Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0001511 (Adhesion)
 5,955 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The alternatively spliced type III connecting segment (IIICS) region of fibronectin contains two distinct sites that support the adhesion of melanoma cells. These sites are contained within the synthetic peptides CS1 and CS5 (residues 1-25 and 90-109 of the IIICS, respectively). Recently, the cellular receptor for the CS1 site has been identified as the integrin heterodimer alpha 4 beta 1. In this report, we have investigated the role of the CS5 sequence in melanoma cell adhesion and the identity of its receptor. Adhesion to CS5, when presented to cells as an immobilized IgG conjugate, was blocked by antifunctional monoclonal antibodies directed against either the alpha 4 or beta 1 integrin subunits, but not by antibodies against other subunits, implying that alpha 4 beta 1 is also the receptor for CS5. In peptide inhibition experiments, CS5 was inhibitory for melanoma cell spreading on both CS5-IgG and CS1-IgG conjugates; conversely, CS1 inhibited spreading on both CS1-IgG and CS5-IgG. In both cases, peptide inhibition could be outcompeted by increasing the concentration of substrate-bound conjugate. These results suggest that CS1 and CS5 are recognized by the same or overlapping sites on alpha 4 beta 1. The minimal active sequence within CS5, the tetrapeptide Arg-Glu-Asp-Val (REDV), is somewhat related to the Arg-Gly-Asp-Ser (RGDS) sequence that represents a major active site in the central cell-binding domain (CCBD) of fibronectin. When RGDS peptide homologues were tested for their ability to inhibit spreading of melanoma cells on CS1- and CS5-IgG conjugates, GRGDS, GRGES, and REDV were found to be inhibitory, while GRDGS had no effect. In contrast, spreading on a fibronectin fragment containing the CCBD was inhibited by GRGDS only. GRGDS was also able to elute alpha 4 beta 1 specifically from a CS1 affinity column, confirming directly that alpha 4 beta 1-IIICS interactions are sensitive to peptides containing this recognition motif. Because the minimal active sequence within CS1 is the tripeptide Leu-Asp-Val (LDV; Komoriya et al., manuscript submitted for publication), these findings together define a new adhesive recognition sequence, X-Asp-Y, used by alpha 4 beta 1 for binding to fibronectin. The central aspartate residue in this tripeptide is almost always essential, but some flexibility in the amino acid residues at X (glycine, leucine, or glutamic acid) and Y (serine or valine) is tolerated. Potential models for the interaction of the IIICS region with alpha 4 beta 1 are discussed.
 ...
PMID:The CS5 peptide is a second site in the IIICS region of fibronectin recognized by the integrin alpha 4 beta 1. Inhibition of alpha 4 beta 1 function by RGD peptide homologues. 175 Sep 29

We investigated the effects of beta 1 integrins on tumor cell (TC) adhesion to unstimulated and interleukin-1 (IL-1) activated endothelial cells (EC). IL-1 treatment (20 units/ml for 6 hours) of cultured human umbilical vein EC significantly increased adhesion of seven human TC lines of different origin. A goat antiserum raised to purified alpha 5 beta 1 integrin abolished the IL-1 induced increment in adhesion of two osteosarcomas, one melanoma, one lung, and one kidney carcinoma, whereas it did not affect adhesion of two colon carcinoma cell lines. Further studies were performed on MG63 osteosarcoma cells. Adhesion of MG63 osteosarcoma cells to EC was dependent on time of EC treatment with IL-1: it was maximal at 12 hours and declined at 24 hours. alpha 5 beta 1 antiserum blocked IL-1 induced increase in MG63 adhesion at any time of EC treatment. This effect appears to be mainly directed to MG63 integrins since selective incubation of the antiserum with EC, but not with MG63, did not modify TC adhesion. Using a series of antibodies to different alpha and beta chains, we found that only monoclonal antibodies (mAb) to alpha 4, alpha 5, and beta 1 could inhibit MG63 adhesion to IL-1 activated EC, whereas alpha 2, alpha 6, and beta 3 antibodies were ineffective. Antibodies to fibronectin had very little activity on MG63 adhesion to EC matrix and did not significantly affect MG63 adhesion to control or IL-1 treated EC. Antibodies to alpha 4, alpha 5, and beta 1 were only partially effective in inhibiting MG63 adhesion to EC matrix. These data indicate that the capacity of alpha 4 beta 1 and alpha 5 beta 1 integrins to bind fibronectin contributed very little to MG63 adhesion to EC. The importance of beta 1 integrins in promoting a direct interaction between EC and MG63 was further shown by inhibition of rosette formation among these cells in suspension by the alpha 5 beta 1 antiserum. Only a VCAM-1/INCAM110 mAb, but not ELAM-1 or ICAM-1 mAbs, could inhibit MG63 adhesion to IL-1 activated EC. Overall these data indicate that at least two members of the beta 1 integrin subfamily (alpha 4 beta 1 and alpha 5 beta 1) are involved in MG63 adhesion to cytokine treated EC. This integrin function might be important at early stages of TC interaction with the vessel wall.
 ...
PMID:Role of beta 1 integrins in tumor cell adhesion to cultured human endothelial cells. 175 2

