Basement membrane destruction by pancreatic stellate cells leads to local invasion in pancreatic ductal adenocarcinoma
Basement membrane destruction by pancreatic stellate cells leads to local invasion in pancreatic ductal adenocarcinoma
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DOI：
10.1016/j.canlet.2018.03.031
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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
间质浸润是胰腺癌进展的重要步骤。然而，具有导管结构的胰腺导管腺癌（PDAC）如何侵入周围间质尚不清楚。在这里，我们阐明了PDAC的基质入侵的机制，使用类器官。从切除的PDAC标本中，我们建立了人类PDAC类器官，其发育了导管和基底膜（BM）结构。当类器官与胶原基质中的胰腺星状细胞（PSC）共培养时，类器官失去了它们的BM和导管结构，并且比单培养的类器官更频繁地侵入胶原基质。有趣的是，在BM破坏之前观察到PSC与PDAC类器官的直接接触，PSC中的基质金属蛋白酶（MMP）2或膜1型MMP（MT1MMP）敲低显著减弱了PSC对BM的破坏，并保留了类器官中的导管结构。我们的研究结果表明，PSC的直接接触诱导骨髓破坏和基质浸润的PDAC通过MMP 2结合到PSC上的MT1 MMP。(C)2018爱思唯尔B.V.保留所有权利。
Stroma invasion is an important step in pancreatic cancer progression. However, how pancreatic ductal adenocarcinoma (PDAC) with ductal structure invades the surrounding stroma has not been clear. Here, we elucidated the mechanism of stromal invasion of PDAC, using organoids. From resected PDAC specimens, we established human PDAC organoids, which developed ductal and basement membrane (BM) structures. When the organoids were co-cultured with pancreatic stellate cells (PSCs) in a collagen matrix, organoids lost their BM and ductal structures, and invaded collagen matrix more frequently than did mono-cultured organoids. interestingly, direct contact by PSCs to PDAC organoids was observed before BM destruction, Matrix metalloproteinase (MMP) 2 or membrane type-1 MMP (MT1MMP) knockdown in PSCs significantly attenuated BM destruction by PSCs, and retained the ductal structures in organoids. Our results imply that direct contact by PSCs induces BM destruction and stromal invasion of PDAC via MMP2 which binds to MT1MMP on PSCs. (C) 2018 Elsevier B.V. All rights reserved.