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PubMed1995

Extracellular matrix interactions. 1: Production of extracellular matrix with attachment and growth-sustaining functions by UWOV2 ovarian cancer cells growing in protein-free conditions.

Constitutive production of extracellular matrix with attachment and growth-promoting effects by an ovarian cancer cell line (UWOV2 (Pf)) growing in entirely protein-free conditions is described. This extracellular matrix has an ordered fibrillar, network structure consisting mainly of type IV collagen and laminin, as well as containing hyaluronan, glycoproteins, and proteoglycans. Type IV collagen appears to provide mainly structural support while other matrix components are responsible for the attachment and growth-promoting effects. This culture system provides an ideal model for studying the effects of extracellular matrix on cell attachment and growth. This system is also important in studying the concept of autonomous growth because the production of extracellular matrix by these cells appears to be growth regulatory even in an entirely protein-free culture system.

Cell Adhesion↗
PubMed2005

Regulation of pituitary hormones and cell proliferation by components of the extracellular matrix.

The extracellular matrix is a three-dimensional network of proteins, glycosaminoglycans and other macromolecules. It has a structural support function as well as a role in cell adhesion, migration, proliferation, differentiation, and survival. The extracellular matrix conveys signals through membrane receptors called integrins and plays an important role in pituitary physiology and tumorigenesis. There is a differential expression of extracellular matrix components and integrins during the pituitary development in the embryo and during tumorigenesis in the adult. Different extracellular matrix components regulate adrenocorticotropin at the level of the proopiomelanocortin gene transcription. The extracellular matrix also controls the proliferation of adrenocorticotropin-secreting tumor cells. On the other hand, laminin regulates the production of prolactin. Laminin has a dynamic pattern of expression during prolactinoma development with lower levels in the early pituitary hyperplasia and a strong reduction in fully grown prolactinomas. Therefore, the expression of extracellular matrix components plays a role in pituitary tumorigenesis. On the other hand, the remodeling of the extracellular matrix affects pituitary cell proliferation. Matrix metalloproteinase activity is very high in all types of human pituitary adenomas. Matrix metalloproteinase secreted by pituitary cells can release growth factors from the extracellular matrix that, in turn, control pituitary cell proliferation and hormone secretion. In summary, the differential expression of extracellular matrix components, integrins and matrix metalloproteinase contributes to the control of pituitary hormone production and cell proliferation during tumorigenesis.

Adenoma↗
PubMed2006

New insights into extracellular matrix assembly and reorganization from dynamic imaging of extracellular matrix proteins in living osteoblasts.

The extracellular matrix (ECM) has been traditionally viewed as a static scaffold that supports cells and tissues. However, recent dynamic imaging studies suggest that ECM components are highly elastic and undergo continual movement and deformation. Latent transforming growth factor beta (TGFbeta) binding protein-1 (LTBP1) is an ECM glycoprotein that binds latent TGFbeta and regulates its availability and activity. LTBP1 initially co-distributes with fibronectin in the extracellular matrix of osteoblasts, and depends on fibronectin for its assembly. To gain further insights into the mechanisms of assembly of LTBP1 and its spatial and temporal interactions with fibronectin, we have performed dual fluorescence time-lapse imaging of these two proteins in living osteoblasts using fluorescent probes. Time-lapse movies showed surprisingly large fibril displacements associated with cellular movement as well as occasional breaking of LTBP1 or fibronectin-containing fibrils. Individual fibrils stretched to as much as 3.5 times or contracted to as much as one fourth of their original length. Motile cells appeared to actively mediate extracellular matrix assembly by adding 'globules' or 'packets' of matrix material onto existing fibrils. They also actively reorganized the extracellular matrix by shunting matrix material from one location to another and exchanging fibrillar material between fibrils. This cell-mediated matrix reorganization was primarily associated with the assembly and remodeling of the initial (early) matrix, whereas mature, established ECM was more stable. Displacement vector mapping showed that different matrix fibrillar networks within the same cultures can show different dynamic motion in response to cell movement and showed that the motion of fibrils was correlated with cell motion. These data suggest novel cell-mediated mechanisms for assembly and reorganization of the extracellular matrix and highlight a role for cell motility in the assembly process.