The purpose of this study was to determine whether a heterodimeric complex immunologically related to the fibrinogen receptor could function as a thrombospondin (TSP) receptor in TSP-mediated cell-substratum adhesion of human melanoma cells. We found that polyclonal antibodies to the platelet GPIIb-IIIa complex, GPIIIa, and the human vitronectin receptor inhibited TSP-mediated cell adhesion by 63-68%. Immunoprecipitation of detergent extracts of 125I-surface-labeled melanoma cells using either anti-human platelet GPIIb-IIIa or anti-human vitronectin receptor antibody revealed the presence of a single heterodimeric complex, suggesting that both antisera recognize the same integrin receptor, GPIIb-IIIa-like antigen. Adhesion of cells to TSP is likely mediated through a region of the TSP molecule containing the arginine-glycine-aspartic (RGD) peptide sequence, since cell attachment to TSP was inhibited 50-66% in the presence of peptides containing RGD. These results strongly suggest that a GPIIb-IIIa-like/vitronectin receptor can serve as a cell binding site for TSP in mediating cell-substratum adhesion.
 ...
PMID:The GPIIB-IIIa-like complex may function as a human melanoma cell adhesion receptor for thrombospondin. 247 Jun 6

Two different types of interactions were described between cells and elastin: 1) the adhesion of cells to insoluble fibrous elastin and 2) the binding of soluble elastin derived peptides by cells. We could show that these are two different mechanisms underlying those two types of interactions. The adhesion of cells to elastin fibers is mediated by a cell-membrane complex with a 120 kD protein as the main adhesive compound which we proposed to designate elastonectin. Three other proteins (67, 60 and 45 kD) were coisolated with elastonectin. Adhesion of insoluble elastin to mesenchymal cells (fibroblasts, smooth muscle cells) is inducible with soluble elastin peptides. Highly metastatic Lewis lung carcinoma cells and human melanoma cells also exhibited the adhesion mechanism, but without a lag phase (constitutive adhesion). Binding curve (Scatchard plots) obtained with radiolabelled elastin peptides indicated the presence of high affinity elastin receptors on mesenchymal cells and human white blood cells (monocytes and PMNs) with Kd-s in the nanomolar range. The binding of elastin peptides triggers several cellular reactions such as chemotaxis, Ca++ influx (increase of Ca++i) and with mononuclear blood cells release of lytic enzymes and oxygen radicals. All these cells which exhibited elastin receptor function also exhibited adhesion although the two processes could be inhibited selectively. The receptor action is mediated by a G-protein-phospholipase-IP3 mechanism, involved in the increase of intracellular Ca++. It appears that this action also triggers the biosynthesis and membrane localization of elastonectin. The coupling of these 2 mechanisms between receptor and adhesion appears to be modified in transformed cells.
 ...
PMID:Elastonectin and the elastin receptor. 255 Aug 76

