3D pancreatic carcinoma spheroids induce a matrix-rich, chemoresistant phenotype offering a better model for drug testing.
3D pancreatic carcinoma spheroids induce a matrix-rich, chemoresistant phenotype offering a better model for drug testing.
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DOI：
10.1186/1471-2407-13-95
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发表时间：
2013-02-27
期刊：
影响因子：
3.8
通讯作者：
Heuchel RL
中科院分区：
文献类型：
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作者：
Longati P;Jia X;Eimer J;Wagman A;Witt MR;Rehnmark S;Verbeke C;Toftgård R;Löhr M;Heuchel RL
胰腺导管腺癌（PDAC）是癌症相关死亡的第四大常见原因。由于几乎完全的化学抗性，它在几乎所有患者中是致命的。大多数（如果不是所有）药物成功通过临床前测试，但在患者身上失败得很惨。这就提出了一个问题，即传统的2D细胞培养是否是药物筛选的正确工具。本研究的目的是开发一种简单的，高通量的人PDAC细胞系的3D模型，并探索可能导致化疗耐药性的从2D到3D转变的机制。测试了几种已建立的人PDAC和KPC小鼠细胞系，从而更详细地研究了Panc-1。用甲基纤维素促进3D球状体形成。通过形态学、电子显微镜和qRT-PCR研究球状体的选定基质基因、相关因子和miRNA。进行了代谢研究，并对一组新药进行了吉西他滨试验。比较3D与2D细胞培养物，基质蛋白显著增加，如lumican、SNED 1、DARP 32和miR-146 a。3D中的细胞代谢转向糖酵解。所有测试的药物在3D中的效果都不太好，除了大蒜素，MT 100和AX，这表明效果。我们开发了一种用于胰腺癌的高通量3D细胞培养药物筛选系统，该系统显示出强烈增加的化疗耐药性。与3D细胞模型相关的特征是基质蛋白和miRNA以及基质标志物如PPP 1 R1 B和SNED 1的表达增加。这支持了细胞粘附介导的耐药性的概念。
Pancreatic ductal adenocarcinoma (PDAC) is the fourth most common cause of cancer related death. It is lethal in nearly all patients, due to an almost complete chemoresistance. Most if not all drugs that pass preclinical tests successfully, fail miserably in the patient. This raises the question whether traditional 2D cell culture is the correct tool for drug screening. The objective of this study is to develop a simple, high-throughput 3D model of human PDAC cell lines, and to explore mechanisms underlying the transition from 2D to 3D that might be responsible for chemoresistance. Several established human PDAC and a KPC mouse cell lines were tested, whereby Panc-1 was studied in more detail. 3D spheroid formation was facilitated with methylcellulose. Spheroids were studied morphologically, electron microscopically and by qRT-PCR for selected matrix genes, related factors and miRNA. Metabolic studies were performed, and a panel of novel drugs was tested against gemcitabine. Comparing 3D to 2D cell culture, matrix proteins were significantly increased as were lumican, SNED1, DARP32, and miR-146a. Cell metabolism in 3D was shifted towards glycolysis. All drugs tested were less effective in 3D, except for allicin, MT100 and AX, which demonstrated effect. We developed a high-throughput 3D cell culture drug screening system for pancreatic cancer, which displays a strongly increased chemoresistance. Features associated to the 3D cell model are increased expression of matrix proteins and miRNA as well as stromal markers such as PPP1R1B and SNED1. This is supporting the concept of cell adhesion mediated drug resistance.
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影响因子：
3.7
作者：
Gu L;Waliany S;Kane SE
通讯作者：
Kane SE
影响因子：
3.6
作者：
Hagmann, Wolfgang;Jesnowski, Ralf;Lohr, J. Matthias
通讯作者：
Lohr, J. Matthias
影响因子：
4.8
作者：
Hagmann, Wolfgang;Jesnowski, Ralf;Loehr, Johannes Matthias
通讯作者：
Loehr, Johannes Matthias
影响因子：
50.3
作者：
Hingorani, SR;Wang, LF;Tuveson, DA
通讯作者：
Tuveson, DA
影响因子：
8.8
作者：
通讯作者：
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