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PubMed1990

Patterning of the membrane cytoskeleton by the extracellular matrix.

The extracellular matrices of different tissues contain components which affect the migration, morphology and differentiation of many types of cells. These forms of cell behavior often involve dramatic changes in cytoskeletal organization. Extracellular matrix components are recognized by specific cell surface receptors which span the membrane and interact with the actin cytoskeleton. In cultured cells, the matrix receptors are concentrated in sites of cell attachment called focal adhesions. Information that is conveyed from the extracellular matrix to the cytoskeleton may involve matrix components, cell surface receptors, as well as the proteins at the cytoplasmic face of the focal adhesion which link the receptors to the actin cytoskeleton.

Actins↗
PubMed1985

Morphogenesis in wing imaginal discs: its relationship to changes in the extracellular matrix.

An extracellular matrix (ECM) lies between the upper and lower epithelial layers of the wing imaginal discs of moths. Organization and composition of this extracellular matrix, as revealed by staining with ruthenium red, tannic acid, and alcian blue, changes in concert with levels of hormones in the haemolymph. The ECM of the wing imaginal disc is an environment for cellular movements. Reorganization of the matrix and increase in ecdysteroid level is coupled with the proximal----distal migration of tracheal cells as well as the distal----proximal outgrowth of sensory neurons.

Animals↗
PubMed1998

Leucine-rich repeat glycoproteins of the extracellular matrix.

The extracellular matrix plays an integral role in the pivotal processes of development, tissue repair, and metastasis by regulating cell proliferation, differentiation, adhesion, and migration. This review is focused on a family of related glycoproteins represented by at least one member in all specialized extracellular matrices. This family currently comprises nine members grouped together on the basis of their presence in the extracellular matrix and by virtue of a leucine-rich repeat motif that dominates the structure of the core protein. It is likely that most, if not all the members of this group exist as proteoglycans in some tissues, and thus have been termed the Small Leucine-Rich Proteoglycan family, or SLRPs. The leucine-rich repeat (LRR) is usually present in tandem array and has been described in an increasing number of proteins, giving rise to a LRR-superfamily. The LRR domain of the SLRP family is unique within the superfamily in that it is flanked by cysteine clusters, and the 24 amino acid consensus for SLRP members is x-x-I/V/L-x-x-x-x-F/P/L-x-x-L/P-x-x-L-x-x-L/I-x-L-x-x-N-x-I/L, where x is any amino acid. Enormous progress has been made in describing the membership, structure and localization of this family, and recently new insight has emerged into the putative function of these molecules not just as modulators of matrix assembly but also on their intriguing role in regulating cell growth, adhesion, and migration. Determination of membership, structure and putative function of this fascinating class of molecules is summarized in this review.

Amino Acid Sequence↗
PubMed1995

In vitro regulation of human breast cancer cell adhesion and invasion via integrin receptors to the extracellular matrix.

The extracellular matrix consists of the interstitium and the basement membrane. Cellular interaction with fibronectin, laminin and collagen provides a possible mechanism by which cancer cells adhere, invade and metastasize. The integrins are a major family of adhesion molecules that recognize epitopes on the extracellular matrix as ligands. These include the alpha 2 beta 1, alpha 3 beta 1, alpha v beta 1 and alpha v beta 5 integrins, most of which were found to be expressed on MCF-7, T47D, MDA-MB-231, ZR75-1 and Hs578T breast cancer cell lines. Each cell line adhered to the matrix proteins in a dose-dependent manner and was inhibited by monoclonal antibodies against relevant integrins. Only Hs578T was significantly invasive through fibronectin but both Hs578T and MDA-MB-231 invaded through laminin and type IV collagen in an in vitro assay. The invasive potential of these cell lines could be inhibited by integrin antibodies added to cells before incubation, but the addition of antibodies after cells were allowed to adhere to the matrix failed to inhibit invasion. Inhibition of cellular adhesion to the matrix reduced the invasive potential of breast cancer cell lines. As integrin antibodies inhibit cell invasion in vitro, the integrins may be of potential value as antitumour therapeutic agents.

