Promotion of malignant phenotype after disruption of the three-dimensional structure of cultured spheroids from colorectal cancer.
Promotion of malignant phenotype after disruption of the three-dimensional structure of cultured spheroids from colorectal cancer.
复制标题
DOI：
10.18632/oncotarget.24641
复制
发表时间：
2018-03-23
期刊：
影响因子：
--
通讯作者：
Inoue M
中科院分区：
文献类型：
--
作者：
Piulats JM;Kondo J;Endo H;Ono H;Hagihara T;Okuyama H;Nishizawa Y;Tomita Y;Ohue M;Okita K;Oyama H;Bono H;Masuko T;Inoue M
单个或小簇的癌细胞可能从主要肿瘤的边缘脱离并侵入血管，这可能是转移的起源；然而，这一现象的机制尚不清楚。利用癌组织起源的球体，我们研究了干扰癌球体的三维结构是否会引发恶性肿瘤的改造过程和进展。我们开发了一种机械破坏方法来实现球体的均匀破坏，同时保持细胞-细胞接触。破坏后，来自9个患者样本的9个球形细胞系在几小时内重组，其中3个细胞系的球形生长加速。标志物表达、球体形成能力和肿瘤发生表明球体破坏后干性增加。此外，11条球面线中有6条球面成形能力有所提高。由基因表达谱确定的破坏特征支持重塑的发生率并预测结直肠癌患者的预后。此外，重组后的球体中WNT和HER3信号通路增加，这些信号通路的抑制减弱了破坏后增加的增殖和干性。总的来说，癌症球体的破坏和随后的重组通过激活WNT和ERBB途径促进了恶性肿瘤相关的表型。
Individual and small clusters of cancer cells may detach from the edges of a main tumor and invade vessels, which can act as the origin of metastasis; however, the mechanism for this phenomenon is not well understood. Using cancer tissue-originated spheroids, we studied whether disturbing the 3D architecture of cancer spheroids can provoke the reformation process and progression of malignancy. We developed a mechanical disruption method to achieve homogenous disruption of the spheroids while maintaining cell–cell contact. After the disruption, 9 spheroid lines from 9 patient samples reformed within a few hours, and 3 of the 9 lines exhibited accelerated spheroid growth. Marker expression, spheroid forming capacity, and tumorigenesis indicated that stemness increased after spheroid disruption. In addition, the spheroid forming capacity increased in 6 of 11 spheroid lines. The disruption signature determined by gene expression profiling supported the incidence of remodeling and predicted the prognosis of patients with colorectal cancer. Furthermore, WNT and HER3 signaling were increased in the reformed spheroids, and suppression of these signaling pathways attenuated the increased proliferation and stemness after the disruption. Overall, the disruption and subsequent reformation of cancer spheroids promoted malignancy-related phenotypes through the activation of the WNT and ERBB pathways.