Loss of cell-surface laminin anchoring promotes tumor growth and is associated with poor clinical outcomes.
Loss of cell-surface laminin anchoring promotes tumor growth and is associated with poor clinical outcomes.
复制标题
细胞表面层粘连蛋白锚定的丧失会促进肿瘤生长，并与不良的临床结果相关。
DOI：
10.1158/0008-5472.can-11-3732
复制
发表时间：
2012-05-15
期刊：
影响因子：
11.2
通讯作者：
Muschler JL
中科院分区：
文献类型：
--
作者：
Akhavan A;Griffith OL;Soroceanu L;Leonoudakis D;Luciani-Torres MG;Daemen A;Gray JW;Muschler JL
细胞外基质（ecm）的组成和组装的扰动有助于包括癌症在内的许多疾病的进展。层粘连蛋白在细胞表面的锚定使许多ecm的组装和信号传导成为可能，但改变的层粘连蛋白锚定对癌症进展的可能贡献仍不确定。在这项研究中，我们研究了有缺陷的层粘连蛋白锚定在癌细胞中的重要性和起源，以及它与癌症亚型和临床结果的关系。我们发现层粘连蛋白锚定的缺失在癌细胞中广泛存在。层粘连蛋白锚定的扰动源于几个不同的缺陷，这些缺陷都导致ECM受体糖基化功能失调。在侵袭性乳腺癌和脑癌中，层粘连蛋白锚定缺陷通常是由于糖基转移酶LARGE的表达抑制所致。LARGE的表达降低是广泛的人类肿瘤的特征，它与侵袭性癌症亚型和不良临床结果相关。值得注意的是，这一缺陷有力地预测了脑癌患者的低生存率。恢复LARGE表达修复外源性和内源性层粘连蛋白的锚定，并调节细胞增殖和肿瘤生长。总之，我们的研究结果表明，层粘连蛋白锚定缺陷通常发生在癌细胞中，是侵袭性癌症亚型的特征，并且是疾病进展的重要驱动因素。
Perturbations in the composition and assembly of extracellular matrices (ECMs) contribute to progression of numerous diseases, including cancers. Anchoring of laminins at the cell surface enables assembly and signaling of many ECMs, but the possible contributions of altered laminin anchoring to cancer progression remain undetermined. In this study, we investigated the prominence and origins of defective laminin anchoring in cancer cells and its association with cancer subtypes and clinical outcomes. We found loss of laminin anchoring to be widespread in cancer cells. Perturbation of laminin anchoring originated from several distinct defects which all led to dysfunctional glycosylation of the ECM receptor dystroglycan. In aggressive breast and brain cancers, defective laminin anchoring was often due to suppressed expression of the glycosyltransferase LARGE. Reduced expression of LARGE characterized a broad array of human tumors where it was associated with aggressive cancer subtypes and poor clinical outcomes. Notably, this defect robustly predicted poor survival in patients with brain cancers. Restoring LARGE expression repaired anchoring of exogenous and endogenous laminin and modulated cell proliferation and tumor growth. Together, our findings suggest that defects in laminin anchoring occur commonly in cancer cells, are characteristic of aggressive cancer subtypes, and are important drivers of disease progression.