Animals↗
PubMed1998

Structure and biological activity of the extracellular matrix.

The extracellular matrix is formed by complex and intricate networks within which molecules are precisely organized. These molecular networks determine the specific histoarchitecture of tissues and provide cells with information and a scaffold. Most of the structural extracellular matrix molecules - collagens, noncollagenous glycoproteins, and proteoglycans - are chimeric and share common domains. Studies of the interactions between extracellular matrix molecules and mapping of the interaction sites to defined structural modules have led to the concept that the function of the extracellular matrix relies largely in the polymers that they form. Furthermore, determination of the tertiary structure of protein motifs involved either in the assembly of the various molecules into polymers or in cell-extracellular matrix interactions has recently opened the field of structural biology of the extracellular matrix.

Animals↗
PubMed2000

Gelatinase A, membrane type 1 matrix metalloproteinase, and extracellular matrix metalloproteinase inducer mRNA expression: correlation with invasive growth of breast cancer.

Invasive breast cancer varies widely in biologic aggressiveness, from fairly indolent tumors to rapidly disseminating carcinomas. Matrix metalloproteinases have enzymatic activity and assist in tumor invasion by degrading basement membranes and extracellular matrix. The extracellular matrix metalloproteinase inducer EMMPRIN is thought to stimulate fibroblasts to produce the zymogen pro-gelatinase A. The membrane type 1-matrix metalloproteinase (MT1-MMP) is thought to assist in tumor invasion and metastasis by activating pro-gelatinase A, which shows enhanced expression in various tumors. Overexpression of gelatinase A has shown to correlate with a malignant phenotype in many tumor forms. The aim of the study was to investigate the mRNA expression pattern of MT1-MMP, gelatinase A, and EMMPRIN in breast tumors. Formalin-fixed paraffin-embedded breast tissue samples from 18 patients operated on with breast-conserving surgery for invasive breast carcinoma <20 mm between 1977 and 1985 were analyzed using the mRNA in situ hybridization technique. Most of the patients were node-negative (15/18) and underwent postoperative irradiation to the breast (16/18). The median age at diagnosis was 52 years (21-83 years). At the time of the study 11 patients were alive, 4 without recurrence; 7 patients had been operated for ipsilateral breast tumor recurrences, and 2 had distant metastases. The median follow-up was 112 months (102-193 months). Seven patients died of disseminated breast cancer; their median follow-up was 43 months (22-116 months). (35)S-labeled antisense and sense mRNA probes transcribed from linearized plasmids containing cDNA for the matrix metalloproteinases gelatinase A and MT1-MMP and the glycoprotein EMMPRIN were hybridized to 5 microm paraffin-embedded tissue sections. Several invasive carcinomas were surrounded by normal tissue and carcinoma in situ lesions. Gelatinase A, MT1-MMP, and EMMPRIN mRNA expression were detected in all of the carcinomas. The gelatinase A mRNA expression was mainly localized to stromal cells at moderate to high levels surrounding the invading carcinoma cells but was also seen in single cells at low levels in in situ lesions and in some normal glandular cells. MT1-MMP and EMMPRIN were expressed in all of the carcinomas and were mainly localized to tumor cells; but they were also seen to some extent in single cells at low levels in in situ lesions and in normal glandular cells. No differences in levels of expression for gelatinase A, MT1-MMP, or EMMPRIN were seen in patients who survived compared to patients who died from metastatic disease. The co-expression of gelatinase A, MT1-MMP, and EMMPRIN mRNA in invasive breast carcinoma supports the theory that these proteins interact and are important for the invasive phenotype in breast carcinoma. Hence EMMPRIN may be a central factor for stimulation of gelatinase A activation. Specific inhibition for individual MMP members could in the future be target-specific events in breast tumor progression. Inhibition of EMMPRIN could be such a target.

Adenocarcinoma↗
PubMed1997

Proteinases and myocardial extracellular matrix turnover.

