Hypoxic stellate cells of pancreatic cancer stroma regulate extracellular matrix fiber organization and cancer cell motility
Hypoxic stellate cells of pancreatic cancer stroma regulate extracellular matrix fiber organization and cancer cell motility
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DOI：
10.1016/j.canlet.2016.01.016
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发表时间：
2016-03-28
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：
Sada, Masafumi;Ohuchida, Kenoki;Nakamura, Masafumi
胰腺癌中的结缔组织增生和缺氧相互影响，并创造了一个支持肿瘤的微环境。在这里，我们表明，缺氧胰腺星状细胞（PSC）的微环境重塑促进癌细胞的运动，通过改变细胞外基质（ECM）纤维结构。与常氧下PSC衍生的3-D基质相比，低氧下PSC衍生的3-D基质表现出高度组织化的平行图案化基质纤维，并且由于平行纤维结构通过诱导癌细胞的定向迁移来促进癌细胞运动。微阵列分析显示，PSC中的前胶原-赖氨酸，2-酮戊二酸5-双加氧酶2（PLOD 2）是在缺氧下潜在地调节ECM纤维结构的基因。间质PLOD 2的表达在胰腺癌的手术标本证实了免疫组织化学。RNA干扰介导的PSC中PLOD 2的敲低阻断了3-D基质的平行纤维结构，导致基质内癌细胞的定向迁移减少。总之，这些发现表明，低氧诱导的PLOD 2在PSC中的表达通过胰腺癌中基质ECM的结构调节为癌细胞的迁移创造了允许的微环境。(C)2016爱思唯尔爱尔兰有限公司版权所有。
Desmoplasia and hypoxia in pancreatic cancer mutually affect each other and create a tumor-supportive microenvironment. Here, we show that microenvironment remodeling by hypoxic pancreatic stellate cells (PSCs) promotes cancer cell motility through alteration of extracellular matrix (ECM) fiber architecture. Three-dimensional (3-D) matrices derived from PSCs under hypoxia exhibited highly organized parallel patterned matrix fibers compared with 3-D matrices derived from PSCs under normoxia, and promoted cancer cell motility by inducing directional migration of cancer cells due to the parallel fiber architecture. Microarray analysis revealed that procollagen-lysine, 2-oxoglutarate 5-dioxygenase 2 (PLOD2) in PSCs was the gene that potentially regulates ECM fiber architecture under hypoxia. Stromal PLOD2 expression in surgical specimens of pancreatic cancer was confirmed by immunohistochemistry. RNA interference-mediated knockdown of PLOD2 in PSCs blocked parallel fiber architecture of 3-D matrices, leading to decreased directional migration of cancer cells within the matrices. In conclusion, these findings indicate that hypoxia-induced PLOD2 expression in PSCs creates a permissive microenvironment for migration of cancer cells through architectural regulation of stromal ECM in pancreatic cancer. (C) 2016 Elsevier Ireland Ltd. All rights reserved.