alpha(v)beta(3) integrin engagement modulates cell adhesion, proliferation, and protease secretion in human lymphoid tumor cells

Objective. The mechanisms used by human lymphoproliferative diseases to inv ade 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 protein s. Hence, the ability of Namalwa (Burkitt's lymphoma), U266 (multiple myelo ma), and CEM (T-cell lymphoblastic leukemia) cells to interact with the ext racellular matrix components vitronectin and fibronectin was determined. Fr esh bone marrow plasma cells from patients with multiple myeloma also were studied. Materials and Methods. Engagement of alpha (v)beta (3) integrin, formation and protein composition of focal adhesion contacts on the cell surface, pho sphorylation of several signal transduction proteins in the contacts, cell proliferation, and enzyme secretion were studied following adhesion to vitr onectin and fibronectin. Results. All three lines adhered to immobilized vitronectin and fibronectin . Adhesion was fully prevented by neutralizing monoclonal anti-alpha (v)bet a (3) integrin antibody. Integrin engagement caused the formation of phosph orylated pp60(src)/focal adhesion kinase complexes and the aggregation of f ocal adhesion plaques containing the beta (3) integrin subunit, the cytoske letal proteins vinculin, cortactin, and paxillin, the tyrosine kinases foca l adhesion kinase and pp60(src), the adapter protein Grb-2, and the mitogen -activated protein kinase ERK-2. Free and immobilized vitronectin and fibro nectin stimulated the proliferation of cells under serum-free conditions an d the production and release of urokinase-type plasminogen activator, and i ncreased the release of the activated forms of matrix metalloproteinase-2 a nd matrix metalloproteinase-9 in an alpha (v)beta (3) integrin-dependent ma nner. Similar results were obtained in myeloma plasma cells. Conclusions. The demonstrated ability of lymphoid tumor cells to interact w ith the extracellular matrix components vitronectin and fibronectin via alp ha (v)beta (3) integrin can be interpreted as evidence of a novel mechanism for their invasion and spreading. This interaction allows them to adhere t o the substratum and enhances their proliferation and protease secretion. ( C) 2001 International Society for Experimental Hematology. Published by Els evier Science Inc.