Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0684249 (lung carcinoma)
 23,830 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The primary structure of tumor invasion-inhibiting factor 2 (IIF-2) purified from bovine liver (A. Isoai et al., Jpn. J. Cancer Res., 81:909-914, 1990) was determined. A computer homology search of the National Biomedical Research Foundation data bank revealed that IIF-2 is identical to the carboxyl-terminal region, residue number [69-89], of high mobility group 17 which is a DNA-binding non-histone protein. IIF-2 synthesized by an automated peptide synthesizer showed similar invasion-inhibitory activity as compared with the purified factor, when tested with the monolayer invasion assay system using highly invasive rat ascites tumor cells. When examined with the other in vitro assay systems using a modified Boyden chamber, the synthetic IIF-2 suppressed the chemotactic migration of highly metastatic B16 melanoma (B16FE7) cells to fibronectin or laminin and invasion through Matrigel. The IIF-2 inhibited neither the cell proliferation nor the binding of cells to fibronectin or Matrigel and also showed no significant inhibition of Mr 90,000 type IV collagenase (gelatinase) obtained from human schwannoma (YST-3) cells. The formation of lung colonies in mice given injections of B16FE7 and Lewis lung carcinoma cells was significantly reduced by the coinjection of the IIF-2. These results suggest that IIF-2 suppresses tumor invasion by impairing cell motility and inhibits the migration of metastasizing cells through extracellular matrix (extravasation steps) following their arrest in the capillary bed of the lung in vivo.
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PMID:Tumor invasion-inhibiting factor 2: primary structure and inhibitory effect on invasion in vitro and pulmonary metastasis of tumor cells. 131 31

Extravasation of circulating cancer cells during metastasis is thought to involve adhesion to the vascular endothelium. To characterize this process, we measured the attachment of A549 human lung carcinoma cells to monolayers of cultured human umbilical vein endothelial cells. Pretreatment of the endothelial cells with 10 ng/ml interleukin 1 alpha (IL-1) for 4 h increased cancer cell attachment 2-5-fold. This increase was blocked by 100 microM glycyl-arginyl-glycyl-aspartyl-serine peptide and was decreased 60 +/- 10% (SD) by a vitronectin receptor polyclonal antiserum or 56 +/- 8% by a vitronectin receptor monoclonal antibody, LM609. Glycyl-arginyl-glycyl-aspartyl-serine or the vitronectin receptor antibodies did not inhibit cancer cell attachment to untreated endothelial cells. A fibronectin receptor antiserum had no effect on attachment to untreated or IL-1-treated endothelial cells. Pretreatment of endothelial cells with IL-1 increased their adhesion to fibronectin and vitronectin and increased the expression of vitronectin receptor and fibronectin receptor as detected by immunofluorescence flow cytometry, quantitative antibody binding, and immunoprecipitation of [35S]methionine-labeled cell extracts. IL-1 pretreatment also increased beta 1, beta 3, and alpha, integrin mRNA. The A549 cells did not express vitronectin receptor, since LM609 did not inhibit A549 adhesion to vitronectin or bind to A549 cells in flow cytometry, and vitronectin receptor antisera failed to immunoprecipitate vitronectin receptor from A549 cells. Furthermore, the beta 3 complementary DNA probe failed to hybridize to A549 RNA. A549 cells did express fibronectin receptor, which was increased by IL-1 treatment. We conclude that IL-1 induces the expression of both vitronectin receptor and fibronectin receptor on endothelial cells and that vitronectin receptor, in turn, facilitates A549 cell adhesion to endothelial cells.
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PMID:Up-regulated biosynthesis and expression of endothelial cell vitronectin receptor enhances cancer cell adhesion. 137 7