Antibodies, Monoclonal↗
PubMed1998

Alpha3beta1-integrin as a critical mediator of the hepatic differentiation response to the extracellular matrix.

The extracellular matrix (ECM) promotes the differentiation of many cell types, and ECM remodeling in the liver has been implicated in embryonic development, tissue injury, and oncogenesis. Integrins are heterodimeric ECM receptors that play critical roles in transducing the composition of the ECM in the cell environment. We previously showed that mouse H2.35 cells, a conditionally transformed, liver-derived cell line, assume a more differentiated hepatocyte morphology and enhanced liver-specific gene expression when the cells are cultured on gelatinous ECM substrata. Here we show that H2. 35 cells express relatively high levels of alpha3beta1-integrins, similar to that previously shown for immature hepatocytes, transformed hepatocytes, and biliary cells. However, the cell morphological responses that depend on alpha3beta1-integrin have not been defined. We found that transfecting H2.35 cells with antisense RNA construct directed to alpha3-subunit messenger RNA perturbs the initial cell attachment to laminin and collagen, and strongly inhibits cell morphological, proliferative, and gene expression responses to a collagen gel substratum. In situ hybridization to mouse embryo tissues demonstrates the presence of alpha3-subunit messenger RNAs in newly formed hepatocytes. We suggest that alpha3beta1-integrins are important for immature and transformed hepatocytes to respond morphologically to the extracellular matrix.

Animals↗
PubMed1996

Dynamic interactions of the extracellular matrix.

The extracellular matrix (ECM) is a dynamic assemblage of interacting molecules that reorganise and regulate cell functions in response to endogenous and exogenous stimulii. Matrix components may affect cell behaviour directly or indirectly through growth factor sequestration and transmembrane signalling, by controlling the speed of various molecules through the ECM, and the access of growth factors, hormones and neurotransmitters to the cell surface.

Animals↗
PubMed2001

Vascular endothelial growth factor in porcine-derived extracellular matrix.

An extracellular matrix (ECM) derived from the submucosa of the porcine small intestine (SIS) has been shown to induce angiogenesis and host tissue remodeling when used as a xenogeneic bioscaffold in animal models of wound repair. In the present study, we compared the in vitro effects of SIS ECM extracts to several purified angiogenic growth factors on human dermal microvascular endothelial cell (HMEC) growth patterns. The SIS ECM was shown to induce tube formation from HMEC in a three-dimensional fibrin-based angiogenesis assay in a manner similar to that caused by the addition of vascular endothelial growth factor (VEGF). This tube formation was blocked in the presence of anti-VEGF neutralizing antibody. Western blots and ELISA procedures showed that the SIS ECM contains as much as 0.77 ng VEGF/g SIS. The closely related endothelial cell mitogen, platelet-derived growth factor (PDGF), was not detectable in the SIS extracts. We conclude that VEGF is present in the SIS extracellular matrix. The role of VEGF in SIS-induced wound repair remains unknown, but its presence in the ECM makes it a possible contributor to the angiogenic effect of SIS when this ECM is used as a tissue repair scaffold in animal models of wound repair.

Animals↗
PubMed1996

Isolation and characterization of Caenorhabditis elegans extracellular matrix.

The extracellular matrix (ECM) plays an important structural and functional role in multicellular organisms. Because of the similarities between C. elegans and vertebrate development, this nematode could serve as a simplified model to study the biology of the ECM. In this study, a method for extracting mammalian ECM was adapted for the extraction of C. elegans ECM. ECM components from C. elegans were found to be homologous to mammalian ECM by immunoblotting. It was also demonstrated that antibodies generated against C. elegans ECM stained basement membrane-like structures in C. elegans eggs, larvae, and adults.

Animals↗
PubMed1994

Extracellular matrix components of the mouse thymus microenvironment. IV. Modulation of thymic nurse cells by extracellular matrix ligands and receptors.