Extracellular structural remodeling is the compensatory response of the tissue following pathological stage. Myocardial infarction, which leads to adverse remodeling, thinning of the ventricle wall, dilatation and heart failure, is one of the leading causes of death. Remodeling implies an alteration in the extracellular matrix and in the spatial orientation of cells and intracellular components. The extracellular matrix is responsible for cardiac cell alignment and myocardial structural integrity. Substances that break down the extracellular matrix, specialized proteinases as well as inhibitors of proteinases, appear to be normally balanced in maintaining the integrity of the myocardium. Myocardial infarction leads to an imbalance in proteinase/antiproteinase activities causing alterations in the stability and integrity of the extracellular matrix and adverse tissue remodeling. To explore mechanisms involved in this process and, in particular, to focus on matrix metalloproteinases, their inhibitors, and activators, an understanding of proteinase and antiproteinase is needed. This review represents new and significant information regarding the role of activated matrix proteinases antiproteinases in remodeling. Such information will have a significant impact both on the understanding of the basic cell biology of extracellular matrix turnover, as well as on potential avenues for pharmacological approaches to the treatment of ischemic heart disease and failure.

Amino Acid Sequence↗
PubMed2006

The role of matrix extracellular proteins and metalloproteinases in head and neck carcinomas: an updated review.

Interactions involving tumor cells and the extracellular matrix (ECM) strongly influence tumor development, including head and neck tumors, affecting cell proliferation and survival as well as the ability to migrate beyond the original location into other tissues to form metastases. These cell migration is often facilitated by partial destruction of the surrounding ECM, which is catalyzed by matrix metalloproteinases (MMPs), a family of more than 20 endopeptidases that is controlled by regulated expression of specific inhibitors (TIMPs). Several studies of ECM and MMPs markers have provided additional diagnostic and prognostic information in head and neck carcinomas. In this review, we are considering the role of ECM and MMPs in tumor progression, emphasizing its proteolytic contributors to this process, and interactions between several members of ECM providing substrate to regulation of this process.

Carcinoma, Squamous Cell↗
PubMed1993

Extracellular matrix. 3: Evolution of the extracellular matrix in invertebrates.

Invertebrates comprise about 95% of animal species, yet most studies of extracellular matrices have centered on vertebrates. Comparative studies of invertebrates will enhance comprehension of evolutionary processes and appreciation of the diversity of extracellular matrices. Moreover, new functions and new structures will be revealed over a wide range of organismic needs. Another important perspective is that several invertebrate species have provided insight into developmental processes, and those processes often have direct relevance to vertebrate development. Thus, studies of fruit flies, nematodes, and sea urchins have revealed common features of cell biology, embryonic development, and matrix properties that pertain throughout the animal kingdom. The advantages of invertebrates are their rapid rates of embryonic development, their amenability to genetic manipulation, availability of innumerable mutants, and their ease of study in the laboratory. Extracellular matrices themselves are readily compared. Invertebrates display a wide diversity of such matrices, at the levels of both tissue architecture and molecular anatomy. Knowledge of that diversity leads to an appreciation of evolutionary variety and eventually to comprehension of the organization of extracellular matrices and of the properties of their constituent macromolecules. The expanding knowledge of unique matrix molecules from invertebrates also has economic potential and is beginning to provide new materials for biotechnology.

Animals↗
PubMed1993

Alternate exon usage is a commonly used mechanism for increasing coding diversity within genes coding for extracellular matrix proteins.

Extracellular matrix proteins are a diverse family of secreted proteins and glycoproteins that are responsible for a variety of critical functions in different tissues. A large number of multiexon genes encode these proteins of the extracellular matrix. Over the last few years, it has become evident that the processing of the pre-mRNA from several of these genes involves alternative splicing. This review summarizes the known examples of alternative splicing in genes coding for the extracellular matrix and attempts to relate the increase in coding diversity generated by alternate exon usage to the function(s) of individual extracellular matrix proteins.

Alternative Splicing↗
PubMed1996

The effect of chronically elevated intraocular pressure on the rat optic nerve head extracellular matrix.

