Quantitative In vivo Imaging of the Effects of Inhibiting Integrin Signaling via Src and FAK on Cancer Cell Movement: Effects on E-cadherin Dynamics

被引:109
作者
Canel, Marta [1 ]
Serrels, Alan [1 ]
Miller, Derek [2 ]
Timpson, Paul [2 ]
Serrels, Bryan [1 ]
Frame, Margaret C. [1 ]
Brunton, Valerie G. [1 ]
机构
[1] Univ Edinburgh, Edinburgh Canc Res Ctr, Inst Genet & Mol Med, Edinburgh EH4 2XR, Midlothian, Scotland
[2] Beatson Inst Canc Res, Glasgow G61 1BD, Lanark, Scotland
关键词
FOCAL ADHESION KINASE; CARCINOMA-CELLS; INVASION; MIGRATION; MOTILITY; BEHAVIOR; TARGETS;
D O I
10.1158/0008-5472.CAN-10-1454
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
Most cancer-related deaths are due to the development of metastatic disease, and several new molecularly targeted agents in clinical development have the potential to prevent disease progression. However, it remains difficult to assess the efficacy of antimetastatic agents in the clinical setting, and an increased understanding of how such agents work at different stages of the metastatic cascade is important in guiding their clinical use. We used optical window chambers combined with photobleaching, photoactivation, and photoswitching to quantitatively measure (a) tumor cell movement and proliferation by tracking small groups of cells in the context of the whole tumor, and (b) E-cadherin molecular dynamics in vivo following perturbation of integrin signaling by inhibiting focal adhesion kinase (FAK) and Src. We show that inhibition of Src and FAK suppresses E-cadherin-dependent collective cell movement in a complex three-dimensional tumor environment, and modulates cell-cell adhesion strength and endocytosis in vitro. This shows a novel role for integrin signaling in the regulation of E-cadherin internalization, which is linked to regulation of collective cancer cell movement. This work highlights the power of fluorescent, direct, in vivo imaging approaches in the preclinical evaluation of chemotherapeutic agents, and shows that inhibition of the Src/FAK signaling axis may provide a strategy to prevent tumor cell spread by deregulating E-cadherin-mediated cell-cell adhesions. Cancer Res; 70(22); 9413-22. (C) 2010 AACR.
引用
收藏
页码:9413 / 9422
页数:10
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