Macrophage-Secreted TNFα and TGFβ1 Influence Migration Speed and Persistence of Cancer Cells in 3D Tissue Culture via Independent Pathways

被引：75

作者：

Li, Ran ^{[1
]}

Hebert, Jess D. ^{[2
,3
]}

Lee, Tara A. ^{[1
]}

Xing, Hao ^{[1
]}

Boussommier-Calleja, Alexandra ^{[4
]}

Hynes, Richard O. ^{[2
,3
,5
]}

Lauffenburger, Douglas A. ^{[1
,3
]}

Kamm, Roger D. ^{[1
,4
]}

机构：

[1] MIT, Dept Biol Engn, 77 Massachusetts Ave, Cambridge, MA 02139 USA

[2] MIT, Dept Biol, Cambridge, MA USA

[3] MIT, Koch Inst Integrat Canc Res, 77 Massachusetts Ave, Cambridge, MA 02139 USA

[4] MIT, Dept Mech Engn, 77 Massachusetts Ave, Cambridge, MA 02139 USA

[5] MIT, Ctr Canc Res, Howard Hughes Med Inst, Cambridge, MA 02139 USA

来源：

CANCER RESEARCH | 2017年 / 77卷 / 02期

关键词：

TUMOR-ASSOCIATED MACROPHAGES; BREAST-CARCINOMA CELLS; MATRIX METALLOPROTEINASES; GENE-EXPRESSION; GROWTH; IDENTIFICATION; POLARIZATION; PROGRESSION; INVASION; PROMOTE;

D O I：

10.1158/0008-5472.CAN-16-0442

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

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 TNF alpha and TGF beta 1 mediated the observed behaviors by two distinct pathways. These factors synergistically enhanced migration persistence through a synergistic induction of NF-kappa B-dependent MMP1 expression in cancer cells. In contrast, macrophagereleased TGF beta 1 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 TNF alpha and TGF beta 1 dual blockade as an antimetastatic strategy in solid tumors. (C) 2016 AACR.

引用

页码：279 / 290

页数：12

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