The extracellular matrix of the optic nerve head is altered in both human glaucoma and in experimental primate models of this disease. However, the relationship of this change to glaucomatous optic nerve degeneration is unknown. This report describes similar matrix alterations in rats with unilateral elevated intraocular pressure. Brown Norway rats received episcleral vein injections of hypertonic saline to produce prolonged elevations of intraocular pressure. After up to 6 months of pressure elevation, optic nerve head sections from the rats were evaluated by light microscopic immunohistochemistry using antibodies to collagens I, III, IV and VI, laminin, elastin and chondroitin and dermatan sulfate proteoglycans. In experimental eyes with 11 days or more of pressure elevation, depositions of collagen IV, collagen VI and laminin were found within regions of the optic nerve head that, in normal eyes, are occupied solely by nerve bundles. Collagen I and III deposition appeared to be more dependent on the level and duration of the pressure rise. Eyes with lower mean intraocular pressures showed deposits of interstitial collagens primarily at the level of the sclera, while eyes with higher mean pressure elevations had depositions in the neck regions as well. Chondroitin and dermatan sulfate proteoglycans were deposited in a pattern similar to that of collagen I. No extracellular matrix deposition was seen in the orbital optic nerve in any experimental eye. These extracellular matrix changes in rats replicate previous findings in human glaucomatous eyes and monkey eyes with experimentally elevated pressures. They also suggest a sequence of extracellular matrix protein deposition in response to pressure elevation. The optic nerve head deposition of matrix materials in response to elevated intraocular pressures may affect the susceptibility of remaining axons to pressure by changing the physical properties of their support tissues, by affecting the support functions of astrocytes and by changing the microenvironment of injured axons. This model may be useful for studying these and other aspects of the process of axonal injury resulting from elevated intraocular pressure.

Animals↗
PubMed1993

[Phylogenesis of the extracellular matrix].

The extracellular matrix constitutes a highly organized intercellular medium. In multicellular animals, it plays important functions for cell cohesion and for the modulation of cell differentiation and behaviour as well. All the investigations conducted in non-vertebrate species have shown that the extracellular matrix is present at the onset of the multicellular life and throughout the animal kingdom. The collagen fibrils are the most constant element. Recent data on the structure of fibrillar collagen molecules and on the organization of the corresponding genes, obtained in sponges and sea-urchins have shown the remarkable conservation of these fibrillar collagens during evolution. This even emphasize their very likely fundamental function. These results, associated with data provided by morphological and biochemical informations obtained in cnidarians suggest that these primitive fibrillar collagens are the direct precursors of some vertebrate minor fibrillar collagens such as type V. Other collagens, with interrupted triple helix, are more variable and their characterization in sponges leads to consider these non-fibrillar collagens as precursors of basement membrane collagens, of fibril-associated collagens (the FACITs collagens), of the so-called "epithelial" collagens. They were probably used as sticking devices, anchoring the animal to its substratum, or as covering layers (cuticles, sheaths), and even as skeletons (i.e. the bath sponge). Adhesive molecules of higher animals ensure the mediation of the interactions between cells (via their membrane receptors of the integrin type) and the fibrous network of the extracellular matrix. It is the same situation at the beginning of the evolution of the multicellular animals where fibronectin, tenascin and then laminin are present. Proteoglycans too are components of primitive extracellular matrices. At last, only collagen mineralized by calcium phosphate (in bone) and elastin (in elastic fibers and laminae) seem to be restricted to vertebrates.

Animals↗
PubMed1988

The function of multiple extracellular matrix receptors in mediating cell adhesion to extracellular matrix: preparation of monoclonal antibodies to the fibronectin receptor that specifically inhibit cell adhesion to fibronectin and react with platelet glycoproteins Ic-IIa.