Extracellular matrix (ECM) proteins can influence cell migration and differentiation in a variety of cell systems. Within the thymus, these molecules are heterogeneously distributed, and their physiological role is poorly understood. This prompted us to carry out in vitro studies using the thymic nurse cell (TNC) model. We observed that fibronectin and laminin accelerate spontaneous in vitro release of thymocytes from TNC, whereas anti-ECM antibodies exhibited a blocking effect. Similar results were obtained with anti-ECM receptor reagents. Moreover, these antibodies abrogated in vitro reconstitution of TNC complexes and thymocyte adhesion to TNC-derived epithelial cultures. Our results indicate that lymphocyte traffic in TNC (comprising both entrance into and exit from the epithelial structure) is affected by interactions involving extracellular matrix ligands and receptors. In this respect, the dynamic analysis of thymic nurse cell complexes should be regarded as a relevant in vitro tool for functional studies of distinct adhesion molecules in intrathymic lymphocyte traffic.

Animals↗
PubMed1997

Plasminogen activator and matrix metalloproteinase production and extracellular matrix degradation by rat prostate cancer cells in vitro: correlation with metastatic behavior in vivo.

BACKGROUND: The plasminogen activation (PA) and metalloproteinase (MMP) system are involved in tumor cell migration and invasion. METHODS: The proteolytic activity of cell lines originating from the rat Dunning R-3327 prostate tumor was analyzed by measuring in vitro extracellular matrix degradation, enzyme activity, and mRNA levels of enzymes, inhibitors, and receptors, and compared with their known metastatic behavior in vivo. RESULTS: Only the highly metastatic sublines AT-3, MATLu, and MATLyLu showed a high extracellular matrix degradation mediated by urokinase-type plasminogen activator (u-PA). Relatively high levels of u-PA were present in the aggressive cell lines. u-PA receptor mRNA was produced in all cells, and all but AT-1 produced LDL-receptor-related-protein (LRP) mRNA. t-PA mRNA was only found in HIF and MATLu. In gelatin, zymography lysis was observed at 72 kD and 74-76 kD in MATLu and MATLyLu cells, respectively. MMP-2 mRNA was present in all cell lines except AT-1 and AT-2, and MMP-3 mRNA was present in AT-2, AT-3, and MATLu. CONCLUSIONS: These in vitro experiments show that in different rat prostate cancer sublines, proteolytic activity and u-PA-mediated extracellular matrix degradation correlate with their known metastatic behavior in vivo.

Analysis of Variance↗
PubMed2001

Co-localization of integrins and matrix metalloproteinases in the extracellular matrix of chondrocyte cultures.

Beta1-integrins were found in the cartilage matrix, suggesting their implication in the assembly of its architectural scaffold, but the mechanism for this event is not yet clear. Matrix metalloproteinases (MMPs) may be involved in an integrin-shedding mechanism and matrix beta1-integrins may act to alter MMP activity. To begin to address this question, this study was designed to determine whether beta1-integrins and MMPs are colocalized in the chondrocytes or in the extracellular matrix of cartilage. We investigated high-density cultures of limb buds of 12-day-old mouse embryos by double immunofluorescence, immunoelectron microscopy and by coimmunoprecipitation assays in order to examine the localization of beta1-integrins and matrix metalloproteinases (MMP-1, MMP-3 and MMP-9) in cartilage. It was found, that all investigated MMPs and beta1-integrins were specifically co-localized in high-density cartilage cultures. Immunogold and immunofluorescence labelling of both beta1-integrins and MMPs were observed not only at the surface of chondrocytes but mainly also in the pericellular space and distributed between collagen fibrils in the extracellular matrix (ECM) as well. Results of immunoprecipitation experiments suggest a functional association of MMPs and beta1-integrins in chondrocytes as already described for other cell types. Further investigations are needed to elucidate the functional association between beta1-integrins and MMPs in chondrocytes.

Animals↗
PubMed2003

Rat pancreatic stellate cells secrete matrix metalloproteinases: implications for extracellular matrix turnover.

