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

Abstract

Vascular endothelial growth factor (VEGF), a multifunctional cytokine, potently stimulates angiogenesis including tumor neovascularization. Although well established in solid tumors, the role of VEGF in bone marrow neoangiogenesis and paracrine tumor-stromal cell interactions in lymphohematopoietic malignancies has not been fully elucidated. In multiple myeloma (MM), marrow 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 biologically 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, indicating that autocrine stimulation is unlikely. In contrast, FLK-1/KDR was abundantly 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 recombinant human (rh) VEGF165 or VEGF121 induced a time- and dose-dependent increase in IL-6 secretion (14- to 27-fold at 50 ng/mL after 24 hours, P < .001). 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 marrow stromal cells triggered by VEGF and IL-6.

Divergence of renal vascular endothelial growth factor mRNA expression and protein level in post‐ischaemic rat kidneys

“…Oxygen deficiency is a strong stimulus, but not the only stimulus for enhanced VEGF synthesis. It has been suggested that IL-6 (Takada et al 1997) and IL-1β (Haq et al 1998) are involved in post-ischaemic renal failure and it has also been shown that they increase VEGF synthesis in vitro (Gloddek et al 1999;Dankbar et al 2000;Levitas et al 2000).…”

“…Previous studies performed on a variety of cultured cells demonstrated that VEGF mRNA and protein expression are markedly increased by hypoxia (Shweiki et al 1992;Ladoux & Frelin, 1993) and different cytokines (Gloddek et al 1999;Finkenzeller et al 1992;Stavri et al 1995;Dankbar et al 2000;Levitas et al 2000). In vivo studies have also shown that VEGF mRNA and protein expression are increased in response to ischaemic injury of different organs (Banai et al 1994;Bernaudin et al 2002).…”

“…As VEGF may support post-ischaemic recovery of the kidney, the aim of the present study was to analyse the renal synthesis and immunohistochemical localization of VEGF in a rat model of I/R-induced ARF. We also investigated the renal mRNA expression of IL-6 and IL-1β, which are implicated in the regulation of VEGF synthesis (Glodddek et al 1999;Dankbar, 2000;Levitas, 2000).…”

Targeting the bone marrow microenvironment in multiple myeloma

“…MM derived ECs are endowed of an over-angiogenic phenotype able to support directly the growth, proliferation, and invasion of MM through the direct secretion of several growth factors, including IL-6 (146). For example, a cross-talk between MM cells and ECs has been described, where MM cells secrete VEGF that stimulates ECs to produce IL-6; this crosstalk ultimately determines simultaneous proliferation of both MM cells and ECs (147). MM ECs, but not MGUS ECs, are able to spontaneously secrete several other growth factors, including bFGF and HGF, which also promote MM cell proliferation and survival (148).…”

Single‐cell RNA sequencing reveals chemokine self‐feeding of myeloma cells promotes extramedullary metastasis

“…Transcriptional factors specific for myeloma cells, such as IRF4, Blimp-1 (PRDM1), and XBP1, are also transcribed in BMMCs [26][27][28][29]. Upregulation of nourishing growth factors for myeloma, such as HGF, IGF1, and VEGF [30][31][32][33], was also confirmed. Furthermore, tumorigenic genes correlated with PC1 [34][35][36][37][38][39] (Fig.…”