Mast cell-derived angiopoietin-1 plays a critical role in the growth of plasma cell tumors
Mast cell-derived angiopoietin-1 plays a critical role in the growth of plasma cell tumors
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DOI：
10.1172/jci200422089
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发表时间：
2004-11-01
影响因子：
15.9
通讯作者：
Tosato, G
中科院分区：
文献类型：
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作者：
Nakayama, T;Yao, L;Tosato, G
人类多发性骨髓瘤通常与肥大细胞浸润和新血管形成相关，这与疾病的严重程度直接相关，但这种关系的机制仍不清楚。在这里，我们报告说，原代小鼠肥大细胞表达血管生成素-1（Ang-1）和低水平的VEGF-A，但不Ang-2和2建立的小鼠浆细胞瘤细胞系表达高水平的VEGF-A，但很少或没有Ang-1或Ang-2。使用细胞外基质组分的体内血管生成测定显示肥大细胞和浆细胞瘤细胞一起促进由扩张的血管组成的显著的新血管形成，其通过VEGF-A和Ang-1的中和而被阻止，但通过VEGF-A或Ang-1的中和而仅部分减少。细胞外基质成分中的肥大细胞表达Ang-1，重组Ang-1与浆细胞瘤细胞一起促进细胞外基质新血管形成，类似于肥大细胞诱导的血管形成。移植试验表明，原代肥大细胞通过已建立的浆细胞瘤细胞系加速肿瘤生长，单独或与VEGF-A一起中和Ang-1可显著降低含肥大细胞的浆细胞瘤的生长。这些结果表明，肥大细胞衍生的Ang-1通过刺激新血管形成促进浆细胞瘤的生长，并提供进一步的证据支持炎症和肿瘤生长之间的因果关系。
Multiple myeloma in humans is frequently associated with mast cell infiltration and neovascularization, which correlate directly with disease severity, but the mechanisms underlying this relationship remain unclear. Here, we report that primary murine mast cells express angiopoietin-1 (Ang-1) and low levels of VEGF-A but not Ang-2 and that 2 established murine plasmacytoma cell lines express high levels of VEGF-A but little or no Ang-1 or Ang-2. An in vivo angiogenesis assay using extracellular matrix components shows that mast cells and plasmacytoma cells, together, promote marked neovascularization composed of dilated vessels, which is prevented by neutralization of VEGF-A and Ang-1 but is only partially reduced by neutralization of either VEGF-A or Ang-1. Mast cells within extracellular matrix components express Ang-1, and recombinant Ang-1 together with plasmacytoma cells promotes extracellular matrix neovascularization similar to that induced by mast cells. A transplantation assay shows that primary mast cells accelerate tumor growth by established plasmacytoma cell lines and that neutralization of Ang-1 alone or with VEGF-A reduces significantly the growth of plasmacytomas containing mast cells. These results demonstrate that mast cell-derived Ang-1 promotes the growth of plasmacytomas by stimulating neovascularization and provide further evidence supporting a causal relationship between inflammation and tumor growth.