Differential impact of TGF-β and EGF on fibroblast differentiation and invasion reciprocally promotes colon cancer cell invasion

被引：79

作者：

Denys, Hannelore ^{[2
]}

Derycke, Lara ^{[1
]}

Hendrix, An ^{[2
]}

Westbroek, Wendy ^{[5
]}

Gheldof, Alexander ^{[1
]}

Narine, Kishan ^{[3
]}

Pauwels, Patrick ^{[4
]}

Gespach, Christian ^{[6
,7
]}

Bracke, Marc ^{[1
]}

De Wever, Olivier ^{[1
]}

机构：

[1] Ghent Univ Hosp, Dept Radiol & Nucl Med, Lab Expt Canc Res, B-9000 Ghent, Belgium

[2] Ghent Univ Hosp, Dept Med Oncol, B-9000 Ghent, Belgium

[3] Ghent Univ Hosp, Dept Cardiac Surg, B-9000 Ghent, Belgium

[4] Ghent Univ Hosp, Dept Pathol, B-9000 Ghent, Belgium

[5] NHGRI, NIH, Bethesda, MD 20892 USA

[6] INSERM, U673, Paris, France

[7] Univ Paris 06, Fac Med, Lab Mol & Clin Oncol Solid Tumors, F-755071 Paris 12, France

来源：

CANCER LETTERS | 2008年 / 266卷 / 02期

基金：

澳大利亚研究理事会;

关键词：

bFGF; Rho-GTPases; heterotypic co-cultures; tenascin-C; spheroid; stress fibers;

D O I：

10.1016/j.canlet.2008.02.068

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

Several studies indicate that cancer-associated fibroblasts play a critical role in cancer cell invasion and metastasis, the hallmarks of malignancy. To better understand the mechanisms underlying such effects, we established a heterotypic model of human fibroblasts (primary colon fibroblasts and immortalized human dermal fibroblasts) in co-culture with human colon cancer cells (HCT-8/E11), using three-dimensional collagen type-1 and Matrigel matrices. We report that TGF-beta is the unique and dominant factor to provide pro-invasive signals to HCT-S/E11 colon cancer cells from TGF-beta-treated human fibroblasts in three-dimensional collagen type I and Matrigel matrices. These effects are not mimicked or reversed by EGF or bFGF, and are associated with the TGF-beta-mediated induction of myofibroblast differentiation and functional markers, such as alpha-SMA, the haptotactic matrix molecule TNC, collagen type 1 maturation enzyme P4H, serine protease FAP, and myofibroblast contractility. Accordingly, TGF-beta induced a strong activation of RhoA and stress fiber formation in fibroblasts, with no impact on Rac1-GTP levels. In contrast, EGF down-regulated Rho-GTP levels in fibroblasts, giving permissive signals for Rac1 activation, fibroblast polarization, and invasion. Taken together, our data imply that TGF-beta and EGF exert invasive growth-promoting actions in human colon tumors through a differential and cumulative impact on the stromal and cancer cell compartments. Our data predict that inhibitors directed at this reciprocal molecular and cellular crosstalk will have therapeutic applications for targeting the invasive growth of human primary tumors and their metastatic spread. (C) 2008 Elsevier Ireland Ltd. All rights reserved.

引用

页码：263 / 274

页数：12

共 32 条

[31] Migration of tumor cells in 3D matrices is governed by matrix stiffness along with cell-matrix adhesion and proteolysis [J].