The integrins are a family of transmembrane glycoproteins that serve as cell-cell and cell-substratum adhesion molecules and help regulate cellular morphology, differentiation, and proliferation. The integrin repertoire of a cell may therefore influence its behavior under resting conditions or following malignant transformation. For this reason, the distribution of integrins in normal lung tissues was determined using monoclonal antibodies against integrins of the beta 1 (VLA) and beta 3 (cytoadhesin) subfamilies and compared with the distribution in a limited number of lung carcinomas. The integrin subunits that bind to collagen and laminin (alpha 1, alpha 2, alpha 3, and alpha 6) and the alpha subunit, which can pair with beta 1, beta 3, or beta 5 and promote fibronectin, fibrinogen, or vitronectin binding, were the predominant integrins expressed on the major cell types of the lung, i.e., bronchial epithelium, vascular endothelium, and smooth muscle. Strong expression of the alpha 5 beta 1 fibronectin receptor and the beta 3 subunit was restricted to the endothelium of large vessels. Integrin expression by the lung carcinoma cells was somewhat heterogeneous; however, the tumors tended to express fewer integrins than did the normal bronchial epithelium.
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PMID:Distribution of integrin cell adhesion receptors in normal and malignant lung tissue. 154 Mar 82

Seven different tumor cell lines (human melanoma SK MEL 28; hamster melanoma HM29; murine melanomas B16F10 and amelanotic melanoma B16a; human colon carcinoma HCT8; murine colon carcinoma CT26; and murine Lewis lung carcinoma) were treated with thrombin at 0.5-1 unit/ml and examined for their ability to bind to adherent platelets; HM29 was studied for its ability to bind to fibronectin and von Willebrand factor; CT26, B16F1, B16F10, and B16a were studied for their ability to form pulmonary metastasis after i.v. injection of thrombin-treated tumor cells; CT26 was studied for its ability to grow s.c. Five of 7 thrombin-treated tumor cell lines increased their adhesion to adherent platelets 2-to 3-fold. HM29 increased its adherence to fibronectin and von Willebrand factor 2- to 3-fold. CT26, B16F1, B16F10, and B16a increased experimental pulmonary metastasis 10- to 156-fold. Thrombin-treated CT26 cells demonstrated 2-fold greater growth in vivo after s.c. injection. The mechanism of enhanced adhesion of thrombin-treated tumor cells to platelets required the platelet integrin GPIIb-GPIIIa since it could be inhibited by agents known to block adhesion of ligands to GPIIb-GPIIIa (monoclonal antibody 10E5, tetrapeptide RGDS, disintegrin Albolabrin); as well as a "GPIIb-GPIIIa-like" structure on tumor cells since it could be inhibited by treatment of thrombin-treated tumor cells with 10E5 and RGDS. The thrombin effect on tumor cells was optimum at 1 h of incubation with thrombin, did not require active thrombin on the tumor cell surface, and did not require protein synthesis (not inhibited by cycloheximide). Thus, thrombin-treated tumor cells markedly enhance pulmonary metastasis. It is suggested that this may be secondary to thrombin-induced enhanced adhesion as well as growth of tumor cells.
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PMID:Effect of thrombin treatment of tumor cells on adhesion of tumor cells to platelets in vitro and tumor metastasis in vivo. 159 84

We have purified a novel member of the integrin gene family from placenta that serves as a vitronectin receptor. This integrin is composed of the alpha v subunit and a beta subunit that we designate beta 5. Purification was accomplished by immunodepleting a placental extract of integrin alpha v beta 3, allowing us to purify alpha v beta 5 from the remaining extract by monoclonal antibody affinity chromatography on LM 142-Sepharose, which binds to the alpha v subunit. Purification to homogeneity was subsequently achieved by affinity chromatography on wheat germ lectin-Sepharose. Western blot analysis with antibodies raised against alpha v beta 5 and alpha v beta 3 demonstrated that beta 3 and beta 5 were distinct but confirmed that the alpha subunit of the two integrins were immunologically identical. Similarly, antibodies that bind beta 3 proximal to the ligand-binding site failed to react with beta 5, indicating an architectural difference at the ligand-binding site of these related integrins. This structural difference apparently results in a functional distinction, since purified alpha v beta 3 bound to vitronectin, fibrinogen, von Willebrand factor, and fibronectin, whereas integrin alpha v beta 5 bound preferentially to vitronectin. Finally, we demonstrate by three criteria that beta 5 and beta x, the latter of which was identified in lung carcinoma cells (Cheresh, D. A., Smith, J. W., Cooper, H. M., and Quaranta, V. (1989) Cell 57, 59-69), are identical. First, peptide maps of beta x and beta 5 are identical. Secondly, polyclonal antibodies raised against alpha v beta 5 immunoprecipitate both beta 5 and beta x, and finally, the amino-terminal amino acid sequences of beta x and beta 5 are identical.
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PMID:Purification and functional characterization of integrin alpha v beta 5. An adhesion receptor for vitronectin. 169 73

