Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0027651 (tumor)
 685,946 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Cell-cell interactions play an important role in the development of cartilage. Heterologous and homologous cell-cell interactions are critical for chondrogenic differentiation during development. Cell-cell interactions in the formation of fracture callus and cartilage neoplasia also invoke the process of cartilage differentiation. We have investigated cell-cell interactions between articular chondrocytes and synovial fibroblasts and show that there was enhanced binding between these two cell types compared to background binding of the labelled cells to the tissue culture plastic surface. The binding of chondrocytes to fibroblasts was temperature- and calcium-dependent, suggesting ligand-integrin involvement. The peptide, GRGDSP, which competes with the ligand-integrin through the tripeptide RGD (arginine-glycine-aspartic acid), almost completely inhibited chondrocyte attachment to synovial fibroblasts. The control peptide, GRGESP, had no inhibitory effect on binding. Antibodies to fibronectin (Fn) inhibited chondrocyte attachment by about 50%. Monoclonal antibodies to the alpha and beta chains of the fibronectin receptor (FnR) interfered with the attachment of chondrocytes to synovial fibroblasts. A combination of antibodies to Fn and to FnR did not completely abrogate chondrocyte binding, suggesting that other ligand-receptors were involved in the adhesion process. Chondrocytes and fibroblasts were shown to express membrane-associated Fn and FnR, by immunofluorescence. The alpha and beta chains of FnR, migrating at 110 and 140 kDa, respectively, could be immunoprecipitated from [35S]methionine-labelled synovial fibroblasts and chondrocytes. Northern blots showed the presence of mRNA for the alpha and beta chains of fibronectin receptors in fibroblasts and chondrocytes. Changes in cell shape were observed in chondrocytes on attachment to fibroblasts, i.e. the chondrocytes appeared fibroblast-like, suggesting that the chondrocytes had dedifferentiated. These studies suggest that chondrocytes specifically bind to synovial fibroblasts through RGD-dependent receptors. beta 1 Integrins are involved in this adhesion process and these heterlogous cell interactions appear to have a negative influence on chondrogenic differentiation.
 ...
PMID:Tripeptide RGD-dependent adhesion of articular chondrocytes to synovial fibroblasts. 138 77

Triflavin, an Arg-Gly-Asp (RGD) containing peptide purified from Trimeresurus flavoviridis snake venom, inhibits human platelet aggregation by blocking fibrinogen binding to fibrinogen receptors associated with glycoprotein IIb/IIIa complex. In this study, we show that triflavin (1-30 micrograms/mouse) inhibits B16-F10 melanoma cell-induced lung colonization in C57BL/6 mice in a dose-dependent manner. In vitro, triflavin dose-dependently inhibits adhesion of B16-F10 melanoma cells to extracellular matrices (ECMs; i.e., fibronectin, fibrinogen, vitronectin, and collagen type I). Triflavin is approximately 600-800 times more potent than GRGDS at inhibiting cell adhesion. In addition, triflavin dose-dependently inhibits B16-F10 cell-induced platelet aggregation. These results imply that the inhibitory effect of triflavin on the adhesion of tumor cells to ECMs (e.g., fibronectin, vitronectin and collagen type I) and/or tumor cell-induced platelet aggregation may be partially responsible for its antimetastatic activity in C57BL/6 mice.
 ...
PMID:Triflavin, an Arg-Gly-Asp-containing antiplatelet peptide inhibits cell-substratum adhesion and melanoma cell-induced lung colonization. 139 25

