RRC ID 52351
著者 Bingel C, Koeneke E, Ridinger J, Bittmann A, Sill M, Peterziel H, Wrobel JK, Rettig I, Milde T, Fernekorn U, Weise F, Schober A, Witt O, Oehme I.
タイトル Three-dimensional tumor cell growth stimulates autophagic flux and recapitulates chemotherapy resistance.
ジャーナル Cell Death Dis
Abstract Current preclinical models in tumor biology are limited in their ability to recapitulate relevant (patho-) physiological processes, including autophagy. Three-dimensional (3D) growth cultures have frequently been proposed to overcome the lack of correlation between two-dimensional (2D) monolayer cell cultures and human tumors in preclinical drug testing. Besides 3D growth, it is also advantageous to simulate shear stress, compound flux and removal of metabolites, e.g., via bioreactor systems, through which culture medium is constantly pumped at a flow rate reflecting physiological conditions. Here we show that both static 3D growth and 3D growth within a bioreactor system modulate key hallmarks of cancer cells, including proliferation and cell death as well as macroautophagy, a recycling pathway often activated by highly proliferative tumors to cope with metabolic stress. The autophagy-related gene expression profiles of 2D-grown cells are substantially different from those of 3D-grown cells and tumor tissue. Autophagy-controlling transcription factors, such as TFEB and FOXO3, are upregulated in tumors, and 3D-grown cells have increased expression compared with cells grown in 2D conditions. Three-dimensional cultures depleted of the autophagy mediators BECN1, ATG5 or ATG7 or the transcription factor FOXO3, are more sensitive to cytotoxic treatment. Accordingly, combining cytotoxic treatment with compounds affecting late autophagic flux, such as chloroquine, renders the 3D-grown cells more susceptible to therapy. Altogether, 3D cultures are a valuable tool to study drug response of tumor cells, as these models more closely mimic tumor (patho-)physiology, including the upregulation of tumor relevant pathways, such as autophagy.
巻・号 8(8)
ページ e3013
公開日 2017-8-24
DOI 10.1038/cddis.2017.398
PII cddis2017398
PMID 28837150
PMC PMC5596581
MeSH Autophagy / physiology* Cell Line, Tumor Cell Proliferation Drug Resistance, Neoplasm / physiology* Humans Neoplasms / drug therapy Neoplasms / pathology*
IF 6.304
引用数 14
リソース情報
ヒト・動物細胞 NB-1(RCB1953)