Myeloma cell-osteoclast interaction enhances angiogenesis together with bone resorption: A role for vascular endothelial cell growth factor and osteopontin
Myeloma cell-osteoclast interaction enhances angiogenesis together with bone resorption: A role for vascular endothelial cell growth factor and osteopontin
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DOI：
10.1158/1078-0432.ccr-06-2258
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发表时间：
2007-02-01
影响因子：
11.5
通讯作者：
Matsumoto, Toshio
中科院分区：
文献类型：
--
作者：
Tanaka, Ybichi;Abe, Masahiro;Matsumoto, Toshio
目的：与破骨细胞生成相似，骨髓瘤患者骨髓中的血管生成随着肿瘤进展而增强。我们以前的研究表明，骨髓瘤细胞和破骨细胞相互刺激，形成恶性循环，从而促进破骨细胞生成和肿瘤生长。本研究旨在阐明骨髓瘤细胞-破骨细胞相互作用是否促进血管生成，以及破骨细胞生成和血管生成之间是否存在相互刺激。实验设计：骨髓瘤细胞和单核细胞来源的破骨细胞共培养，通过体外血管小管形成试验和人脐血管内皮细胞(HUVEC)迁移和存活来评估共培养产生的血管生成活性。结果：骨髓瘤细胞和破骨细胞分别分泌促血管生成因子、血管内皮生长因子和骨桥蛋白。骨髓瘤细胞和破骨细胞之间的细胞间相互作用有效地促进了血管小管的形成。阻断血管内皮生长因子和骨桥蛋白的作用几乎完全阻断了骨髓瘤细胞和破骨细胞共培养的条件培养液促进的血管小管形成以及迁移和存活。结论：破骨细胞来源的骨桥蛋白与骨髓瘤细胞来源的血管内皮生长因子协同促进血管生成，并通过血管内皮细胞诱导破骨细胞生成破骨细胞。这些观察表明，骨髓瘤细胞、破骨细胞和血管内皮细胞之间存在密切联系，形成了骨破坏、血管生成和骨髓瘤扩大之间的恶性循环。
Purpose: Similar to osteoclastogenesis, angiogenesis is enhanced in the bone marrow in myeloma in parallel with tumor progression. We showed previously that myeloma cells and osteoclasts are mutually stimulated to form a vicious cycle to lead to enhance both osteoclastogenesis and tumor growth. The present study was undertaken to clarify whether myeloma cell-osteoclast interaction enhances angiogenesis and whether there is any mutual stimulation between osteoclastogenesis and angiogenesis.Experimental Design: Myeloma cells and monocyte-derived osteoclasts were cocultured, and angiogenic activity produced by the cocultures was assessed with in vitro vascular tubule formation assays and human umbilical vascular endothelial cell (HUVEC) migration and survival. Osteoclastogenic activity was determined with rabbit bone cell cultures on dentine slices.Results: Myeloma cells and osteoclasts constitutively secrete proangiogenic factors, vascular endothelial growth factor (VEGF) and osteopontin, respectively. A cell-to-cell interaction between myeloma cells and osteoclasts potently enhanced vascular tubule formation. Blockade of both VEGF and osteopontin actions almost completely abrogated such vascular tubule formation as well as migration and survival of HUVECs enhanced by conditioned medium from cocultures of myeloma cells and osteoclasts. Furthermore, these factors in combination triggered the production of osteoclastogenic activity by HUVEC.Conclusions: Osteoclast-derived osteopontin and VEGF from myeloma cells cooperatively enhance angiogenesis and also induce osteoclastogenic activity by vascular endothelial cells. These observations suggest the presence of a close link between myeloma cells, osteoclasts, and vascular endothelial cells to form a vicious cycle between bone destruction, angiogenesis, and myeloma expansion.