The integrin heterodimer VLA-2, previously known as a collagen receptor, is now shown also to be a laminin receptor. Adhesion of the human melanoma cell line LOX to laminin was inhibited by anti-VLA alpha 2 antibodies. Because VLA-2-mediated LOX cell attachment to laminin was not inhibited by digestion with collagenase, collagen contamination of laminin was not a factor. In addition, VLA-2 from LOX cells bound to immobilized laminin, and binding was disrupted by EDTA but not by Arg-Gly-Asp (RGD) peptides. VLA-3 also bound to laminin-Sepharose, although less avidly than VLA-2. Thus, at least four separate members of the integrin beta 1 subfamily serve as laminin receptors--i.e., VLA-2 and VLA-3 (this study) together with VLA-1 and VLA-6 (other reports). Whereas LOX and other cell lines used VLA-2 as both a laminin and collagen receptor, fibroblast VLA-2 mediated collagen but not laminin binding. Likewise, VLA-2 from platelets did not interact with laminin. Despite this functional discordancy, VLA-2 from laminin-binding and nonbinding sources was indistinguishable by all immunochemical and biochemical criteria examined. Thus, functional differences in VLA-2 may be due to cell type-specific modulation.
 ...
PMID:The human integrin VLA-2 is a collagen receptor on some cells and a collagen/laminin receptor on others. 255 34

Adhesion to specific extracellular matrix molecules appears to be an important prerequisite for successful target organ colonization by metastasizing tumour cells. Interference in the adhesive function of malignant cells with antiadhesive agents is therefore one potential approach for preventing metastasis. Recently, synthetic peptides taken from the cell interaction sites of fibronectin have been characterized as inhibitors of cellular adhesion in vitro. Using these antiadhesive probes we have examined the role of cell adhesion to fibronectin in tumour metastasis using the B16-F10 murine melanoma model system. Two sequences from the IIICS cell-binding domain, the 25-mer CS1 peptide and the tetrapeptide Arg-Glu-Asp-Val (REDV), had no detectable activity, but the pentapeptide Gly-Arg-Gly-Asp-Ser (GRGDS), an active sequence from the central cell-binding domain, exhibited potent, dose-dependent inhibition, indicating a role for this cell recognition determinant in tumour metastasis. Under appropriate conditions GRGDS treatment afforded remarkable protection to the host; mice injected with melanoma cells and peptide were still alive 15 months after injection whereas mice injected with melanoma cells alone died within six weeks. Kinetic analyses of the retention of tumour cells in the lungs and of the vascular clearance rate of labelled GRGDS predict an early time frame of activity for the peptide. From the results of a variety of in vitro invasion and migration assays it appears that GRGDS may interfere with multiple, fibronectin-mediated adhesive and migratory events at different points of the metastatic cascade. In preliminary studies designed to optimize the therapeutic usefulness of GRGDS-like agents, peptide conjugates have been found to possess enhanced antiadhesive activity as well as an extended vascular clearance rate. In the future, therefore, these or related peptide derivatives may be potentially useful agents for the prevention of tumour metastasis.
 ...
PMID:The cell interaction sites of fibronectin in tumour metastasis. 285 15

Clinical and experimental observations suggest that tumor-induced endothelial cell (EC) injury may be one of several initial events in the establishment of tumor metastases. This work investigates tumor-induced EC injury and the interaction between tumor-damaged EC and platelets. We used cultured bovine EC and extracts of four cultured human malignancies. EC injury was assessed by 51Cr and lactic dehydrogenase (LDH) release. Incubation of EC with melanoma, breast carcinoma or lung carcinoma caused significant LDH and 51Cr release, whereas colon cancer seemed ineffective. Increased adhesion of platelets to tumor-injured EC was noted. These observations indicate that certain varieties of tumor cause EC injury. Adhesion of platelets to tumor-injured EC results in the formation of platelet-tumor thrombi at the endothelial surface, an event that may initiate tumor invasion of the vessel wall.
 ...
PMID:Tumor interaction with vascular endothelium. 366 82

