Vascular endothelial growth factor and interleukin-6 in paracrine tumor-stromal cell interactions in multiple myeloma
Vascular endothelial growth factor and interleukin-6 in paracrine tumor-stromal cell interactions in multiple myeloma
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DOI：
10.1182/blood.v95.8.2630
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发表时间：
2000-04-15
期刊：
影响因子：
20.3
通讯作者：
Kienast, J
中科院分区：
文献类型：
--
作者：
Dankbar, B;Padró, T;Kienast, J
血管内皮生长因子（VEGF）是一种多功能的细胞因子，能有效地刺激血管生成，包括肿瘤新生血管的形成。虽然在实体瘤中已经确立，但VEGF在淋巴造血系统恶性肿瘤中骨髓新血管生成和旁分泌肿瘤-基质细胞相互作用中的作用尚未完全阐明。在多发性骨髓瘤（MM）中，骨髓新生血管与疾病进展平行。这一平行现象促使我们研究骨髓瘤细胞VEGF的表达和分泌及其在骨髓瘤-骨髓基质相互作用中的潜在作用。从MM患者骨髓中分离的骨髓瘤细胞系和浆细胞表达和分泌具有生物活性的剪接变体VEGF 165和VEGF 121。如免疫细胞化学或RT-PCR所示，骨髓瘤细胞不表达或弱表达VEGF受体FLT-1和FLK-1/KDR，表明自分泌刺激不太可能。相比之下，FLK-1/KDR在骨髓基质细胞中大量表达，因此，我们研究了VEGF对骨髓基质的影响，重点关注白细胞介素-6（IL-6）的分泌，白细胞介素-6是骨髓瘤细胞的一种有效生长因子，也是一种浆细胞的抑制剂细胞凋亡，间质和微血管内皮细胞暴露于重组人（rh）VEGF 165或VEGF 121诱导IL-16表达的时间和剂量依赖性增加。6分泌（在50 ng/mL下24小时后为14- 27倍，P < .001）。相反，rhIL-6刺激骨髓瘤细胞系中VEGF的表达和分泌（40%-60%; P <0.05），并在不同程度上（高达5.3倍; P <0.005）刺激从MM患者骨髓中纯化的浆细胞中VEGF的表达和分泌。这种相互刺激表明VEGF和IL-6触发骨髓瘤和骨髓基质细胞之间的旁分泌相互作用。（血。2000;95：2630-2636）（C）2000由美国血液学学会。
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. (Blood. 2000;95:2630-2636) (C) 2000 by The American Society of Hematology.