Vesalius Research Center (VRC), Vlaams Instituut voor Biotechnologie (VIB), Leuven, Belgium.
Blood. 2010 Mar 18;115(11):2264-73. doi: 10.1182/blood-2009-06-228684. Epub 2009 Nov 20.
The transforming and tumor growth-promoting properties of Axl, a member of the Tyro3, Axl, and Mer (TAM) family of receptor tyrosine kinases (TAMRs), are well recognized. In contrast, little is known about the role of the TAMR ligand growth arrest-specific gene 6 (Gas6) in tumor biology. By using Gas6-deficient (Gas6(-/-)) mice, we show that bone marrow-derived Gas6 promotes growth and metastasis in different experimental cancer models, including one resistant to vascular endothelial growth factor inhibitors. Mechanistic studies reveal that circulating leukocytes produce minimal Gas6. However, once infiltrated in the tumor, leukocytes up-regulate Gas6, which is mitogenic for tumor cells. Consistent herewith, impaired tumor growth in Gas6(-/-) mice is rescued by transplantation of wild-type bone marrow and, conversely, mimicked by transplantation of Gas6(-/-) bone marrow into wild-type hosts. These findings highlight a novel role for Gas6 in a positive amplification loop, whereby tumors promote their growth by educating infiltrating leukocytes to up-regulate the production of the mitogen Gas6. Hence, inhibition of Gas6 might offer novel opportunities for the treatment of cancer.
Axl 是 Tyro3、Axl 和 Mer（TAM）受体酪氨酸激酶家族（TAMRs）的成员，其转化和肿瘤促进生长的特性已得到广泛认可。相比之下，人们对 TAMR 配体生长停滞特异性基因 6（Gas6）在肿瘤生物学中的作用知之甚少。通过使用 Gas6 缺陷（Gas6(-/-)）小鼠，我们表明骨髓来源的 Gas6 促进了不同实验性癌症模型中的生长和转移，包括一种对血管内皮生长因子抑制剂有抗性的模型。机制研究表明，循环白细胞产生的 Gas6 很少。然而，一旦浸润到肿瘤中，白细胞就会上调 Gas6，这对肿瘤细胞具有有丝分裂作用。与此一致，Gas6(-/-) 小鼠中的肿瘤生长受损可通过移植野生型骨髓来挽救，反之亦然，即将 Gas6(-/-) 骨髓移植到野生型宿主中可模拟肿瘤生长受损。这些发现强调了 Gas6 在正放大环中的一个新作用，即肿瘤通过教育浸润的白细胞上调有丝分裂原 Gas6 的产生来促进自身生长。因此，抑制 Gas6 可能为癌症治疗提供新的机会。
