Loss of Cell-Surface Laminin Anchoring Promotes Tumor Growth and Is Associated with Poor Clinical Outcomes

被引:57
作者
Akhavan, Armin [4 ]
Griffith, Obi L. [5 ]
Soroceanu, Liliana [4 ]
Leonoudakis, Dmitri [4 ]
Luciani-Torres, Maria Gloria [4 ]
Daemen, Anneleen [5 ]
Gray, Joe W. [1 ,2 ,3 ,5 ]
Muschler, John L. [1 ,4 ]
机构
[1] Oregon Hlth & Sci Univ, Dept Biomed Engn, Portland, OR 97239 USA
[2] Oregon Hlth & Sci Univ, Ctr Spatial Syst Biomed, Portland, OR 97239 USA
[3] Oregon Hlth & Sci Univ, Knight Canc Inst, Portland, OR 97239 USA
[4] Calif Pacific Med Ctr, Res Inst, San Francisco, CA USA
[5] Univ Calif Berkeley, Lawrence Berkeley Natl Lab, Life Sci Div, Berkeley, CA 94720 USA
基金
加拿大健康研究院;
关键词
BREAST EPITHELIAL-CELLS; GENE-EXPRESSION; CANCER PROGRESSION; DYSTROGLYCAN; DISEASE; CARCINOMA; ANGIOGENESIS; METASTASIS; PROFILES; POLARITY;
D O I
10.1158/0008-5472.CAN-11-3732
中图分类号
R73 [肿瘤学];
学科分类号
100214 [肿瘤学];
摘要
Perturbations in the composition and assembly of extracellular matrices (ECM) 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 in which 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. Cancer Res; 72(10); 2578-88. (C) 2012 AACR.
引用
收藏
页码:2578 / 2588
页数:11
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