The Arg-Gly-Asp (RGD) sequence is a universal cell-recognition site of various extracellular proteins that interact with integrin cell-surface receptors. In order to design low-molecular-mass RGD protein antagonists, the determination of the biologically active conformation is a prerequisite. We present a method that yields detailed insight into the steric factors which govern the binding of the ligands to their receptors by systematically scanning the conformational space accessible for the tripeptide sequence RGD. The investigation is based on the conformationally controlled design of homodetic cyclic oligopeptides and their structural determination, coupled with biological assays. For this purpose, a whole set of cyclic pentapeptides and hexapeptides has been synthesized and their three-dimensional structures in solution analyzed by modern two-dimensional NMR techniques in combination with restrained and free molecular dynamics simulations. Their biological activity was compared with that of linear GRGDS in inhibition assays of tumor cell adhesion to laminin P1 and vitronectin substrates. An up to 100-fold, and in part selective, increase in activity was observed for two cyclic pentapeptides. Most other peptides showed a decreased activity which, however, was useful to correlate activity with rather small variations in conformation. Detailed comparative studies of the systematically designed conformations and the corresponding anti-adhesive activities offer an access to lead structures for a rational indirect drug design of peptide and peptidomimetic pharmaceuticals with strong interfering activity for integrin-mediated cell-cell and cell-matrix interactions.
 ...
PMID:Conformation/activity studies of rationally designed potent anti-adhesive RGD peptides. 148 74

Adhesive interactions between tumor cells and host tissue occur at several stages of metastasis. Such interactions might be inhibited by microbial metabolites resembling the binding regions of matrix molecules. Certain metabolite sequences including Gly, Asp, Arg, and Ser (GAAS) proved to be critical for cell interactions, e.g. with fibronectin. In vitro, the rosette formation of murine pulmonary cells and sarcoma L-1 cells decreased significantly in the presence of Propionibacterium acnes-metabolites rich in GAAS. In vivo, coinjection of Propionibacterium acnes-metabolites and sarcoma L-1 cells significantly inhibited the formation of lung colonies in BALB/c mice. The inhibition of lung colonization by these metabolites appeared to be noncytotoxic and obviously did not result from impairment of cellular tumorigenicity.
 ...
PMID:Propionibacterium acnes-metabolites inhibit experimental lung metastasis of murine sarcoma L-1 in BALB/c-mice. 148 36

Triflavin, an Arg-Gly-Asp (RGD)-containing peptide, purified from snake venom of Trimeresurus flavoviridis, inhibits human platelet aggregation through the blockade of fibrinogen binding to fibrinogen receptors associated with glycoprotein IIb/IIIa complex. In this report, we examined the effect of triflavin on tumor cells (human hepatoma J-5)-induced platelet aggregation (TCIPA) of heparinized platelet-rich plasma (PRP). ADP-scavenger agents, apyrase (10 U/ml) and creatine phosphate (5 mM)/creatine phosphokinase (5 U/ml) did not inhibit TCIPA while hirudin (5 U/ml) completely inhibited it. J-5 cells initially induced platelet aggregation, then blood coagulation occurred. J-5 cells concentration-dependently shortened the recalcification time of normal as well as Factor VIII, IX-deficient human plasmas, while it was inactive at shortening the recalcification time of Factor VII-deficient plasma, suggesting J-5 cells induced platelet aggregation through activation of extrinsic pathway, leading to thrombin formation as evidenced by the amidolytic activity on s-2238 by expressing tissue factor-like activity. Triflavin inhibited TCIPA in a dose-dependent manner (IC50, 0.02 microM). When compared on molar ratio, triflavin was approximately 30,000 times more potent than GRGDS (IC50, 0.58 mM). On the other hand, GRGES showed no significant effect on TCIPA, even its concentration was raised to 4 mM. Additionally, the monoclonal antibodies, raised against glycoprotein IIb/IIIa complex (i.e., 7E3 and 10 E5) inhibited J-5 TCIPA. In conclusion, we suggest the inhibitory effect of triflavin on J-5 TCIPA may be chiefly mediated by the binding of triflavin to the fibrinogen receptor associated with glycoprotein IIb/IIIa complex on platelet surface membrane.
 ...
PMID:Triflavin, an Arg-Gly-Asp containing snake venom peptide, inhibits aggregation of human platelets induced by human hepatoma cell line. 151 27

