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Results for “Extracellular Matrix”

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PubMed1993

The sign of Leser-Trélat: a cutaneous sign of internal malignancy: weakened subepithelial matrix from the effect of neoplasms on the extracellular matrix of the host.

The sudden onset of many seborrheic keratoses (SK) associated with an internal malignancy (most commonly adenocarcinoma) is called the sign of Leser-Trélat. It is associated with acanthosis nigricans (AN) in 20% of the cases. There are marked changes in the extracellular matrix (ECM) around tumors. Various fractions and depolymerized glycosaminoglycans enter circulation. They can incorporate in the general extracellular matrix. Mechanical factors present in AN produce extrusions of this poor quality ECM in the form of papillae and folds. The poor quality of subepithelial extracellular matrix produces the marked epithelial changes of acanthosis nigricans which shows hyperkeratosis, papillomatosis, slight irregular acanthosis, and keratin material formation. The neoplasm can produce the same qualitative changes in the subepithelial ECM on otherwise normal appearing skin. When the altered same epithelial changes occur on this biologically altered skin the result is many SK (the sign of Leser-Trélat).

Acanthosis Nigricans↗

PubMed2001

The molecular effects of oncogenesis on cell-extracellular matrix adhesion (review).

Cell-extracellular matrix adhesive interactions provide a key regulatory mode of cellular behavior. The molecular basis of adhesion-mediated signaling responses has been under investigation over the past few years. Tyrosine phosphorylation initiated by cell adhesion plays a crucial role in regulating adhesion-mediated signaling and cytoskeletal rearrangement. Oncogenesis involves aberrant interactions between cells and the extracellular matrix. The mechanisms that underline the functions of oncogenes and tumor suppressors often involve modulation of specific tyrosine phosphorylated cytoplasmic proteins, thereby affecting directly adhesion-mediated signaling. The constitutive kinase activity of oncogenes such as v-Src and BCR/Abl hyper-phosphorylates cytoskeletal and signaling molecules, and modulates the functions of integrins, the predominant family of extracellular matrix receptors. The tumor suppressor gene PTEN was recently identified as a key regulator of adhesion-mediated signaling. This review summarizes the direct effects of oncogenes, tumor suppressor genes and their products on the adhesive responses of cells. Understanding of the molecular basis of these effects may provide the means to develop novel therapeutics to control pathological processes associated with aberrant cell-extracellular matrix interactions.

Animals↗

PubMed1999

Extracellular matrix remodelling and cellular differentiation.

The extracellular matrix is not merely a passive structure. In the past few years, it has emerged that the matrix is a dynamic action zone that functions to instruct cellular phenotype. Extracellular matrix proteins interact directly with cell surface receptors to initiate signal transduction pathways and to modulate those triggered by differentiation and growth factors. The extracellular matrix also controls the activity and presentation of a wide range of growth factors. Thus modulation of the extracellular matrix, by remodelling its structure and activity, has profound effects on its function and the consequent behaviour of cells residing on or within it.

Animals↗

PubMed2006

Modulation of response to tumor therapies by the extracellular matrix.

The composition of the extracellular matrix in tumors is vastly different from that found in the normal tissue counterparts. As the extracellular matrix can signal to cells via integrin binding and activation, which is known to modulate cell proliferation, survival and migration, it may influence the response of both tumor and endothelial cells to anticancer therapies. Certain tumor-associated extracellular matrix proteins have been shown to confer resistance to chemotherapeutic drugs, radiation and anti-angiogenic factors. The current literature regarding this phenomenon and the potential therapeutic modalities to overcome extracellular matrix-induced resistance will be discussed.

Extracellular Matrix↗

PubMed2001

Extracellular matrix and keratinocyte migration.

We are just beginning to understand some of the cellular mechanisms involved in human keratinocyte migration on extracellular matrix. Extracellular matrix components have differing effects on keratinocyte motility. Signalling through integrin receptors and secretion of collagenase are both components of this process. An understanding of the effect of extracellular matrix on keratinocyte migration has direct relevance to the problem of wound re-epithelialization and will assist in the development of therapeutic efforts to enhance wound healing artificially.

Cell Movement↗

PubMed1991

Common structural motifs in proteins of the extracellular matrix.

Proteins of the extracellular matrix are composed of many structurally and often functionally different autonomous domains which frequently occur as modular units in several different extracellular matrix proteins, but also in proteins of different origin. Some domains serve related assembly functions in different proteins but for domains involved in cell attachment and other cellular activities only a few generalizations are possible.

Animals↗

PubMedDate not supplied

Gefitinib decreases the synthesis of matrix metalloproteinase and the adhesion to extracellular matrix proteins of colon cancer cells.

