↗
PubMed1995

Detection of errors in individual patients in radiotherapy by systematic in vivo dosimetry.

We report 5 years of systematic measurements of the dose delivered to each patient undergoing radiotherapy treatment with photon beams in order to detect any systematic error that may have escaped the different checks performed at each step of planning and calculation prior to the first treatment session, or may have arisen during the set-up or the treatment delivery. For each patient the target-absorbed dose is derived from the entrance and exit doses measured by silicon diodes, on the beam axis at the patient's skin. Depending on the discrepancies observed between the measured and expected doses we have set decision levels for the corrective actions to be taken. In addition these measurements allow us to obtain information on the overall accuracy or on the quality of a specific treatment. During 5 years, 7519 patients have been measured and 79 errors were detected. Half could have induced a variation of over 10% in the dose delivered. Seventy-eight out of 79 errors were of human origin. As part of an overall quality assurance programme, it is of the utmost importance to check the dose delivered for each patient undergoing radiotherapy treatment in order to avoid systematic underdosing or overdosing.

Absorption↗
PubMed1994

[Breast cancer invasion: the key role of normal cells of host tissues].

Tumor progression is influenced by extracellular matrices and by soluble factors or cytokines locally produced by host tissue cells (fibroblasts, immune cells ...). Such factors may also accumulate in close association with some extracellular matrix molecules in the tumor. They may also be unmasked during breaking down of extracellular matrices. The most insidious aspect of tumors is their propensity to locally invade normal tissues of the host and to form secondary foci in organs at distant sites from the primary tumor called metastases. During this process, invasive cells come into contact with host tissue cells such as fibroblasts, endothelial cells, macrophages, lymphocytes. These cells are not the passive witnesses of the metastatic cascade but actively participate to the malignant invasion. Through soluble messages (cytokines) and through insoluble molecules of the extracellular matrix, neoplastic and normal cells mutually modulate their activities. Cancer cells regulate the biosynthetic activities of fibroblasts and alter in this way the scaffold of the tumor. Reciprocally, host cells secrete extracellular matrix proteins and cytokines which influence the growth and activities of tumor cells. They also produce at the periphery of tumor cells proteolytic enzymes which promote host tissue destruction and cancerous cells migration. Among these enzymes, matrix metalloproteinases appear to play a key role during invasion and metastasis. Tumors represent thus a complex ecosystem. Tumor cells interact with several components of the extracellular matrix and with host cells (immune cells, fibroblasts, endothelial cells). Such multiple cell-cell and cell-matrix interactions condition angiogenesis, tumor growth, destruction of host tissues, local migration of cancer cells and their metastatic dissemination. It is probable that a precise knowledge of the genes which are selectively activated in tumors under the influence of the host cells or of the tumor cells will allow to define new therapeutic strategies. These treatments will aim not at destroying the metastatic neoplastic cells but at preventing their growth by interfering with their microenvironment.

Animals↗
PubMed1992

Basement membrane components (matrigel) promote the tumorigenicity of human breast adenocarcinoma MCF7 cells and provide an in vivo model to assess the responsiveness of cells to estrogen.

The ability to transplant human tumors into athymic nude mice allows studies of tumor cells in vivo. However, after s.c. injection the incidence of tumor and metastases in nude mice is frequently low. We have studied the tumorigenicity in nude mice of estradiol (E2)-sensitive breast adenocarcinoma MCF7 cells. Matrigel, an extract of basement membrane proteins, induces rapid tumor development after s.c. injection of MCF7 cells. In the absence of this matrice, MCF7 cells failed to induce tumor growth. In this in vivo model, MCF7 cells were analysed for their E2 sensitivity. Two weeks after inoculation in the presence of matrigel, cells formed growing tumors in intact mice supplemented with E2. In ovariectomized or untreated mice, tumor appearance was delayed and the growth level was very low. Thus, MCF7 cells formed tumors in the absence of E2 but retained in vivo their responsiveness to estrogen. Growing human tumors in nude mice provides a rapid and useful model for testing the sensitivity of cells to hormone.

Adenocarcinoma↗
PubMed1992

Modulation of collagen and fibronectin synthesis in fibroblasts by normal and malignant cells.

The influence of various normal and malignant human cells on the level of collagen synthesis by human fibroblasts was tested in coculture. As revealed by immunoperoxidase staining, in cocultures with breast adenocarcinoma cells (MCF7, SA52, T47D) fibroblasts synthesized collagen while tumor cells did not. Fibroblasts displayed increased collagen production without change in the overall protein synthesis. Several other types of cells derived from normal human tissues (keratinocytes, normal mammary cells) or from fibrosarcoma, melanoma, cervical carcinoma, choriocarcinoma, or other breast adenocarcinoma (SW613, MDA, BT20) did not affect collagen synthesis of fibroblasts. Although to a lesser extent, this stimulating effect was reproduced by using the conditioned medium (CM) of the active cells but not with CM of the other cell types. A slight stimulation was also obtained when tumoral MCF7 cells and fibroblasts shared the same medium but were physically separated, suggesting that close contact was required for optimal stimulation of collagen synthesis. The collagen synthesis stimulating activity was not related to a modification of fibroblast proliferation rate. The production of collagen types I, III, and VI and fibronectin were increased in cocultures of fibroblasts with MCF7 cells. The increased synthesis of collagen types I and III and fibronectin was paralleled by similar changes in the steady-state level of their mRNAs. On the contrary, the increased production of collagen type VI appeared regulated at a post-transcriptional level.

Adenocarcinoma↗