Pancreatic stellate cells reorganize matrix components and lead pancreatic cancer invasion via the function of Endo180
Pancreatic stellate cells reorganize matrix components and lead pancreatic cancer invasion via the function of Endo180
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DOI：
10.1016/j.canlet.2017.10.010
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发表时间：
2018-01-01
期刊：
影响因子：
9.7
通讯作者：
Nakamura, Masafumi
中科院分区：
文献类型：
--
作者：
Koikawa, Kazuhiro;Ohuchida, Kenoki;Nakamura, Masafumi
引导癌症局部侵袭的特定细胞群被称为“引导细胞”。然而，其潜在机制尚不清楚。在这里，我们确定了胰腺癌中的主导细胞，并确定了这些细胞如何导致和促进癌细胞在细胞外基质（ECM）中的侵袭。利用三维基质重塑实验，我们发现胰腺星状细胞（PSCs）经常与胰腺癌细胞（PCCs）一起侵入胶原基质，而PCCs则在侵入的PSCs后面侵入。此外，侵入的PSC改变了胶原纤维的排列，导致ECM重塑和沿侵入PSC方向的平行纤维沿着增加。PSCs中Endo180的表达高于PCCs，PSCs中Endo180的敲低可减弱PSCs和PCCs的侵袭能力，并降低磷酸化肌球蛋白轻链2（MLC2）的表达水平。在小鼠模型中，Endo180敲低的PSC抑制了与PCCs共移植的肿瘤生长和胶原纤维取向的变化。我们的研究结果表明，PSC通过物理重塑ECM（可能是通过Endo 180的功能）来引导PCC的局部侵袭，Endo 180通过MLC2的磷酸化来重建肌动蛋白细胞骨架。(C)2017爱思唯尔B.V.保留所有权利。
Specific cell populations leading the local invasion of cancer are called "leading cells". However, the underlying mechanisms are unclear. Here, we identified leading cells in pancreatic cancer and determined how these cells lead and promote cancer cell invasion in the extracellular matrix (ECM). Using three-dimensional matrix remodeling assay, we found that pancreatic stellate cells (PSCs) frequently invaded the collagen matrix with pancreatic cancer cells (PCCs), which invaded behind the invading PSCs. In addition, invading PSCs changed the alignment of collagen fibers, resulting in ECM remodeling and an increase in the parallel fibers along the direction of invading PSCs. Endo180 expression was higher in PSCs than in PCCs, Endo180 knockdown in PSCs attenuated the invasive abilities of PSCs and co-cultured PCCs, and decreased the expression level of phosphorylated myosin light chain 2 (MLC2). In mouse models, Endo180-knockdown PSCs suppressed tumor growth and changes in collagen fiber orientation in co-transplantation with PCCs. Our findings suggest that PSCs lead the local invasion of PCCs by physically remodeling the ECM, possibly via the function of Endo180, which reconstructs the actin cell skeleton by phosphorylation of MLC2. (C) 2017 Elsevier B.V. All rights reserved.