Genentech Inc, South San Francisco, CA 94080, USA.
Proc Natl Acad Sci U S A. 2010 Dec 14;107(50):21248-55. doi: 10.1073/pnas.1015855107. Epub 2010 Nov 16.
Priming of the organ-specific premetastatic sites is thought to be an important yet incompletely understood step during metastasis. In this study, we show that the metastatic tumors we examined overexpress granulocyte-colony stimulating factor (G-CSF), which expands and mobilizes Ly6G+Ly6C+ granulocytes and facilitates their subsequent homing at distant organs even before the arrival of tumor cells. Moreover, G-CSF-mobilized Ly6G+Ly6C+ cells produce the Bv8 protein, which has been implicated in angiogenesis and mobilization of myeloid cells. Anti-G-CSF or anti-Bv8 antibodies significantly reduced lung metastasis. Transplantation of Bv8 null fetal liver cells into lethally irradiated hosts also reduced metastasis. We identified an unexpected role for Bv8: the ability to stimulate tumor cell migration through activation of one of the Bv8 receptors, prokineticin receptor (PKR)-1. Finally, we show that administration of recombinant G-CSF is sufficient to increase the numbers of Ly6G+Ly6C+ cells in organ-specific metastatic sites and results in enhanced metastatic ability of several tumors.
器官特异性前转移部位的预激活被认为是转移过程中一个重要但尚未完全理解的步骤。在这项研究中，我们表明，我们检查的转移性肿瘤过度表达粒细胞集落刺激因子 (G-CSF)，G-CSF 扩增和动员 Ly6G+Ly6C+粒细胞，并促进它们随后在肿瘤细胞到达之前向远处器官归巢。此外，G-CSF 动员的 Ly6G+Ly6C+细胞产生 Bv8 蛋白，该蛋白已被牵涉到血管生成和髓样细胞动员中。抗 G-CSF 或抗 Bv8 抗体显著减少了肺转移。将 Bv8 缺失的胎肝细胞移植到致死性辐射的宿主中也减少了转移。我们发现了 Bv8 的一个意外作用：通过激活 Bv8 受体之一，促动力蛋白受体 (PKR)-1，刺激肿瘤细胞迁移的能力。最后，我们表明，给予重组 G-CSF 足以增加器官特异性转移性部位的 Ly6G+Ly6C+细胞数量，并增强几种肿瘤的转移能力。