Discrete functions have been attributed to precise regions of the human androgen receptor (hAR) by expression of deletion mutants in COS and HeLa cells. A large C-terminal domain constitutes the hormone-binding region and a central basis, cysteine-rich domain is responsible for DNA binding. In addition, separate domains responsible for transactivation and nuclear translocation have been identified. In LNCaP cells (a prostate tumor cell line) the hAR is a heterogeneous protein which is synthesized as a single 110 kDa protein, but becomes rapidly phosphorylated to a 112 kDa protein. Metabolic labeling experiments using radioactive orthophosphate also indicated that the hAR is a phosphoprotein. Structural analysis of the AR gene in LNCaP cells and in 46, XY-individuals displaying androgen insensitivity (AIS) has revealed several different point mutations. In LNCaP cells the mutation affects both binding specificity and transactivation by different steroids. In a person with complete AIS a point mutation was identified in the splice donor site of intron 4, which prevents normal splicing and activates a cryptic splice donor site in exon 4. The consequence is a functionally inactive AR protein due to an in-frame deletion in the steroid-binding domain. In two unrelated individuals with complete AIS, two different single nucleotide alterations in codon 686 (Asp) were found. Both mutations resulted in functionally inactive ARs due to rapidly dissociating hormone-AR complexes. It is concluded that the hAR is a heterogeneous phosphoprotein in which functional errors have a dramatic impact on phenotype and fertility of 46, XY-individuals.
 ...
PMID:The human androgen receptor: structure/function relationship in normal and pathological situations. 156 11

We have previously shown that transfection of NIH 3T3 cells with the T24 H-ras oncogene converts the cells to a tumorigenic and metastatic phenotype, in proportion to levels of ras expression. We hypothesize that ras-induced increases in malignancy occur via altered expression of various genes. We have identified OPN (osteopontin; also known as Secreted Phosphoprotein, 2ar, Eta-1, and transformation-associated phosphoprotein) as a ras-induced gene in these cells. We report here that expression of OPN RNA and secretion of OPN protein are increased in a series of ras-transformed NIH 3T3 cells, in proportion to levels of expression of ras. Detection of secreted OPN protein was facilitated by a barium citrate precipitation procedure. Although the function of this protein in tumor cells is not known, OPN contains a conserved GRGDS (glycine-arginine-glycine-aspartic acid-serine) amino acid sequence, which may function as a cell attachment site for this protein. We speculate that increased expression of OPN contributes to the increased malignancy of ras oncogene-transformed NIH 3T3 cells, perhaps by alterations in either adhesive properties or integrin-mediated signal transduction pathways.
 ...
PMID:Induction of expression of osteopontin (OPN; secreted phosphoprotein) in metastatic, ras-transformed NIH 3T3 cells. 156 80

This study examined the role of fibronectin in promoting particulate attachment to sites of urothelial injury. Variables influencing adherence of the rat transitional carcinoma cell line 4909 and "non-cellular" styrene-divinylbenzene microspheres to fibronectin were studied in an in vitro system. A soluble synthetic peptide fragment (Gly-Arg-Gly-Asp-Ser [GRGDS]) duplicating the receptor binding domain of fibronectin (RGD) was used to determine whether cell adherence could be inhibited by fibronectin receptor blockade. In vitro findings were correlated with an in vivo assay of both cellular and non-cellular particulate adherence to injured urothelium. Time, plated cell density, substrate concentration, GRGDS concentration, and cell viability, were all found to be significant independent variables influencing in vitro cellular adherence (p less than 0.0001). Receptor blockade with GRGDS significantly decreased in vitro tumor cell adherence to fibronectin. In vitro microsphere binding increased as a direct function of fibronectin concentration but was not time dependent (p less than 0.0001 and p = 0.14 for fibronectin concentration and time respectively). The in vivo adherence of both tumor cells and microspheres was significantly increased in injured bladders compared to controls (p less than 0.01). Receptor blockade with GRGDS failed to inhibit in vivo cell adherence to sites of urothelial injury. Microspheres proved to be competitive inhibitors of cellular adherence in competitive binding assays. In vitro microsphere binding demonstrated a pH dependence with maximal binding at pH 7.2. These data suggest that in vitro tumor cell adherence to fibronectin differs from in vivo tumor cell adherence to sites of urothelial injury. Manipulations which inhibit in vitro adherence, specifically fibronectin receptor blockade and cell death, fail to effect in vivo binding to the extreme that non-cellular particulate appears to bind to the same site, and with similar affinity, as cellular particles.
 ...
PMID:In vitro particulate adherence to fibronectin: correlation with in vivo particulate adherence to sites of bladder injury. 156 98