We studied the effects of various protein kinase inhibitors on the attachment of mouse lung carcinoma 3LL cells to the fibronectin (FN) substratum. Calmodulin antagonists (W-7 and W-13) and myosin light chain kinase inhibitors (ML-7 and ML-9) exhibited the inhibitory effect for the attachment, while inhibitors of protein kinases A and C were ineffective. Since Arg-Gly-Asp-containing hexapeptide blocked the attachment, cell surface FN receptor appeared to be involved in this mechanism. These results support the hypothesis that the cell attachment requires the rearrangement of the cytoskeleton in association with the phosphorylation of myosin light chain which would lead to the clustering of the cell surface FN receptors.
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PMID:Myosin light chain kinase inhibitors ML-7 and ML-9 inhibit mouse lung carcinoma cell attachment to the fibronectin substratum. 177 44

The effect of sphingosine (SPH) on the adhesive properties of Lewis lung carcinoma (3LL) cells was investigated using plastic precoated with the extracellular matrix proteins, laminin, fibronectin, or type IV collagen. Treatment of 3LL cells with SPH (0.5-10 microM) resulted in a dose-dependent decrease in the ability to bind to laminin and type IV collagen but had little or no effect on attachment to fibronectin. Phorbol 12-myristate 13-acetate (PMA) selectively enhanced attachment of 3LL cells to laminin and collagen. The inhibitory effect of SPH on attachment to both proteins was competitively antagonized by PMA. These results suggest that SPH acts as a negative effector for cell attachment to laminin and collagen, and that the cell attachment process to both proteins might be regulated in part by protein kinase C.
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PMID:Sphingosine inhibits attachment of murine Lewis lung carcinoma cells to laminin and type IV collagen. 186 77

The capability of the integrin VLA-3 to function as a receptor for collagen (Coll), laminin (Lm), and fibronectin (Fn) was addressed using both whole cell adhesion assays and ligand affinity columns. Analysis of VLA-3-mediated cell adhesion was facilitated by the use of a small cell lung carcinoma line (NCI-H69), which expresses VLA-3 but few other integrins. While VLA-3 interaction with Fn was often low or undetectable in cells having both VLA-3 and VLA-5, NCI-H69 cells readily attached to Fn in a VLA-3-dependent manner. Both Arg-Gly-Asp (RGD) peptide inhibition studies, and Fn fragment affinity columns suggested that VLA-3, like VLA-5, may bind to the RGD site in human Fn. However, unlike Fn, both Coll and Lm supported VLA-3-mediated adhesion that was not inhibited by RGD peptide, and was totally unaffected by the presence of VLA-5. In addition, VLA-3-mediated binding to Fn was low in the presence of Ca++, but was increased 6.6-fold with Mg++, and 30-fold in the presence of Mn++. In contrast, binding to Coll was increased only 1.2-fold with Mg++, and 1.7-fold in Mn++, as compared to the level seen with Ca++. Together, these experiments indicate that VLA-3 can bind Coll, Lm, and Fn, and also show that (a) VLA-3 can recognize both RGD-dependent and RGD-independent ligands, and (b) different VLA-3 ligands have distinctly dissimilar divalent cation sensitivities.
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PMID:Receptor functions for the integrin VLA-3: fibronectin, collagen, and laminin binding are differentially influenced by Arg-Gly-Asp peptide and by divalent cations. 198 4

