Tissue inhibitor of metalloproteinase-1 alters the tumorigenicity of Burkitt's lymphoma via divergent effects on tumor growth and angiogenesis

Epstein-Barr virus (EBV)-postive Burkitt's lymphoma cells and EBV-infected B cells elicit humoral factors that inhibit tumor-induced angiogenesis, res ulting in tumor necrosis and regression, Of the chemokine factors identifie d in association with this growth behavior, none have induced complete tumo r regression, We have previously identified tissue inhibitors of metallopto teinase (TIMP)-1 in various B cell lymphoma cell lines. Here we show that I nduction of TEMP-1 expression in an EBV-negative Burkitt's lymphoma cell li ne results in a biphasic, in vivo tumor growth pattern in the nude mouse th at is essentially identical to EBV-positive Burkitt's lymphoma cell lines, The initial effect of TIMP-1 is to enhance tumor growth, consistent with th e reported anti-apoptotic effect of TIMP-1 on B cell growth. Tumor necrosis and regression then follow the initial period of rapid, increased tumor gr owth. Only microscopic foci of residual, proliferating tumor cells are obse rved on biopsy of the tumor site. This latter effect is mediated by TEMP-1 inhibition of an angiogenic response within the developing tumor mass, as d emonstrated by immunostaining and microvessel counts. These findings sugges t that TIMP-1 is an important mediator of the in vivo growth properties of EBV-positive Burkitt's lymphoma.