Vascular endothelial growth factor and interleukin-6 in paracrine tumor-stromal cell interactions in multiple myeloma

Vascular endothelial growth factor (VEGF), a multifunctional cytokine, pote ntly stimulates angiogenesis including tumor neovascularization. Although w ell established in solid tumors, the role of VEGF in bone marrow neoangioge nesis and paracrine tumor-stromal cell interactions in lymphohematopoietic malignancies has not been fully elucidated. In multiple myeloma (MM), marro w neovascularization parallels disease progression. This parallel prompted us to investigate the expression and secretion of VEGF by myeloma cells and its potential effects in myeloma-marrow stroma interactions. The biologica lly active splice variants VEGF165 and VEGF121 were expressed and secreted by myeloma cell lines and plasma cells isolated from the marrow of patients with MM, As shown by immunocytochemistry or RT-PCR, myeloma cells did not express or weakly expressed the VEGF receptors FLT-1 and FLK-1/KDR, indicat ing that autocrine stimulation is unlikely. In contrast, FLK-1/KDR was abun dantly expressed by marrow stromal cells, Therefore, we studied the effects of VEGF on marrow stroma, focusing on the secretion of interleukin-6 (IL-6 ), a potent growth factor for myeloma cells and an inhibitor of plasma cell apoptosis, Exposure of stromal and microvascular endothelial cells to reco mbinant human (rh) VEGF165 or VEGF121 induced a time- and dose-dependent in crease in IL-6 secretion (14- to 27-fold at 50 ng/mL after 24 hours, P < .0 01). Conversely, rhIL-6 stimulated VEGF expression and secretion in myeloma cell lines (40%-60%; P < .05) and to a variable degree (up to 5.3-fold; P < .005) in plasma cells purified from the marrow of patients with MM, This mutual stimulation suggests paracrine interactions between myeloma and marr ow stromal cells triggered by VEGF and IL-6. (Blood. 2000;95:2630-2636) (C) 2000 by The American Society of Hematology.