Tumor Cell Invasion Can Be Blocked by Modulators of Collagen Fibril Alignment That Control Assembly of the Extracellular Matrix
Tumor Cell Invasion Can Be Blocked by Modulators of Collagen Fibril Alignment That Control Assembly of the Extracellular Matrix
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DOI：
10.1158/0008-5472.can-15-2813
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发表时间：
2016-07-15
期刊：
影响因子：
11.2
通讯作者：
Sagi, Irit
中科院分区：
文献类型：
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作者：
Grossman, Moran;Ben-Chetrit, Nir;Sagi, Irit
细胞外基质（ECM）中胶原纤维结构异常是包括癌症在内的许多侵袭性疾病的标志。针对体内胶原组装的特定阶段提出了一个巨大的挑战，因为在ECM构建的多步骤、分层过程中涉及各种交联酶。使用先进的显微镜工具，我们监测了原纤维胶原在天然成纤维细胞衍生的3D基质系统中的组装阶段，并鉴定了抗赖氨酸氧化酶样2 （LOXL2）抗体，这些抗体改变了内源性原纤维胶原的自然排列和宽度，而不影响ECM的组成。被破坏的胶原形态干扰了人类乳腺癌细胞的粘附和侵袭特性。用抑制性抗体治疗携带乳腺癌异种移植物的小鼠，导致致瘤性胶原蛋白上层结构的破坏，并减少原发肿瘤的生长。我们的方法可以作为一种通用的方法来确定针对纤维蛋白组织的新疗法来治疗ecm相关的病理。AACR (C) 2016人。
Abnormal architectures of collagen fibers in the extracellular matrix (ECM) are hallmarks of many invasive diseases, including cancer. Targeting specific stages of collagen assembly in vivo presents a great challenge due to the involvement of various crosslinking enzymes in the multistep, hierarchical process of ECM build-up. Using advanced microscopic tools, we monitored stages of fibrillary collagen assembly in a native fibroblast-derived 3D matrix system and identified anti-lysyl oxidase-like 2 (LOXL2) antibodies that alter the natural alignment and width of endo-genic fibrillary collagens without affecting ECM composition. The disrupted collagen morphologies interfered with the adhesion and invasion properties of human breast cancer cells. Treatment of mice bearing breast cancer xenografts with the inhibitory antibodies resulted in disruption of the tumorigenic collagen superstructure and in reduction of primary tumor growth. Our approach could serve as a general methodology to identify novel therapeutics targeting fibrillary protein organization to treat ECM-associated pathologies. (C)2016 AACR.