BACKGROUND: Adhesion to extracellular matrix (ECM) proteins and degradation of basement membranes by matrix metalloproteinase (MMP) play important roles in cancer metastasis. In this study, the effects of gefitinib on the enzymatic activity of MMP and adhesion to ECM proteins in the HT29 colon cancer cell line were investigated. MATERIALS AND METHODS: Microtiter plates, coated with ECM proteins, were used to investigate the adhesion of cancer cells to ECM proteins. The expression of MMPs was examined by zymography and semiquantitative RT-PCR. RESULTS: Gefitinib inhibited MMP-9 and MMP-2 secretion and mRNA expression in HT29 cells. Gefitinib also reduced the ability to adhere to laminin and type IV collagen. These effects were observed at such low doses that gefitinib had neither an antiproliferative effect nor the ability to induce apoptosis. CONCLUSION: Gefitinib decreased the production of MMPs and the adhesion to ECM proteins, important steps associated with cancer metastasis. These results suggest that gefitinib may have antimetastatic activity in colon cancer.

Antineoplastic Agents↗

PubMedDate not supplied

Matrix metalloproteinases in neoplasm-induced extracellular matrix remodeling in breast carcinomas.

Structural changes in the extracellular matrix (ECM) are necessary for cell migration during normal and pathologic tissue remodeling and neoplastic cell invasion. The matrix metalloproteinases (MMPs) and their inhibitors have been identified to be critical modulators of ECM composition and are thus, crucial in neoplastic cell progression, invasion and metastasis. Expression of MMP-2, -3, -9, -10, and -13 was investigated in human breast carcinomas (BCs) employing an indirect, biotin-streptavidin based, alkaline phosphatase conjugated immunocytochemical technique. Evaluation of the results was based on (a) the percent of neoplastically transformed cells/surrounding stroma that reacted positively and (b) a measure of staining intensity [graded from A (highest) to D (negative)]. The two forms of stromelysin, MMP-3 and -10, share 82% sequence homology, but exhibit differences in cellular synthesis and inducibility by cytokines and growth factors in vitro. Strong overall expression of MMP-3 and -10 was found in BCs, especially in the ECM adjacent to blood vessels. Positive immunoreactivity could be seen for these two MMPs in the ECM surrounding over 90% of the neoplastically transformed cells (++++), and the staining intensity was also the strongest possible (A). High intensity immunoreactivity (A,B) but focal was detected employing a MoAB targeted against the MMP-9 enzyme. No presence of MMP-2 or -13 could be established in the BC cases observed by us. Based on these results we propose that MMP-3 and -10 are implicated in the pathogenesis of BC, while MMP-9 is possibly involved in neo-angiogenic events also closely associated with growth and expansion of the neoplastically transformed cell mass, as well as metastasis of individual, extremely aggressive, expressing dedifferentiated cellular immunophenotype (IP) cell clones selected during the microevolution of the BC.

Alkaline Phosphatase↗

PubMed2002

Integration of concepts: cardiac extracellular matrix remodeling after myocardial infarction.

The cardiac extracellular matrix consists of a three-dimensional structural network of interstitial collagens to which other matrix components are attached. The main physiological functions of this network are to retain tissue integrity and cardiac pump function. Collagen deposition is controlled and can be modulated by hormonal factors, growth factors, cytokines, regulatory proteins and/or hemodynamic factors. Increased collagen deposition is a prerequisite to prevent dilatation of the infarcted area. Excessive accumulation of collagen leads to ventricular diastolic and systolic dysfunction and ultimately contributes to heart failure. An appropriate balance of extracellular matrix synthesis and degradation is required for normal morphogenesis and maintenance of tissue architecture. A disbalance in the extracellular matrix turnover either by decreased matrix synthesis and/or increased degradation leads to less than normal extracellular matrix in the myocardium which in its turn may lead to cardiac dilatation or even rupture. Extracellular matrix degrading enzymes expressed after myocardial infarction belong to the families of serine and matrix metalloproteinases (MMPs) and are secreted as latent proenzymes that have to be activated. It is crucial to keep the activity of these enzymes under tight control by either influencing the synthesis, activation or inhibition by tissue inhibitors of MMPs (TIMPs) or alpha2-macroglobulin. First studies using MMP inhibitors in experimental models of myocardial infarction seem to give attenuation of ventricular geometry but not always improvement of cardiac function. A central role in the activation of MMPs plays the plasminogen-plasmin system. Invasion of inflammatory cells and hitherto the rest of the wound healing cascade is inhibited in plasminogen or uPA deficient mice, most likely by the inhibition of MMP activity. Regulating the balance of extracellular matrix remodeling either by extracellular matrix synthesis or degradation might be one of the possible prevention mechanisms for heart failure. But also regeneration of the vascular and cardiomyocyte network might be potential new treatments for people with heart failure.

