Membrane-bound ICAM-1 contributes to the onset of proinvasive tumor stroma by controlling acto-myosin contractility in carcinoma-associated fibroblasts.
Membrane-bound ICAM-1 contributes to the onset of proinvasive tumor stroma by controlling acto-myosin contractility in carcinoma-associated fibroblasts.
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DOI：
10.18632/oncotarget.13610
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发表时间：
2017-01-03
期刊：
影响因子：
--
通讯作者：
Gaggioli C
中科院分区：
文献类型：
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作者：
Bonan S;Albrengues J;Grasset E;Kuzet SE;Nottet N;Bourget I;Bertero T;Mari B;Meneguzzi G;Gaggioli C
癌相关成纤维细胞的肌动蛋白收缩性导致肿瘤细胞外基质的组装。促炎细胞因子LIF通过调节肌球蛋白轻链2活性来调控癌症中成纤维细胞的活化。然而，到目前为止，LIF如何介导细胞骨架收缩仍然未知。通过在成纤维细胞中敲除liff依赖基因的表型筛选试验，我们发现糖蛋白ICAM-1是间质成纤维细胞前侵入性基质重塑的关键调节因子。我们证明膜结合的ICAM-1异构体是促进炎症依赖性细胞外基质收缩的必要和充分的，这有利于癌细胞的侵袭。事实上，ICAM-1介导间质成纤维细胞Src激酶下游肌动蛋白收缩性的产生。此外，肌动蛋白收缩性通过建立正反馈信号调节ICAM-1的表达。因此，靶向间质ICAM-1可能是对抗肿瘤细胞侵袭和传播的可能治疗手段。
Acto-myosin contractility in carcinoma-associated fibroblasts leads to assembly of the tumor extracellular matrix. The pro-inflammatory cytokine LIF governs fibroblast activation in cancer by regulating the myosin light chain 2 activity. So far, however, how LIF mediates cytoskeleton contractility remains unknown. Using phenotypic screening assays based on knock-down of LIF-dependent genes in fibroblasts, we identified the glycoprotein ICAM-1 as a crucial regulator of stroma fibroblast proinvasive matrix remodeling. We demonstrate that the membrane-bound ICAM-1 isoform is necessary and sufficient to promote inflammation-dependent extracellular matrix contraction, which favors cancer cell invasion. Indeed, ICAM-1 mediates generation of acto-myosin contractility downstream of the Src kinases in stromal fibroblasts. Moreover, acto-myosin contractility regulates ICAM-1 expression by establishing a positive feedback signaling. Thus, targeting stromal ICAM-1 might constitute a possible therapeutic mean to counteract tumor cell invasion and dissemination.