We have identified monoclonal antibodies that inhibit human cell adhesion to collagen (P1H5), fibronectin (P1F8 or P1D6), and collagen and fibronectin (P1B5) that react with a family of structurally similar glycoproteins referred to as extracellular matrix receptors (ECMRs) II, VI, and I, respectively. Each member of this family contains a unique alpha subunit, recognized by the antibodies, and a common beta subunit, each of approximately 140 kD. We show here that ECMR VI is identical to the fibronectin receptor (FNR), very late antigen (VLA) 5, and platelet glycoproteins Ic-IIa and shall be referred to as FNR. Monoclonal antibodies to FNR inhibit lymphocyte, fibroblast, and platelet adhesion to fibronectin-coated surfaces. ECMRs I, II, and FNR were differentially expressed in platelets, resting or activated lymphocytes, and myeloid, epithelial, endothelial, and fibroblast cell populations, suggesting a functional role for the receptors in vascular emigration and selective tissue localization. Tissue staining of human fetal skin localized ECMRs I and II to the basal epidermis primarily, while monoclonal antibodies to the FNR stained both the dermis and epidermis. Experiments carried out to investigate the functional roles of these receptors in mediating cell adhesion to complex extracellular matrix (ECM) produced by cells in culture revealed that complete inhibition of cell adhesion to ECM required antibodies to both the FNR and ECMR II, the collagen adhesion receptor. These results show that multiple ECMRs function in combination to mediate cell adhesion to complex EMC templates and predicts that variation in ECM composition and ECMR expression may direct cell localization to specific tissue domains.

Antibodies, Monoclonal↗
PubMed1991

Modifications of the intermediate filament and nuclear matrix networks by the extracellular matrix.

The tissue matrix system is a dynamic, interacting structural network directly linking the nuclear matrix, cytoskeleton and the extracellular matrix. We report here that interaction of normal rat kidney epithelial cells (NRK) and Kirsten-ras transformed rat kidney cells, with an extracellular matrix secreted by tumor cells, causes modifications to the protein composition of the intermediate filament and nuclear matrix networks. The matrix networks are different between normal and transformed cells; however, these alterations by the tumor extracellular matrix are similar in both cell types. These data represent the first report that modification of the extracellular matrix environment can have an effect on the protein composition of the nuclear matrix.

Animals↗
PubMed1998

Growth factors in infant germinal matrix: relationship to extracellular matrix and cell adhesion molecules.

We examined the expression of selected growth factors, growth factor receptors, elements of extracellular matrix and cell adhesion molecules in the germinal matrix layer (GML) utilizing immunohistochemistry and reverse transcriptase polymerase chain reaction. At autopsy brain samples from 10 neonatal infants were used. Epidermal growth factor receptor (EGFR) was significantly expressed in the matrix cells. While transforming growth factor alpha and heparin-binding epidermal growth factor-like growth factor were found in the matrix cells or vascular wall as ligands, epidermal growth factor was not expressed. EGFR and its ligands are thought to be important factors for the maintenance of the matrix cells and cell-to-cell interactions. Insulin like growth factor I, its receptor Ibeta and tenascin were found in the stroma of the GML and periventricular region. Vascular endothelial growth factor and receptor Flk-1, laminin A and B2, fibronectin, collagen type IV and integrins such as beta3, alpha5beta1 and alphaVbeta3 were found mainly in or around the vascular wall indicating their important roles for vascularization. Transforming growth factor beta2 and its receptor II were expressed in the matrix cells and/or vascular wall suggesting a role in proliferation and/or regression of the vasculature. CD44 and Thy-1 were also expressed in the matrix cells.

Autopsy↗
PubMed2002

[The role of matrix metalloproteinases in extracellular matrix remodelling in chronic obstructive pulmonary disease rat models].

