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)

Adult T-cell leukemia (ATL) is characterized by massive infiltration of circulating ATL cells into a variety of tissues, a finding often associated with poor prognosis. Leukocyte migration from circulation into tissue depends on integrin-mediated adhesion to endothelium, and integrins are tightly regulated by several stimuli, such as inflammatory chemokines. However, the exact mechanisms that enhance adherence of leukemic cells to the endothelium and infiltration into tissues remain to be fully understood. We investigated the mechanisms of extravasation of leukemic cells using ATL cells and report the following novel features of endogenous chemokine-induced adhesion of ATL cells to the endothelium. ATL cells spontaneously adhered to endothelial cells without exogenous stimulation. Integrin leukocyte function-associated antigen-1 (LFA-1) on ATL cells was spontaneously activated. ATL cells produced high amounts of chemokines, macrophage inflammatory protein-1alpha (MIP-1alpha), and MIP-1beta. Adhesion of ATL cells to endothelial cells and the expression of activated form of LFA-1 were reduced by pretreatment with pertussis toxin, wortmannin, or anti-MIP-1alpha and MIP-1beta antibodies or transfection with antisense of MIP-1alpha or MIP-1beta. Spontaneous polymerization of cytoskeletal F-actin was observed in ATL cells, which was also inhibited by pertussis toxin and wortmannin. We propose that ATL cells adhere to endothelial cells through an adhesion cascade similar to normal leukocytes and that the chemokines produced by ATL cells are involved in triggering integrin LFA-1 through cytoskeletal rearrangement induced by G-protein-dependent activation of phosphoinositide 3-kinases in an autocrine manner. These events result in a strong adhesion of ATL cells to the endothelium and spontaneous transendothelial migration.
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PMID:Constitutive chemokine production results in activation of leukocyte function-associated antigen-1 on adult T-cell leukemia cells. 957 29

Tumor-reactive T cells, known as tumor-infiltrating lymphocyte(TIL)s are known to infiltrate various tumors. Although TILs exert cytotoxic activities against tumor cells, only a small percentage of tumors usually contain TILs that specifically react to tumor antigens. Because the exact role of these lymphocytes is unclear, we investigated the mechanisms of migration and adhesion of TILs to bone metastatic tumors, particularly to osteoblasts and bone marrow-derived stromal cell(BMSC)s. Histopathological examination showed that most TILs in secondary bone metastatic tumors (from primary tumors in the lung or breast) were found in the supporting tissue stroma between the bone and tumor mass. Cultured TILs (obtained from breast tumors) adhered spontaneously to osteoblasts and BMSCs (obtained from patients with osteoarthritis) without exogenous stimulation. Adhesion was further enhanced by chemokines macrophage inflammatory protein (MIP)-1alpha and MIP-1beta. TILs highly expressed activation antigens CD25 and CD69. A spontaneous activation of an integrin, lymphocyte function-associated antigen-1 (LFA-1), was also detected on TILs. TILs produced high concentrations of MIP-1alpha and MIP-1beta and spontaneous polymerization of cytoskeletal F-actin was observed in these cells. Adhesion of TILs to osteoblasts and BMSCs via LFA-1 and very late antigen-4 was associated with the production of osteoclastogen interleukin 6 by the latter cells. Our results indicate that integrins on TILs are activated in an autocrine manner by MIP-1alpha and MIP-1beta, and that treatment with the chemokines increases the binding of TILs on osteoblasts and stromal cells via a mechanism involving intercellular adhesion molecule-1 and vascular cell adhesion molecule-1 as targets for the integrin. Our data also indicated that interactions between TILs and osteoblasts/stromal cells lead to the secretion by the latter of the osteoclastogenic cytokine interleukin 6.
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PMID:Constitutive up-regulation of integrin-mediated adhesion of tumor-infiltrating lymphocytes to osteoblasts and bone marrow-derived stromal cells. 975 26

The adhesive function of integrins is regulated through cytoplasmic signaling. The present study was performed to investigate the relevance of cytoplasmic signaling and cytoskeletal assembly to integrin-mediated adhesion induced by chemokines. Adhesion of T cells induced by chemokines macrophage inflammatory protein (MIP)-1alpha and MIP-1beta was inhibited by pertussis toxin, wortmannin, and cytochalasin B, suggesting that both G protein-sensitive phosphatidylinositol (PI) 3-kinase activation and cytoskeletal assemblies are involved. The chemokine-induced T cell adhesion could be mimicked by expression of small G proteins, fully activated H-RasV12, or H-RasV12Y40C mutant, which selectively binds to PI 3-kinase, in T cells, inducing activated form of LFA-1alpha and LFA-1-dependent adhesion to ICAM-1. H-Ras expression also induced F-actin polymerization which colocalized with profilin in T cells. Adult T cell leukemia (ATL) cells spontaneously adhered to ICAM-1, which depended on endogenous MIP-1alpha and MIP-1beta through activation of G protein-sensitive PI 3-kinase. H-Ras signal pathway, leading to PI 3-kinase activation, also induced active configuration of LFA-1 and LFA-1-mediated adhesion of ATL cells, whereas expression of a dominant-negative H-Ras mutant failed to do. Profilin-dependent spontaneous polymerization of F-actin in ATL cells was reduced by PI 3-kinase inhibitors. In this paper we propose that H-Ras-mediated activation of PI 3-kinase can be involved in induction of LFA-1-dependent adhesion of T cells, which is relevant to chemokine-mediated signaling, and that profilin may form an important link between chemokine- and/or H-Ras-mediated signals and F-actin polymerization, which results in triggering of LFA-1 on T cells or leukemic T cells.
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PMID:H-Ras signals to cytoskeletal machinery in induction of integrin-mediated adhesion of T cells. 1057 Mar 13

Multiple myeloma (MM) cell adhesion to stromal cells via very late antigen (VLA)-4 and vascular cell adhesion molecule (VCAM)-1 interaction causes enhanced secretion of osteoclastogenic activity by MM cells. We have reported that MM cell-derived macrophage inflammatory protein (MIP)-1alpha and MIP-1beta are responsible for most of the osteoclastogenic activity in MM. Thus, adhesion-mediated osteoclastogenesis may be caused by enhanced production of MIP-1 via VLA-4-VCAM-1 interaction. The present study was undertaken to clarify whether MM cell-derived MIP-1 plays a role in VLA-4-VCAM-1 adhesion-mediated osteoclastogenesis. Adhesion of MM cells to VCAM-1 upregulated MIP-1alpha and MIP-1beta production from MM cells and enhanced production of osteoclastogenic activity by MM cells. Blockade of MIP-1alpha and MIP-1beta actions not only abrogated elaboration of osteoclastogenic activity, but also suppressed spontaneous MM cell adhesion to VCAM-1. These results demonstrate that MM cell adhesion to VCAM-1 upregulates MIP-1 production by MM cells to cause enhancement of osteoclastogenesis. In addition, the results suggest that the increased production of MIP-1 further enhances MM cell binding to stromal cells via stimulation of VLA-4-VCAM-1 adhesion, forming a "vicious cycle" between MM cell adhesion to stromal cells and MIP-1 production via VLA-4-VCAM-1 interaction.
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PMID:Vicious cycle between myeloma cell binding to bone marrow stromal cells via VLA-4-VCAM-1 adhesion and macrophage inflammatory protein-1alpha and MIP-1beta production. 1905 41