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Three-dimensional tumor cell growth stimulates autophagic flux and recapitulates chemotherapy resistance.

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.

journal_name

Cell Death Dis

journal_title

Cell death & disease

authors

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

doi

10.1038/cddis.2017.398

subject

Has Abstract

pub_date

2017-08-24 00:00:00

pages

e3013

issue

8

issn

2041-4889

pii

cddis2017398

journal_volume

8

pub_type

杂志文章

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