Pancreatic stellate cells derived from human pancreatic cancer demonstrate aberrant SPARC-dependent ECM remodeling in 3D engineered fibrotic tissue of clinically relevant thickness
Pancreatic stellate cells derived from human pancreatic cancer demonstrate aberrant SPARC-dependent ECM remodeling in 3D engineered fibrotic tissue of clinically relevant thickness
复制标题
源自人类胰腺癌的胰腺星状细胞在临床相关厚度的 3D 工程纤维化组织中表现出异常的 SPARC 依赖性 ECM 重塑
DOI：
10.1016/j.biomaterials.2018.11.023
复制
发表时间：
2019
期刊：
影响因子：
14
通讯作者：
Kano Mitsunobu R.
中科院分区：
文献类型：
--
作者：
Tanaka Hiroyoshi Y.;Kitahara Kentaro;Sasaki Naoki;Nakao Natsumi;Sato Kae;Narita Hirokazu;Shimoda Hiroshi;Matsusaki Michiya;Nishihara Hiroshi;Masamune Atsushi;Kano Mitsunobu R.
结缔组织形成是胰腺癌的一个标志，由纤维化细胞和分泌的细胞外基质 (ECM) 成分组成。各种体外三维（3D）结缔组织模型已被报道，但人们对工程纤维化组织的相关厚度知之甚少。因此，我们测量了人类胰腺癌中纤维化组织的厚度，定义为血管壁到肿瘤细胞的距离。然后，我们使用胰腺星状细胞（PSC）（胰腺癌结缔组织增生的主要细胞成分）生成了厚度达到临床观察范围的 3D 纤维化模型。使用该模型，我们发现胶原纤维沉积增加，纤连蛋白原纤维方向被 PSC（而非正常成纤维细胞）彻底重塑，其方式依赖于转化生长因子 (TGF)-β/Rho 相关激酶 (ROCK) 信号传导和基质金属蛋白酶 (MMP) 活性。最后，通过siRNA靶向富含半胱氨酸的酸性分泌蛋白(SPARC)，我们发现PSCs中SPARC的表达对于ECM重塑是必要的。总之，我们开发了具有临床相关厚度的胰腺癌 3D 纤维化模型，并观察到癌症来源的 PSC 中异常的 SPARC 依赖性 ECM 重塑。
Desmoplasia is a hallmark of pancreatic cancer and consists of fibrotic cells and secreted extracellular matrix (ECM) components. Variousin vitrothree-dimensional (3D) models of desmoplasia have been reported, but little is known about the relevant thickness of the engineered fibrotic tissue. We thus measured the thickness of fibrotic tissue in human pancreatic cancer, as defined by the distance from the blood vessel wall to tumor cells. We then generated a 3D fibrosis model with a thickness reaching the clinically observed range using pancreatic stellate cells (PSCs), the main cellular constituent of pancreatic cancer desmoplasia. Using this model, we found that Collagen fiber deposition was increased and Fibronectin fibril orientation drastically remodeled by PSCs, but not normal fibroblasts, in a manner dependent on Transforming Growth Factor (TGF)-β/Rho-Associated Kinase (ROCK) signaling and Matrix Metalloproteinase (MMP) activity. Finally, by targeting Secreted Protein, Acidic and Rich in Cysteine (SPARC) by siRNA, we found thatSPARCexpression in PSCs was necessary for ECM remodeling. Taken together, we developed a 3D fibrosis model of pancreatic cancer with a clinically relevant thickness and observed aberrant SPARC-dependent ECM remodeling in cancer-derived PSCs.