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DOI: 10.1055/s-0036-1593549
Three-dimensional tumor cell growth models in vivo drug resistance mechanisms
The success rates for investigational cancer drugs in clinical development are poor, reflecting the current limitations of preclinical models in recapitulating relevant (patho-)physiological mechanisms of drug resistance, including autophagy. Recently, three-dimensional (3D) growth cultures have been introduced for preclinical drug testing to improve the lack of correlation between monolayer cell cultures and human tumors. Besides 3D growth, it is also important 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 evaluated the effect of 3D growth on several hallmarks of cancer. Three-dimensionally grown neuroblastoma cell lines slowed down proliferation, escaped drug-induced cell death and activated macroautophagy, a recycling pathway often activated by highly proliferative tumors to cope with metabolic stress. Cell culture settings employing more tumor-like models that reflect in vivo resistance mechanisms are of high importance to improve preclinical drug testing, and thereby have great potential to reduce failure rates in drug development.