Animals↗

PubMed1999

The role of the extracellular matrix in skeletal muscle development.

Skeletal muscle fibers are surrounded by an extracellular matrix. The extracellular matrix is composed of glycoproteins, collagen, and proteoglycans. Proteoglycans have been suggested to play an important functional role in tissue differentiation; however, an understanding of how the extracellular matrix affects skeletal muscle development and function is largely unknown. Proteoglycans can regulate collagen fibrillogenesis, inhibit cell growth, and modulate the response to growth factors. Our studies have focused on the proteoglycan decorin, which interacts with transforming growth factor-beta and regulates collagen fibrillogenesis and cellular growth properties in the avian genetic muscle weakness Low Score Normal. Low Score Normal pectoral muscle development is characterized by a late embryonic increase in the expression of decorin followed by a subsequent increase in collagen crosslinking and modified collagen fibril organization. This paper reviews the interaction of extracellular matrix molecules, cell-extracellular matrix interactions, and modulation of growth factor activity. How proteoglycans may interface with each of these key events during skeletal muscle myogenesis is discussed.

Animals↗

PubMed1987

A lectin, peanut agglutinin, as a probe for the extracellular matrix in living neuromuscular junctions.

The extracellular matrix plays important roles in the differentiation of synapses. To identify molecules concentrated specifically in the synaptic extracellular matrix, fluorescently-labelled lectins were applied to neuromuscular junctions. A lectin, peanut agglutinin (PNA), stains the neuromuscular region selectively and irreversibly (up to at least 3 weeks in situ), outlining the periphery of the nerve terminal arborization in the frog. Snake neuromuscular junctions also stain intensely with fluorescent PNA, while mouse diaphragm staining is faint. At the electron microscopic level, the reaction products of horseradish peroxidase-conjugated PNA are found primarily in the extracellular matrix flanking Schwann cells in the frog endplate regions. Fluorescently labelled PNA does not affect synaptic potentials and can serve as a simple stain for correlating functional studies of living neuromuscular junctions. Moreover, it can be combined with a presynaptic dye to observe nerve terminals and synaptic extracellular matrix in the same junctions in situ. This report reveals the existence of synapse-specific carbohydrates associated with Schwann cell extracellular matrix in the frog neuromuscular junction. The specific binding and its physiological compatibility make PNA a useful probe for further investigation of synaptic differentiation, plasticity and maintenance.

Animals↗

PubMed2002

Complexities in ETS-domain transcription factor function and regulation: lessons from the TCF (ternary complex factor) subfamily. The Colworth Medal Lecture.

The ETS-domain transcription factor family can be divided into a series of subfamilies. Elk-1 represents the founding member of the ternary complex factor (TCF) subfamily. By focusing on the TCF subfamily, we can demonstrate the complexities that exist in the function and regulation of ETS-domain transcription factors. This article focuses on Elk-1 in detail and summarizes the functions of other TCFs. The key themes covered include the domain structure of the TCFs, the mechanisms of complex formation with serum response factor, regulation of TCFs by mitogen-activated protein kinase cascades, and transcriptional regulatory properties of the TCFs. Finally, the emerging role of the TCFs in vivo is discussed. A picture is developing indicating that, while these proteins exhibit significant sequence and functional conservation, key differences in their structure and regulation are being identified which may relate to unique functions of these proteins in vivo.

Amino Acid Sequence↗

PubMed2001

Pathobiology of pulmonary hypertension. Extracellular matrix.

Changes in the extracellular matrix underlie the structural and functional abnormalities in the vessel wall that lead to progressive pulmonary vascular disease. Studies are reviewed aimed at addressing the cellular and molecular programs that regulate the production of the extracellular matrix describing new ways to arrest proliferation and migration of smooth muscle cells and to induce apoptosis. The latter can lead to the reversal of pathology at least in experimental animal models.

Animals↗

PubMed1989

Liver fibrosis and extracellular matrix.

Liver fibrosis and extracellular matrix play a central role in liver function impairment. Little information is available on the dynamic aspects and the natural history of fibroplasia, even if there is growing evidence that extracellular matrix accumulation (collagen I, III, IV, fibronectin, laminin, proteoglycans, etc.) is not to be considered only a passive structural support for damaged hepatic tissue, but may actively modulate liver cell behaviour. Clinicians need to date liver fibrosis and to monitor connective tissue synthesis and degradation, but attempts to develop reliable serological markers for collagen metabolism are hampered by the absence of a well defined golden standard to validate them. Nevertheless, serum type III aminoterminal procollagen peptide, at the moment, seems to be the most acceptable parameter of fibrogenesis. The data concerning the mechanisms of collagen production-degradation are becoming so precise and numerous that even if they have not, to date, led to 'routine' advantages for patients, they will end up becoming important tools in the clinical practice and management of liver fibrosis.