Adhesion molecules are likely to play a role in the process of tumour progression. We investigated the expression of integrins, ICAM-1, and CD44 and the influence of interferon-alpha (IFN-alpha), interferon-gamma (IFN-gamma), and tumour necrosis factor-alpha (TNF-alpha) on expression of these molecules on four uveal melanoma cell lines. The in vitro integrin expression was quite variable. The alpha V and beta 1 subunits were expressed on all cell lines, and none of the cell lines showed any alpha 3, beta 2, or beta 4 expression. Other integrin subunits showed a more variable pattern. ICAM-1 and CD44 were strongly expressed on all cell lines. IFN-alpha, IFN-gamma, and TNF-alpha upregulated alpha 1, alpha 2, and alpha 3 expression, and did not alter alpha 4, alpha 5, alpha 6, beta 2, alpha v beta 3, and beta 4 expression. The effects on alpha V and alpha V beta 5 were variable. ICAM-1 was upregulated by IFN-gamma and TNF-alpha, but not by IFN-alpha. Cytokine treatment hardly changed CD44 expression. In one case a comparison was made between expression on cultured cells and on tissue sections of the tumour of origin. Differences in expression were observed for the integrin subunits alpha 2, alpha 3, and alpha 5. This study shows that integrins and ICAM-1 expression on uveal melanoma cells in vitro are susceptible to cytokine treatment, but that the effects on integrin expression are cytokine and cell line dependent. Furthermore, some differences in integrin expression between cells in vivo and in vitro exist.
Melanoma Res 1995 Aug
PMID:Cytokine-mediated modulation of integrin, ICAM-1 and CD44 expression on human uveal melanoma cells in vitro. 749 58

Changes in glycoconjugate production have been reported for tumor cells. In this study, we investigated the glycoconjugate expression pattern in normal human melanocytes and in a panel of 6 human melanoma cell lines with different metastatic capacity after s.c. inoculation into nude mice. Glycoconjugates were labeled in vitro with [35S] sulphate and [3H] glucosamine, purified from cells and culture medium by column chromatography and identified by treatment with specific glycosidases. Characterization of the purified glycoconjugate fractions as well as alcian-blue staining of xenograft lesions revealed that hyaluronic acid (HA) is the main glycoconjugate produced by all cell lines. Highly metastatic cell lines expressed higher levels of HA than melanocytes and than weakly metastatic or non-metastatic cell lines. In addition, a shift in dominance from chondroitin-sulphate proteoglycan to heparan-sulphate proteoglycan was observed with increasing metastatic capacity. We also studied the expression and binding activity of the HA receptor CD44. Immunoprecipitation experiments indicated high CD44 synthesis only in highly metastatic cell lines, but FACS analysis demonstrated approximately the same surface expression in melanocytes as in all cell lines. Adhesion assays to immobilized HA showed that CD44 can be present in an inactive or an active conformation. Our data suggest that a combination of increased HA production and the expression of CD44 on the cell surface may be associated with high metastatic potential of human melanoma cell lines in nude mice.
 ...
PMID:Glycoconjugate profile and CD44 expression in human melanoma cell lines with different metastatic capacity. 753 56

Four disintegrins, eristostatin, albolabrin, barbourin and echistatin, injected IV into C57BL/6 mice in combination with B16F10 murine melanoma cells, inhibited formation of experimental lung metastases with ID50s of 0.05, 1.0, 0.9, and 3.7 mumoles per mouse, respectively. When injected 1 h after tumor cells, albolabrin, echistatin and barbourin had the same antimetastatic activity, while eristostatin was not active. Eristostatin (IC50 7-8 nM) was more potent than echistatin (IC50 74-75 nM), barbourin (IC50 46-60 nM), and albolabrin (IC50 130-165 nM) as an inhibitor of murine platelet aggregation induced by ADP or tumor cells. Fibronectin was the best substrate for melanoma cell adhesion (95%), followed by laminin (47%) and vitronectin (24%). Albolabrin was the strongest and eristostatin the weakest inhibitor of cell adhesion to all substrata. Adhesion of melanoma cells to albolabrin, echistatin, and barbourin was partially inhibited by monoclonal antibody against mouse alpha v subunit. This antibody bound to B16F10 melanoma cells in suspension and inhibited binding of fluorescein isothiocyanate (FITC)-labeled disintegrins to these cells, being the most effective with FITC-labeled albolabrin. Our study suggests that a major contribution of eristostatin to inhibition of lung colonization is via preferential binding to platelet alpha IIb beta 3 integrin and blocking tumor cells interaction with platelets. A major contribution of albolabrin, barbourin and echistatin appears to be by interference with other integrin receptors on the tumor cell surface. Albolabrin appeared to inhibit RGD-dependent integrins containing alpha v subunit, such as alpha v beta 3 and alpha v beta 1.
 ...
PMID:Effect of four disintegrins on the adhesive and metastatic properties of B16F10 melanoma cells in a murine model. 754 46


<< Previous 1 2 3 4 5 6 7 8 9 Next >>