Tanaka Yoichi, Abe Masahiro, Hiasa Masahiro, Oda Asuka, Amou Hiroe, Nakano Ayako, Takeuchi Kyoko, Kitazoe Kenichi, Kido Shinsuke, Inoue Daisuke, Moriyama Keiji, Hashimoto Toshihiro, Ozaki Shuji, Matsumoto Toshio
Department of Medicine and Bioregulatory Sciences, University of Tokushima Graduate School of Medical Sciences, and Division of Transfusion Medicine, Tokushima University Hospital, Japan.
Clin Cancer Res. 2007 Feb 1;13(3):816-23. doi: 10.1158/1078-0432.CCR-06-2258.
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.
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.
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.
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.
与破骨细胞生成相似，骨髓瘤患者骨髓中的血管生成会随着肿瘤进展而增强。我们之前的研究表明，骨髓瘤细胞与破骨细胞相互刺激，形成恶性循环，导致破骨细胞生成和肿瘤生长均增强。本研究旨在阐明骨髓瘤细胞与破骨细胞的相互作用是否会增强血管生成，以及破骨细胞生成与血管生成之间是否存在相互刺激作用。
将骨髓瘤细胞与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以及人脐静脉血管内皮细胞（HUVEC）迁移和存活情况来评估共培养物产生的血管生成活性。通过兔骨细胞在牙本质切片上的培养来测定破骨细胞生成活性。
骨髓瘤细胞和破骨细胞分别组成性分泌促血管生成因子血管内皮生长因子（VEGF）和骨桥蛋白。骨髓瘤细胞与破骨细胞之间的细胞间相互作用有力地增强了血管小管形成。同时阻断VEGF和骨桥蛋白的作用几乎完全消除了这种血管小管形成以及骨髓瘤细胞与破骨细胞共培养条件培养基所增强的HUVEC迁移和存活。此外，这些因子共同触发了HUVEC产生破骨细胞生成活性。
破骨细胞来源的骨桥蛋白和骨髓瘤细胞来源的VEGF协同增强血管生成，并且还诱导血管内皮细胞产生破骨细胞生成活性。这些观察结果表明骨髓瘤细胞、破骨细胞和血管内皮细胞之间存在紧密联系，在骨破坏、血管生成和骨髓瘤扩展之间形成恶性循环。
