Lysyl oxidase enzymatic function increases stiffness to drive colorectal cancer progression through FAK
Lysyl oxidase enzymatic function increases stiffness to drive colorectal cancer progression through FAK
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DOI：
10.1038/onc.2012.202
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发表时间：
2013-04-01
期刊：
影响因子：
8
通讯作者：
Erler, J. T.
中科院分区：
文献类型：
--
作者：
Baker, A-M;Bird, D.;Erler, J. T.
最近，细胞外基质修饰酶赖氨酰氧化酶 (LOX) 与结直肠癌 (CRC) 进展有关，特别是与侵袭和转移阶段有关。在本报告中，我们使用表达 LOX 催化失活突变体形式的细胞系来表明，在 CRC 体外和体内模型中，LOX 介导的增殖和侵袭作用需要催化活性。此外，我们使用流变学来测量改性胶原基质和皮下肿瘤的相对刚度，并表明 LOX 诱导的胶原交联导致基质在体外和体内变硬。我们观察到基质硬度与 FAK（粘着斑激酶）/SRC 信号通路激活之间存在很强的相关性，较硬的环境会导致 FAK/SRC 磷酸化增加以及更具增殖性和侵袭性的表型。我们首次证明了 LOX 酶活性与组织硬度之间的直接关系，并证明了硬度在驱动 CRC 进展中的作用。我们的研究结果提供了重要的证据表明，治疗性抑制 LOX 活性可能为转移性 CRC 患者提供一种新的有效治疗选择。癌基因 (2013) 32, 1863-1868; doi：10.1038/onc.2012.202； 2012 年 5 月 28 日在线发布
The extracellular, matrix-modifying enzyme lysyl oxidase (LOX) has recently been linked to colorectal cancer (CRC) progression, in particular to the stages of invasion and metastasis. In this report, we use cell lines expressing a catalytically inactive mutant form of LOX to show that catalytic activity is required for LOX-mediated effects on proliferation and invasion in both in vitro and in vivo models of CRC. Furthermore, we use rheology to measure the relative stiffness of modified collagen matrices and subcutaneous tumors, and show that LOX-induced collagen cross-linking results in stiffening of the matrix both in vitro and in vivo. We observe a strong association between matrix stiffness and activation of the FAK (focal adhesion kinase)/SRC-signaling pathway, with a stiffer environment resulting in increased FAK/SRC phosphorylation and a more proliferative and invasive phenotype. We are the first to show a direct relationship between LOX enzymatic activity and tissue stiffness, and to demonstrate a role for stiffness in driving CRC progression. Our findings provide significant evidence to suggest that therapeutic inhibition of LOX activity may provide a novel effective treatment option for patients with metastatic CRC. Oncogene (2013) 32, 1863-1868; doi: 10.1038/onc.2012.202; published online 28 May 2012