HUMAN LYMPHOBLASTOID-CELLS PRODUCE EXTRACELLULAR-MATRIX DEGRADING ENZYMES AND INDUCE ENDOTHELIAL-CELL PROLIFERATION, MIGRATION, MORPHOGENESIS, AND ANGIOGENESIS

Human lymphoproliferative diseases can be hypothesized to invade local ly and to metastatize via mechanisms similar to those developed by a v ariety of solid tumors, i.e., the secretion of extracellular matrix-de grading enzymes and stimulation of angiogenesis. To assess this hypoth esis, Namalwa, Raji, and Daudi cell lines (Burkitt's lymphoma), LIK an d SB cell lines (B-cell lymphoblastic leukemia), CEM and Jurkat cell l ines (T-cell lymphoblastic leukemia), and U266 cell line (multiple mye loma) were evaluated for their capacity to produce matrix metalloprote inase-2 and -9, and urokinase-type plasminogen activator. These cell l ines were also assessed for their ability: (1) to produce the angiogen ic basic fibroblast growth factor and vascular endothelial growth fact or; (2) to induce an angiogenic phenotype in cultured endothelial cell s, represented by cell proliferation, chemotaxis, and morphogenesis; ( 3) to stimulate angiogenesis in different in vivo experimental models. All cell lines expressed the mRNA for one or both metalloproteinases. Namalwa, Raji, LIK, SB, and U266 cells secreted the active form of bo th metalloproteinases, while Daudi, GEM, and Jurkat cells produced met alloproteinase-2 but not -9. In contrast, urokinase-type plasminogen a ctivator was secreted only by SB cells. While Raji, LIK, SB, GEM, and Jurkat cells secreted both basic fibroblast growth factor and vascular endothelial growth factor, Daudi and U266 cells produced only the for mer, and Namalwa cells only the latter. Accordingly, the conditioned m edium of all cell lines stimulated cell proliferation and/or chemotaxi s in cultured endothelial cells, with the exception of that of Namalwa cells which was ineffective. The conditioned medium of CEM and Jurkat cells induced morphogenesis in cultured endothelial cells gown on a r econstituted basement membrane (Matrigel). Lastly, Namalwa, Raji, LIK, SB, U266, GEM, and Jurkat cells induced angiogenesis and mononuclear cell recruitment in the murine Matrigel sponge model and in a chick em bryo chorioallantoic membrane assay. The extent of angiogenesis in bot h models was strictly correlated with the density of the mononuclear c ell infiltrate. The results indicate that human lymphoproliferative di sease cells possess both local and remote invasive ability via the sec retion of matrix-degrading enzymes and the induction of angiogenesis w hich is fostered by host inflammatory cells and by an intervening ense mble of angiogenic factors.