BACKGROUND: Pancreatic fibrosis is a characteristic feature of chronic pancreatic injury and is thought to result from a change in the balance between synthesis and degradation of extracellular matrix (ECM) proteins. Recent studies suggest that activated pancreatic stellate cells (PSCs) play a central role in pancreatic fibrogenesis via increased synthesis of ECM proteins. However, the role of these cells in ECM protein degradation has not been fully elucidated. AIMS: To determine: (i) whether PSCs secrete matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) and, if so (ii) whether MMP and TIMP secretion by PSCs is altered in response to known PSC activating factors such as tumour necrosis factor alpha (TNF-alpha), transforming growth factor beta1 (TGF-beta1), interleukin 6 (IL-6), ethanol, and acetaldehyde. METHODS: Cultured rat PSCs (n=3-5 separate cell preparations) were incubated at 37 degrees C for 24 hours with serum free culture medium containing TNF-alpha (5-25 U/ml), TGF-beta1 (0.5-1 ng/ml), IL-6 (0.001-10 ng/ml), ethanol (10-50 mM), or acetaldehyde (150-200 micro M), or no additions (controls). Medium from control cells was examined for the presence of MMPs by zymography using a 10% polyacrylamide-0.1% gelatin gel. Reverse transcriptase-polymerase chain reaction (RT-PCR) was used to examine gene expression of MMP9 and the tissue inhibitors of metalloproteinases TIMP1 and TIMP2. Western blotting was used to identify a specific MMP, MMP2 (a gelatinase that digests basement membrane collagen and the dominant MMP observed on zymography) and a specific TIMP, TIMP2. Reverse zymography was used to examine functional TIMPs in PSC secretions. The effect of TNF-alpha, TGF-beta1, and IL-6 on MMP2 secretion was assessed by densitometry of western blots. The effect of ethanol and acetaldehyde on MMP2 and TIMP2 secretion was also assessed by this method. RESULTS: Zymography revealed that PSCs secrete a number of MMPs including proteinases with molecular weights consistent with MMP2, MMP9, and MMP13. RT-PCR demonstrated the presence of mRNA for metalloproteinase inhibitors TIMP1 and TIMP2 in PSCs while reverse zymography revealed the presence of functional TIMP2 in PSC secretions. MMP2 secretion by PSCs was significantly increased by TGF-beta1 and IL-6, but was not affected by TNF-alpha. Ethanol and acetaldehyde induced secretion of both MMP2 and TIMP2 by PSCs. CONCLUSIONS: Pancreatic stellate cells have the capacity to synthesise a number of matrix metalloproteinases, including MMP2, MMP9, and MMP13 and their inhibitors TIMP1 and TIMP2. MMP2 secretion by PSCs is significantly increased on exposure to the proinflammatory cytokines TGF-beta1 and IL-6. Both ethanol and its metabolite acetaldehyde increase MMP2 as well as TIMP2 secretion by PSCs. IMPLICATION: The role of pancreatic stellate cells in extracellular matrix formation and fibrogenesis may be related to their capacity to regulate the degradation as well as the synthesis of extracellular matrix proteins.

Acetaldehyde↗
PubMed2006

On the origins of the extracellular matrix in vertebrates.

Extracellular matrix (ECM) is a key metazoan characteristic. In addition to providing structure and orientation to tissues, it is involved in many cellular processes such as adhesion, migration, proliferation and differentiation. Here we provide a comprehensive analysis of ECM molecules focussing on when vertebrate specific matrices evolved. We identify 60 ECM genes and 20 associated processing enzymes in the genome of the urochordate Ciona intestinalis. A comparison with vertebrate and protostome genomes has permitted the identification of both a core set of metazoan matrix genes and vertebrate-specific innovations in the ECM. We have identified a few potential cases of de novo vertebrate ECM gene innovation, but the majority of ECM genes have resulted from duplication of pre-existing genes present in the ancestral vertebrate. In conclusion, the modern complexity we see in vertebrate ECM has come about largely by duplication and modification of pre-existing matrix molecules. Extracellular matrix genes and their processing enzymes appear to be over-represented in the vertebrate genome suggesting that these genes played an active role enabling and underpinning the evolution of vertebrates.

