title: alpha(v)beta(3) integrin engagement modulates cell adhesion, proliferation, and protease secretion in human lymphoid tumor cells.
abstract: OBJECTIVE
  The mechanisms used by human lymphoproliferative diseases to invade locally and metastasize are thought to be similar to those developed by solid tumors, including cell proliferation and secretion of extracellular matrix-degrading enzymes following adhesion to extracellular matrix proteins. Hence, the ability of Namalwa (Burkitt's lymphoma), U266 (multiple myeloma), and CEM (T-cell lymphoblastic leukemia) cells to interact with the extracellular matrix components vitronectin and fibronectin was determined. Fresh bone marrow plasma cells from patients with multiple myeloma also were studied.
  
  
  METHODS
  Engagement of alpha(v)beta(3) integrin, formation and protein composition of focal adhesion contacts on the cell surface, phosphorylation of several signal transduction proteins in the contacts, cell proliferation, and enzyme secretion were studied following adhesion to vitronectin and fibronectin.
  
  
  RESULTS
  All three lines adhered to immobilized vitronectin and fibronectin. Adhesion was fully prevented by neutralizing monoclonal anti-alpha(v)beta(3) integrin antibody. Integrin engagement caused the formation of phosphorylated pp60(src)/focal adhesion kinase complexes and the aggregation of focal adhesion plaques containing the beta(3) integrin subunit, the cytoskeletal proteins vinculin, cortactin, and paxillin, the tyrosine kinases focal adhesion kinase and pp60(src), the adapter protein Grb-2, and the mitogen-activated protein kinase ERK-2. Free and immobilized vitronectin and fibronectin stimulated the proliferation of cells under serum-free conditions and the production and release of urokinase-type plasminogen activator, and increased the release of the activated forms of matrix metalloproteinase-2 and matrix metalloproteinase-9 in an alpha(v)beta(3) integrin-dependent manner. Similar results were obtained in myeloma plasma cells.
  
  
  CONCLUSIONS
  The demonstrated ability of lymphoid tumor cells to interact with the extracellular matrix components vitronectin and fibronectin via alpha(v)beta(3) integrin can be interpreted as evidence of a novel mechanism for their invasion and spreading. This interaction allows them to adhere to the substratum and enhances their proliferation and protease secretion.
authors.affiliation: Department of Biomedical Sciences, University of Bari Medical School, Bari, Italy. avacca@hotmail.com
authors.forename: A
authors.initials: A
authors.lastname: Vacca
authors.forename: R
authors.initials: R
authors.lastname: Ria
authors.forename: M
authors.initials: M
authors.lastname: Presta
authors.forename: D
authors.initials: D
authors.lastname: Ribatti
authors.forename: M
authors.initials: M
authors.lastname: Iurlaro
authors.forename: F
authors.initials: F
authors.lastname: Merchionne
authors.forename: E
authors.initials: E
authors.lastname: Tanghetti
authors.forename: F
authors.initials: F
authors.lastname: Dammacco
mesh_terms: D000911:Antibodies, Monoclonal / Q000494:pharmacology; D001854:Bone Marrow Cells / Q000473:pathology*; D002448:Cell Adhesion / Q000502:physiology*; D002455:Cell Division / Q000502:physiology*; D010450:Endopeptidases / Q000378:metabolism*; D004789:Enzyme Activation; D005353:Fibronectins; D051417:Focal Adhesion Kinase 1; D051416:Focal Adhesion Protein-Tyrosine Kinases; D006801:Humans; D007700:Kinetics; D008223:Lymphoma; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D009101:Multiple Myeloma / Q000473:pathology*; D010766:Phosphorylation; D010950:Plasma Cells / Q000473:pathology*; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D019030:Receptors, Vitronectin / Q000276:immunology / Q000502:physiology*; D014407:Tumor Cells, Cultured; D014568:Urokinase-Type Plasminogen Activator / Q000378:metabolism; D019096:Vitronectin
chemical_list: D000911:Antibodies, Monoclonal; D005353:Fibronectins; D019030:Receptors, Vitronectin; D019096:Vitronectin; D011505:Protein-Tyrosine Kinases; D051417:Focal Adhesion Kinase 1; D051416:Focal Adhesion Protein-Tyrosine Kinases; C496050:PTK2 protein, human; D019950:Mitogen-Activated Protein Kinase 1; D010450:Endopeptidases; D014568:Urokinase-Type Plasminogen Activator; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9