Absorption↗

PubMed2004

Regulation of angiogenesis by extracellular matrix.

During angiogenesis, endothelial cell growth, migration, and tube formation are regulated by pro- and anti-angiogenic factors, matrix-degrading proteases, and cell-extracellular matrix interactions. Temporal and spatial regulation of extracellular matrix remodeling events allows for local changes in net matrix deposition or degradation, which in turn contributes to control of cell growth, migration, and differentiation during different stages of angiogenesis. Remodeling of the extracellular matrix can have either pro- or anti-angiogenic effects. Extracellular matrix remodeling by proteases promotes cell migration, a critical event in the formation of new vessels. Matrix-bound growth factors released by proteases and/or by angiogenic factors promote angiogenesis by enhancing endothelial migration and growth. Extracellular matrix molecules, such as thrombospondin-1 and -2, and proteolytic fragments of matrix molecules, such as endostatin, can exert anti-angiogenic effects by inhibiting endothelial cell proliferation, migration and tube formation. In contrast, other matrix molecules promote endothelial cell growth and morphogenesis, and/or stabilize nascent blood vessels. Hence, extracellular matrix molecules and extracellular matrix remodelling events play a key role in regulating angiogenesis.

Angiogenesis Inducing Agents↗

PubMed1990

Elevated expression of transforming growth factor-beta and proteoglycan production in experimental glomerulonephritis. Possible role in expansion of the mesangial extracellular matrix.

Glomerular accumulation of extracellular matrix is a prominent feature of progressive glomerulonephritis. Previously, we have shown that transforming growth factor-beta (TGF-beta) is unique among growth factors in regulating the production of the proteoglycans biglycan and decorin by glomerular mesangial cells in vitro. We now provide evidence of an elevated expression of TGF-beta, proteoglycans, and fibronectin in glomerulonephritis induced in rats by injection of anti-thymocyte serum (ATS). Glomeruli were cultured from rat kidneys at 1, 4, 7, 14, and 28 d after ATS administration. Increased proteoglycan synthesis was detected beginning on day 4, which peaked at a 4,900% increase compared with control on day 7, and returned toward control levels by day 28. The increased proteoglycan synthesis by cultured nephritic glomeruli, as well as that of fibronectin, were greatly reduced by addition of antiserum raised against a synthetic peptide from TGF-beta. Conditioned media from ATS glomerular cultures, when added to normal cultured mesangial cells, induced elevated proteoglycan synthesis that also peaked on day 7 and that mimicked the response to added exogenous TGF-beta. The stimulatory activity of the conditioned media was blocked by addition of TGF-beta antiserum. Prior addition of the immunizing peptide to the antiserum abolished the blocking effect. The main induced proteoglycans were identified as biglycan and decorin by immunoprecipitation with antiserum made against synthetic peptides from the proteoglycan core proteins. Glomerular histology showed mesangial matrix expansion in a time course that roughly paralleled both the elevated proteoglycan synthesis by the ATS glomeruli and the ability of the conditioned media from these glomeruli to induce proteoglycan synthesis. At the same time there was an increased expression of TGF-beta mRNA and TGF-beta protein in the glomeruli. These results suggest a central role for TGF-beta in the accumulation of pathological extracellular matrix in glomerulonephritis.

Animals↗

PubMed1999

[Adhesive glycoproteins of the extracellular matrix].

Glycoproteins of the extracellular matrix and basement membrane play crucial role in cell recognition, adhesion, migration and proliferation. Morphogenesis and tissue and organ development in embryo, as well as healing processes in adults are dependent on the interactions of extracellular proteins with cell surface receptors. In this paper the structure and function of major adhesive proteins: fibronectin, tenascin, laminin and nidogen are reviewed. Recent data on the role of small leucine-rich and modular proteoglycans, such as decorin, biglycan, fibromodulin, versican, perlecan, neurocan, agrecan, agrin and other are given. Modifications of the expression and localization of extracellular glycoproteins in pathology are also presented.

Adult↗

PubMed2006

What mouse mutants teach us about extracellular matrix function.

For many years the extracellular matrix was viewed as a benign scaffold for arranging cells within connective tissues, but it is now being redefined as a dynamic, mobile, and flexible key player in defining cellular behavior. Gene targeting, transgene expression, and spontaneous mutations of extracellular matrix proteins in mice have greatly accelerated our mechanistic view of the structural and instructive functions of the extracellular matrix in developmental and regenerative processes. This review summarizes the phenotypes of genetic mouse models carrying mutations in extracellular matrix proteins, with specific emphasis on recent advances. The application of reverse genetics has demonstrated the multifunctionality of matrix proteins in a biological context and, in addition, has brought a novel perspective to the understanding of human pathologies.

Animals↗