Animals↗
PubMed1992

Signal transduction by integrin receptors for extracellular matrix: cooperative processing of extracellular information.

Adhesion receptors allow cells to interact with a dynamic and information-rich environment of extracellular matrix molecules. The integrin family of adhesion receptors transduces signals from the extracellular matrix that regulate growth, gene expression and differentiation, as well as cell shape, motility and cytoskeletal architecture. Recent data support the hypothesis that integrins transduce signals cooperatively with other classes of adhesion receptors or with growth factor receptors. Furthermore, the ability of integrins to interact with the cytoskeleton appears to be fundamental to their mechanism for signal transduction.

Animals↗
PubMed1993

Regulation of cell function by extracellular matrix.

The extracellular matrix (ECM) provides structural support and adhesive substrates for the body tissues. Recent advances in our understanding of the biology of matrix indicate that the ECM also plays a significant role in regulating the behavior of cells. Matrix proteins engender changes in cell shape and movement, bind growth factors, and facilitate cell-cell and cell-matrix interactions. Matrix-induced differentiation results from multiple stimuli that include: tensile forces on the cell, cytokine- or growth factor-mediated stimulation, and interaction with bioactive domains of matrix glycoproteins. Because these signals are important determinants of cell behavior, pharmacological manipulation of cell-matrix interactions may offer a valuable new approach to disease treatment.

Animals↗
PubMed1991

Association between proteoglycans and matrix vesicles in the extracellular matrix of growth plate cartilage.

Matrix vesicles (MV) are microstructures localized to the extracellular matrix of developing hard tissues that induce mineral formation. MV proteins are not well characterized, and little is known of how they interact with the surrounding matrix. However, recent electron microscopic studies indicate that MV interact with matrix proteins in growth plate cartilage. In the studies now reported, procedures developed for dissecting various components from isolated MV led to the discovery that two major vesicle proteins (38 and 46 kDa) are readily released from MV by low ionic strength solutions. These low ionic strength-soluble proteins (LISSP) were shown to be major fragments of the link protein (LP) and hyaluronic acid-binding region (HABR) of matrix proteoglycans: they react immunologically with highly specific monoclonal antibodies to LP and HABR, and the NH2-terminal sequence of the 38-kDa LISSP is essentially identical to residues 40-78 of chicken cartilage LP and that the 46-kDa LISSP represents HABR. Release of both LISSP is enhanced by hyaluronidase treatment, indicating anchorage by a hyaluronate-mediated mechanism. Both LP and HABR are firmly attached to MV in either isotonic or hypertonic solutions. In contrast, our other studies show that dissociation of type II collagen from MV occurs only with hypertonic salts which do not release the LISSP. Thus, strong interactions occur under physiological conditions between MV and both the proteoglycans and collagens, but these take place by different mechanisms.

Amino Acid Sequence↗
PubMed1994

In vivo modulation of human tumor cell growth by normal human extracellular matrix.

The extracellular matrix (ECM) is actively involved in the growth and maintenance of normal and neoplastic mammalian cells. It has been suggested that the growth-promoting factors sequestered within the matrix exclusively regulate the observed phenomena. We postulate, however, that ECM components alone, when derived from normal human tissues, and devoid of major growth factors, can modulate the growth of human tumor cells in vivo. In this submission we provide evidence that Amgel, an ECM created by us from nontumorigenic human placental tissues, can enhance or retard human cell growth in vivo, depending upon type, when placed in the subcutaneous tissue of athymic mice. Further, we provide evidence that these results differ from those obtained utilizing a tumor-derived ECM. Our findings suggest that specific tumor cell-matrix interactions are responsible for the observed results. To the best of our knowledge, this is the first report of a normal, human tissue-derived ECM both promoting and inhibiting selected human tumor cell growth in vivo. Thus, Amgel should prove useful in elucidating the underlying mechanisms of cell-matrix interactions during the growth and progression of human neoplasms.

Analysis of Variance↗