OBJECTIVE: To study the role of metalloproteinases(MMPs) in the airway extracellular matrix (ECM) remodelling of chronic obstructive pulmonary disease (COPD) rat models. METHODS: The COPD rat models which was established by intratracheal instillation of 200 microg lipopolysaccharide once for every two weeks(twice), and exposed to 5% smoke for 0.5 h/d for 4 weeks. The pathological changes were observed, lung function and blood gas changes were also deter mined. The fibroblasts, lymphocytes of bronchial walls and alveolar macrophages were counted. The hydroxyproline of bronchial lung tissue homogenates were deter mined by biochemistry method. The expression of MMP-9,MMP-2 and tissue inhibitor of metalloproteinase-1(TIMP-1) in bronchi and lung tissue was verfied by immunohistochemical analysis and by reverse transcription-polymerase chain reaction analysis. The gelatinolytic activities of MMPs of lung tissue were performed by gelatin zymographic analysis. RESULTS: The pathological changes of bronchi and lung tissue, the changes of lung function and blood gas analysis were similar to those of the COPD patients. The number of fibroblasts, lymphocytes and alveolar macrophages of model group were significantly increased than those of control group (P < 0.001). The hydroxyproline of model group was significantly in creased than that of control group (P < 0.001). By using image analyzer, immunoreactivity of MMP-9, MMP-2,TIMP-1 were markedly increased in epithelial cells of bronchi, fibroblasts, macrophages, endothelial cells and pneumocytes in model group as compared with those of control group. The protein expressions of MMP-9, MMP-2 and TIMP-1 in model group were significantly increased than those in control group(P < 0.0001 or P < 0.01). The mRNA expression of MMP-2, MMP-9 and TIMP-1 in COPD model group (1.11 +/- 0.06,1.04 +/- 0.26 and 0.85 +/- 0.34,respectively) were significantly increased than those in control group (0.30 +/- 0.17,0.36 +/- 0.09 and 0.23 +/- 0.08,respectively) as well(P < 0.001 or P < "0.01). The relative gelatinolytic activities of 72 000 MMP-2, 92 000 MMP-9 in model group (3 263.5 +/- 665.1 and 1 338.4 +/- 241.2, respectively) were also significantly higher than those in the model group(388.6 +/- 60.8 and 116.1 +/- 49.8,respectively, P < 0.001). CONCLUSION: The findings suggested that there were up regulations of MMP-9,MMP-2 and TIMP-1 of lung tissue in COPD model group which may contribute to the pathogenesis of airflow limitation through the airway remodelling and alveolar structure destruction(emphysema). The ECM degradation and deposition were imbalanced and abnormally activated. The evaluation of MMP-9,MMP-2 which are responsible for the inflammation and destruction process, and the evaluation of TIMP-1 which is responsible for the repair and remodelling process of the airways, may play an important role in the airway ECM remodelling in COPD.

Animals↗
PubMed1993

The vascular endothelial growth factor (VEGF) isoforms: differential deposition into the subepithelial extracellular matrix and bioactivity of extracellular matrix-bound VEGF.

Vascular endothelial growth factor (VEGF)mRNA undergoes alternative splicing events that generate four different homodimeric isoforms, VEGF121, VEGF165, VEGF189, or VEGF206. VEGF121 is a nonheparin-binding acidic protein, which is freely diffusible. The longer forms, VEGF189 or VEGF206, are highly basic proteins tightly bound to extracellular heparin-containing proteoglycans. VEGF165 has intermediate properties. To determine the localization of VEGF isoforms, transfected human embryonic kidney CEN4 cells expressing VEGF165, VEGF189, or VEGF206 were stained by immunofluorescence with a specific monoclonal antibody. The staining was found in patches and streaks suggestive of extracellular matrix (ECM). VEGF165 was observed largely in Golgi apparatus-like structures. Immunogold labeling of cells expressing VEGF189 or VEGF206 revealed that the staining was localized to the subepithelial ECM. VEGF associated with the ECM was bioactive, because endothelial cells cultured on ECM derived from cells expressing VEGF189 or VEGF206 were markedly stimulated to proliferate. In addition, ECM-bound VEGF can be released into a soluble and bioactive form by heparin or plasmin. ECM-bound VEGF189 and VEGF206 have molecular masses consistent with the intact polypeptides. The ECM may represent an important source of VEGF and angiogenic potential.

Amino Acid Sequence↗
PubMed1996

Brain extracellular matrix.

The extracellular matrix of the adult brain tissue has a unique composition. The striking feature of this matrix is the prominence of lecticans, proteoglycans that contain a lectin domain and a hyaluronic acid-binding domain. Hyaluronic acid and tenascin family adhesive/anti-adhesive proteins are also abundant. Matrix proteins common in other tissues are nearly absent in adult brain. The brain extracellular matrix appears to have trophic effects on neuronal cells and affect neurite outgrowth. The unique composition of this matrix may be responsible for the resistance of brain tissue toward invasion by tumors of non-neuronal origin.

Adult↗