Matrix-bound fibronectin (FN) appears to be involved in cell adhesion and motility mediated by integrin receptors. Although lymphoid cells and other cell types are capable of producing and secreting FN, the precise role of this secreted FN-like factor in regulating immune reactions is unclear. In the present study we analyzed the adhesive properties of FN secreted by rat CD4+ T cells and clone cells activated by the T cell mitogen concanavalin A (Con A), antigen, or via the CD2 pathways, or by macrophages (M phi) activated by lipopolysaccharide (LPS). Immobilized culture supernatant (CS) from the activated T cells or M phi supports the adhesion of activated rat or human CD4+ T cell or murine tumor cell. These CS contained FN and were more potent at facilitating cell adhesion then plasma FN. The adhesion activity of CS was attributed to FN because (a) gelatin columns depleted the FN present in the CS and (b) pretreating the cells with peptides of the cell-binding domain of FN abrogated their ability to bind CS. CS-mediated adhesion appears to occur primarily via the recognition of the Arg-Gly-Asp (RGD) by the beta 1-integrin-specific receptors of the adhesive cells. Thus, we postulate that FN secreted by various types of leukocytes is involved in promoting essential cell-matrix interactions, possibly affecting cell-adhesive and migratory processes at inflammatory or extravasation sites.
 ...
PMID:Activated T lymphocytes and macrophages secrete fibronectin which strongly supports cell adhesion. 157 55

We have investigated the anti-angiogenic effect of a polymeric peptide based on the Arg-Gly-Asp (RGD) core sequence of fibronectin as a monomer unit, i.e., poly(RGD), in syngeneic mice and in vitro. Single intratumoral administration of poly(RGD) on day 0, 1 or 7 after tumor implantation achieved a significant reduction of B16-BL6 melanoma colonization in the lungs, but did not affect the size of the primary tumor at the time of amputation. The number of capillary blood vessels oriented toward the tumor mass increased during the early growth phase after the intradermal inoculation of the tumor. Poly(RGD) significantly inhibited the formation of tumor neovascularization when co-injected with the tumor cells or separately injected intratumorally or intravenously on day 1 or 3 after tumor inoculation. This inhibitory effect of poly(RGD) was dose-dependent. Poly(RGD) was able to inhibit the haptotactic migration of endothelial cells along a gradient of substratum-immobilized fibronectin but not laminin. Tumor-conditioned medium (CM) by itself did not act as a chemoattractant when it was added in the lower compartment of a Transwell chamber, but promoted the endothelial cell migration to immobilized fibronectin or laminin. Poly(RGD) inhibited the enhanced cell migration to fibronectin but not to laminin in response to CM. Thus, poly(RGD)-mediated inhibition of tumor metastasis may be partly due to the inhibition of tumor-induced angiogenesis at primary and secondary sites.
 ...
PMID:Inhibition of tumor angiogenesis by a synthetic cell-adhesive polypeptide containing the Arg-Gly-Asp (RGD) sequence of fibronectin, poly(RGD). 169 94


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>