Shojaei Farbod, Wu Xiumin, Zhong Cuiling, Yu Lanlan, Liang Xiao-Huan, Yao Jenny, Blanchard Dominique, Bais Carlos, Peale Franklin V, van Bruggen Nicholas, Ho Calvin, Ross Jed, Tan Martha, Carano Richard A D, Meng Y Gloria, Ferrara Napoleone
Genentech Inc., 1 DNA Way, South San Francisco, California 94080, USA.
Nature. 2007 Dec 6;450(7171):825-31. doi: 10.1038/nature06348.
Bone-marrow-derived cells facilitate tumour angiogenesis, but the molecular mechanisms of this facilitation are incompletely understood. We have previously shown that the related EG-VEGF and Bv8 proteins, also known as prokineticin 1 (Prok1) and prokineticin 2 (Prok2), promote both tissue-specific angiogenesis and haematopoietic cell mobilization. Unlike EG-VEGF, Bv8 is expressed in the bone marrow. Here we show that implantation of tumour cells in mice resulted in upregulation of Bv8 in CD11b+Gr1+ myeloid cells. We identified granulocyte colony-stimulating factor as a major positive regulator of Bv8 expression. Anti-Bv8 antibodies reduced CD11b+Gr1+ cell mobilization elicited by granulocyte colony-stimulating factor. Adenoviral delivery of Bv8 into tumours was shown to promote angiogenesis. Anti-Bv8 antibodies inhibited growth of several tumours in mice and suppressed angiogenesis. Anti-Bv8 treatment also reduced CD11b+Gr1+ cells, both in peripheral blood and in tumours. The effects of anti-Bv8 antibodies were additive to those of anti-Vegf antibodies or cytotoxic chemotherapy. Thus, Bv8 modulates mobilization of CD11b+Gr1+ cells from the bone marrow during tumour development and also promotes angiogenesis locally.
骨髓来源的细胞促进肿瘤血管生成，但其促进机制尚未完全明确。我们之前已经表明，相关的内皮生长因子（EG-VEGF）和Bv8蛋白，也被称为促胃动素1（Prok1）和促胃动素2（Prok2），既能促进组织特异性血管生成，又能促进造血细胞动员。与EG-VEGF不同，Bv8在骨髓中表达。在此我们表明，将肿瘤细胞植入小鼠体内会导致CD11b+Gr1+髓样细胞中Bv8上调。我们确定粒细胞集落刺激因子是Bv8表达的主要正调控因子。抗Bv8抗体可减少粒细胞集落刺激因子引起的CD11b+Gr1+细胞动员。将Bv8通过腺病毒载体导入肿瘤可促进血管生成。抗Bv8抗体可抑制小鼠体内多种肿瘤的生长并抑制血管生成。抗Bv8治疗还可减少外周血和肿瘤中的CD11b+Gr1+细胞。抗Bv8抗体的作用与抗Vegf抗体或细胞毒性化疗的作用具有相加性。因此，Bv8在肿瘤发生发展过程中调节CD11b+Gr1+细胞从骨髓中的动员，并在局部促进血管生成。
