Li Ran, Hebert Jess D, Lee Tara A, Xing Hao, Boussommier-Calleja Alexandra, Hynes Richard O, Lauffenburger Douglas A, Kamm Roger D
Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts.
Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts.
Cancer Res. 2017 Jan 15;77(2):279-290. doi: 10.1158/0008-5472.CAN-16-0442. Epub 2016 Nov 21.
The ability of a cancer cell to migrate through the dense extracellular matrix within and surrounding the solid tumor is a critical determinant of metastasis. Macrophages enhance invasion and metastasis in the tumor microenvironment, but the basis for their effects is not fully understood. Using a microfluidic 3D cell migration assay, we found that the presence of macrophages enhanced the speed and persistence of cancer cell migration through a 3D extracellular matrix in a matrix metalloproteinases (MMP)-dependent fashion. Mechanistic investigations revealed that macrophage-released TNFα and TGFβ1 mediated the observed behaviors by two distinct pathways. These factors synergistically enhanced migration persistence through a synergistic induction of NF-κB-dependent MMP1 expression in cancer cells. In contrast, macrophage-released TGFβ1 enhanced migration speed primarily by inducing MT1-MMP expression. Taken together, our results reveal new insights into how macrophages enhance cancer cell metastasis, and they identify TNFα and TGFβ1 dual blockade as an antimetastatic strategy in solid tumors. Cancer Res; 77(2); 279-90. ©2016 AACR.
癌细胞穿过实体瘤内部及周围致密细胞外基质的迁移能力是转移的关键决定因素。巨噬细胞在肿瘤微环境中增强侵袭和转移，但它们发挥作用的基础尚未完全明确。通过微流控3D细胞迁移试验，我们发现巨噬细胞的存在以基质金属蛋白酶（MMP）依赖的方式提高了癌细胞在三维细胞外基质中的迁移速度和持续性。机制研究表明，巨噬细胞释放的TNFα和TGFβ1通过两条不同途径介导了所观察到的行为。这些因子通过协同诱导癌细胞中NF-κB依赖的MMP1表达，协同增强迁移持续性。相比之下，巨噬细胞释放的TGFβ1主要通过诱导MT1-MMP表达来提高迁移速度。综上所述，我们的结果揭示了巨噬细胞如何增强癌细胞转移的新见解，并确定TNFα和TGFβ1双重阻断作为实体瘤中的一种抗转移策略。《癌症研究》；77(2)；279 - 90。©2016美国癌症研究协会。
