Histopathology Unit, Cancer Research UK London Research Institute, UK.
J Pathol. 2010 Mar;220(4):435-45. doi: 10.1002/path.2660.
beta3-Integrin is a cell surface adhesion and signalling molecule important in the regulation of tumour angiogenesis. Mice with a global deficiency in beta3-integrin show increased pathological angiogenesis, most likely due to increased vascular endothelial growth factor receptor 2 expression on beta3-null endothelial cells. Here we transplanted beta3-null bone marrow (BM) into wild-type (WT) mice to dissect the role of BM beta3-integrin deficiency in pathological angiogenesis. Mice transplanted with beta3-null bone marrow show significantly enhanced angiogenesis in subcutaneous B16F0 melanoma and Lewis lung carcinoma (LLC) cell models and in B16F0 melanoma lung metastasis when compared with tumours grown in mice transplanted with WT bone marrow. The effect of bone marrow beta3-integrin deficiency was also assessed in the RIPTAg mouse model of pancreatic tumour growth. Again, angiogenesis in mice lacking BM beta3-integrin was enhanced. However, tumour weight between the groups was not significantly altered, suggesting that the enhanced blood vessel density in the mice transplanted with beta3-null bone marrow was not functional. Indeed, we demonstrate that in mice transplanted with beta3-null bone marrow a significant proportion of tumour blood vessels are non-functional when compared with tumour blood vessels in WT-transplanted controls. Furthermore, beta3-null-transplanted mice showed an increased angiogenic response to VEGF in vivo when compared with WT-transplanted animals. BM beta3-integrin deficiency affects the mobilization of progenitor cells to the peripheral circulation. We show that VEGF-induced mobilization of endothelial progenitor cells is enhanced in mice transplanted with beta3-null bone marrow when compared with WT-transplanted controls, suggesting a possible mechanism underlying the increased blood vessel density seen in beta3-null-transplanted mice. In conclusion, although BM beta3-integrin is not required for pathological angiogenesis, our studies demonstrate a role for BM beta3-integrin in VEGF-induced mobilization of bone marrow-derived cells to the peripheral circulation and for the functionality of those vessels in which BM-derived cells become incorporated.
β3 整合素是一种细胞表面黏附和信号分子，在肿瘤血管生成的调节中起着重要作用。β3 整合素全身性缺失的小鼠表现出病理性血管生成增加，这很可能是由于β3 缺失的内皮细胞中血管内皮生长因子受体 2 表达增加所致。在这里，我们将β3 缺失的骨髓（BM）移植到野生型（WT）小鼠中，以剖析 BMβ3 整合素缺失在病理性血管生成中的作用。与 WT 骨髓移植小鼠相比，移植β3 缺失的骨髓的小鼠在皮下 B16F0 黑色素瘤和 Lewis 肺癌（LLC）细胞模型以及 B16F0 黑色素瘤肺转移模型中表现出明显增强的血管生成。我们还在 RIPTAg 小鼠胰腺肿瘤生长模型中评估了骨髓β3 整合素缺失的作用。同样，缺乏 BMβ3 整合素的小鼠的血管生成也增强了。然而，两组之间的肿瘤重量没有明显改变，这表明移植β3 缺失的骨髓的小鼠中增强的血管密度没有功能。事实上，我们证明与 WT 移植对照组相比，移植β3 缺失的骨髓的小鼠中，相当一部分肿瘤血管是无功能的。此外，与 WT 移植动物相比，移植β3 缺失的骨髓的小鼠在体内对 VEGF 的血管生成反应增强。BMβ3 整合素缺失会影响祖细胞向外周循环的动员。我们表明，与 WT 移植对照组相比，VEGF 诱导的内皮祖细胞动员在移植β3 缺失的骨髓的小鼠中增强，这表明了在β3 缺失的骨髓移植小鼠中看到的增加的血管密度的一个可能机制。总之，尽管 BMβ3 整合素不是病理性血管生成所必需的，但我们的研究表明，BMβ3 整合素在 VEGF 诱导的骨髓源性细胞向外周循环的动员以及 BM 源性细胞进入的那些血管的功能中起作用。