Purified native forms of human parathyroid hormone-related peptide (PTHrp) have recently been reported to display biological activities characteristic of transforming growth factor beta (TGF-beta). The TGF-beta-like property of PTHrp may reside within the amino N-terminal PTH-receptor binding region of the polypeptide, since a synthetic analog corresponding to amino acids 1-36 of human PTHrp is as active as purified native PTHrp in bioassays specific to TGF-beta. Complete lack of structural similarity between PTHrp and TGF-beta prompted us to address the question whether copresence of the TGF-beta-like and PTH-like biological activities in the N-terminal sequence of the PTHrp molecule is a general phenomenon observable with different N-terminal PTHrp peptides of varying amino acid chain length in a variety of target cells that respond in defined ways to TGF-beta in vitro. Two forms of synthetic N-terminal human PTHrp, PTHrp-(1-34) and [Tyr40]PTHrp-(1-40), which are fully active in conventional assays for PTH/PTHrp, were tested for effects in three in vitro bioassay systems for TGF-beta: 1) stimulation, and 2) inhibition, respectively, of epidermal growth factor-dependent soft-agar colony formation of either normal rat kidney-derived fibroblasts (NRK 49F) or human lung carcinoma cells (A549); and 3) biosynthesis of metabolically labeled fibronectin in both NRK 49F cells and clonal osteoblastic rat osteosarcoma cells (ROS 17/2.8). Human TGF-beta over the dose range of 2.5-80 pM significantly stimulated or inhibited soft-agar colony formation of either NRK 49F or A549 cells, respectively, and caused a severalfold increase in biosynthetically labeled [35S]fibronectin in NRK 49F and ROS 17/2.8 cells. In contrast, none of PTHrp-(1-34), [Tyr40]PTHrp-(1-40), and synthetic human PTH-(1-34), each tested at 0.1-10 nM, displayed detectable biological activity in any of the three assay systems. In addition, covalent cross-linking of intact NRK 49F and ROS 17/2.8 cells with either [125I]TGF-beta or 125I-[Tyr40] PTHrp-(1-40) revealed the presence of several distinct affinity-labeled receptor species for TGF-beta in both cell types and the 80K PTH/PTHrp receptors in ROS 17/2.8 cells. The affinity-labeled TGF-beta receptor species were insensitive to excess PTHrp and PTH peptides, and the 80K PTH/PTHrp receptors were insensitive to excess TGF-beta, indicating that PTHrp and TGF-beta do not cross-react with respect to receptor binding for interaction with these cells.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:On the transforming growth factor beta-like activity of synthetic polypeptides comprising the amino-terminal sequence of human parathyroid hormone-related peptide. 199 44

In view of the increasing evidence that glucosphingolipids (GSLs) on tumor cell surfaces play an important role in tumor metastasis, an inhibitor of glucosylceramide synthase, D-threo-1-phenyl-2-decanoylamino-3-morpholino-1-propanol (D-PDMP) was used to evaluate the role of GSLs in this respect. Treatment of Lewis lung carcinoma cells with 5 microM D-PDMP resulted in a time-dependent marked decrease in levels of all cellular GSLs (glucosylceramide, lactosylceramide, ceramide trihexoside, globoside, and ganglioside GM3). By 6 days, the total GSL content was reduced to approximately 20% of the level in the untreated control cells and at the same time the lung-colonizing capacity of the PDMP-treated cells in inoculated mice was greatly reduced. Closely associated with the degree of GSL depletion, the ability of the cells to invade reconstituted basement membranes in vitro was also reduced, suggesting that GSLs in tumor cell membranes modulate the cell surface interaction with basement membrane components. In order to assess a possible contribution of the defective capacities to drug-induced suppression of experimental metastasis and invasion, we tested the effect of D-PDMP on attachment and migration to laminin and fibronectin and found that the inhibitor specifically reduced the laminin-mediated attachment and migration, whereas it had no effect on fibronectin-mediated attachment and migration. These effects of the inhibitor on lung colonizing capacity in vivo and the invasion, adhesion, and migration properties of the cells in vitro were reversible within 24 h after removal of the drug. By contrast, L-PDMP (the enantiomeric form of D-PDMP), which has no inhibitory activity on glucosylceramide synthesis, did not cause any of the changes produced by D-PDMP. Together, these results suggest that GSLs in tumor cell membranes are essential for the metastatic spread of tumor cells through basement membranes, modulating the interaction of laminin and its receptors.
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PMID:Inhibition of experimental metastasis of murine Lewis lung carcinoma by an inhibitor of glucosylceramide synthase and its possible mechanism of action. 214 65


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