Anchorage-dependent multicellular aggregate formation induces a quiescent stem-like intractable phenotype in pancreatic cancer cells.
Anchorage-dependent multicellular aggregate formation induces a quiescent stem-like intractable phenotype in pancreatic cancer cells.
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DOI：
10.18632/oncotarget.25732
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发表时间：
2018-07-06
期刊：
影响因子：
--
通讯作者：
Kasahara M
中科院分区：
文献类型：
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作者：
Miyatake Y;Ohta Y;Ikeshita S;Kasahara M
胰导管腺癌（Pancreatic ductal adencarcinoma， PDAC）是最致命的难治性癌症之一。PDAC细胞的侵袭性特征已经得到了很好的研究，但PDAC细胞群体表现出的侵袭性特征在很大程度上是未知的。我们在这里表明，与上皮样饲养细胞共培养在体外形成锚定依赖性多细胞聚集体（Ad-MCAs，集体细胞的一种行为）的PDAC细胞上赋予更多的恶性表型。CD44v3-10high/CD44slow PDAC细胞系在上皮-间质转化（epithelial - mesenchymal transition， EMT）发生前表现为上皮表型，将其与单层HEK293T细胞共培养过夜后，它们在饲养层形成Ad-MCAs，并获得吉西他滨抗性。CD44v8-10表达显著升高，Ki-67染色降低，提示形成Ad-MCAs的PDAC细胞获得了类似癌症干细胞（CSC）的难治性。我们发现，与HEK293T细胞共培养的PDAC细胞中高度下调的基因在胰腺癌患者的恶性病变中显著上调。我们的研究表明，形成Ad-MCAs的PDAC细胞在EMT发生前部分恢复到正常组织基因谱。PDAC细胞形成Ad-MCA等集体细胞行为可能模拟了癌细胞在转移定殖的早期阶段发生的关键事件。
Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal refractory cancers. Aggressive features in PDAC cells have been well studied, but those exhibited by a population of PDAC cells are largely unknown. We show here that coculture with epithelial-like feeder cells confers more malignant phenotypes upon PDAC cells forming anchorage-dependent multicellular aggregates (Ad-MCAs, a behavior of collective cells), in vitro. When CD44v3-10high/CD44slow PDAC cell lines, which exhibited an epithelial phenotype before the onset of epithelial–mesenchymal transition (EMT), were cocultured with a monolayer of HEK293T cells overnight, they formed Ad-MCAs on the feeder layer and acquired gemcitabine resistance. CD44v8-10 expression was dramatically increased and Ki-67 staining decreased, suggesting that PDAC cells forming Ad-MCAs acquired cancer stem cell (CSC)-like intractable properties. We found that highly downregulated genes in PDAC cells cocultured with HEK293T cells were significantly upregulated in malignant lesions from pancreatic cancer patients. Our work implies that PDAC cells forming Ad-MCAs partially return to a normal tissue gene profile before the onset of EMT. The collective cell behavior like Ad-MCA formation by PDAC cells may mimic critical events that occur in cancer cells at the very early phase of metastatic colonization.