Three‑dimensional cell culture: A powerful tool in tumor research and drug discovery (Review)

Lv, Donglai; Hu, Zongtao; Lü, Lin; Lu, Husheng; Xu, Xiaoquan

doi:10.3892/ol.2017.7134

Cited by 245 publications

(274 citation statements)

References 88 publications

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“…Detailed investigation of mechanism of drug sensitivity difference between 3D and 2D environments revealed that cells cultured in 3D cell models possessed enhanced gene expression profile, which correlated with increased mutation rates and the ability of tumor cells to invade other tissues and form metastasis . Routine use of 3D tumor spheroid model for drug testing can result in reduction of false positive and negative results, therefore decreasing usually high failure rates and costs of drug development, and ultimately leading to reduction of unnecessary animal experiments . In order to employ spheroid models for routine screening applications, it is necessary to have reliable and affordable high‐throughput platforms enabling formation, culturing, and screening of hundreds of uniform spheroids in one‐spheroid‐per‐well format.…”

Section: Introductionmentioning

confidence: 99%

“…Current well established and routine methods for 3D spheroids fabrication include spinner flasks, bacterial grade dishes, culturing cells on ultralow attachment surfaces including (ULA) plates and method of hanging drop . Using spinner flasks, bacterial grade dishes, and ULA plates result in formation of multiple spheroids per flask/dish/well that show high variability in size.…”

Section: Introductionmentioning

confidence: 99%

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Facile One Step Formation and Screening of Tumor Spheroids Using Droplet‐Microarray Platform

Popova

Tronser

Demir

et al. 2019

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Tumor spheroids or microtumors are important 3D in vitro tumor models that closely resemble a tumor's in vivo “microenvironment” compared to 2D cell culture. Microtumors are widely applied in the fields of fundamental cancer research, drug discovery, and precision medicine. In precision medicine tumor spheroids derived from patient tumor cells represent a promising system for drug sensitivity and resistance testing. Established and commonly used platforms for routine screenings of cell spheroids, based on microtiter plates of 96‐ and 384‐well formats, require relatively large numbers of cells and compounds, and often lead to the formation of multiple spheroids per well. In this study, an application of the Droplet Microarray platform, based on hydrophilic–superhydrophobic patterning, in combination with the method of hanging droplet, is demonstrated for the formation of highly miniaturized single‐spheroid‐microarrays. Formation of spheroids from several commonly used cancer cell lines in 100 nL droplets starting with as few as 150 cells per spheroid within 24–48 h is demonstrated. Established methodology carries a potential to be adopted for routine workflows of high‐throughput compound screening in 3D cancer spheroids or microtumors, which is crucial for the fields of fundamental cancer research, drug discovery, and precision medicine.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Facile One Step Formation and Screening of Tumor Spheroids Using Droplet‐Microarray Platform

Popova

Tronser

Demir

et al. 2019

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“…Other studies have recently reported that the presence of EC in the microenvironment of the microfluidic device affect in the establishment and growth of MCTS. (Katt et al, ; Lv, Hu, Lu, Lu, & Xu, ; H. F. Tsai, Trubelja, Shen, & Bao, ; van Duinen et al, ). However, conventional MCTS generation methods still have limitations in fully mimicking in vivo tumor‐microenvironment interactions and tumor progression.…”

Section: Introductionmentioning

confidence: 99%

In vitro lung cancer multicellular tumor spheroid formation using a microfluidic device

Lee

Hong

Jung

et al. 2019

Biotech & Bioengineering

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The purpose of this study was to demonstrate self‐organizing in vitro multicellular tumor spheroid (MCTS) formation in a microfluidic system and to observe the behavior of MCTSs under controlled microenvironment. The employed microfluidic system was designed for simple and effective formation of MCTSs by generating nutrient and oxygen gradients. The MCTSs were composed of cancer cells, vascular endothelial cells, and type I collagen matrix to mimic the in vivo tumor microenvironment (TME). Cell culture medium was perfused to the microfluidic device loaded with MCTSs by a passive fluidic pump at a constant flow rate. The dose response to an MMPs inhibitor was investigated to demonstrate the effects of biochemical substances. The result of long‐term stability of MCTSs revealed that continuous perfusion of cell culture medium is one of the major factors for the successful MCTS formation. A continuous flow of cell culture medium in the in vitro TME greatly affected both the proliferation of cancer cells in the micro‐wells and the sustainability of the endothelial cell‐layer integrity in the lumen of microfluidic channels. Addition of MMP inhibitor to the cell culture medium improved the stability of the collagen matrix by preventing the detachment and shrinkage of the collagen matrix surrounding the MCTSs. In summary, the present constant flow assisted microfluidic system is highly advantageous for long‐term observation of the MCTS generation, tumorous tissue formation process and drug responses. MCTS formation in a microfluidic system may serve as a potent tool for studying drug screening, tumorigenesis and metastasis.

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“…Drug discovery efforts are expected to benefit from the higher predictability of cellular phenotypic responses observed in 3D when compared to classical 2D or monolayer cell cultures . As such, homotypic multicellular elliptical or spherical structures assembled from human cancer cell lines, also referred as spheroids, have emerged as a useful avascular tumor model for preclinical anticancer drug screening …”

Section: Introductionmentioning

confidence: 99%

A High‐Throughput Automated Confocal Microscopy Platform for Quantitative Phenotyping of Nanoparticle Uptake and Transport in Spheroids

Cutrona

Simpson

2019

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There is a high demand for advanced, image‐based, automated high‐content screening (HCS) approaches to facilitate phenotypic screening in 3D cell culture models. A major challenge lies in retaining the resolution of fine cellular detail but at the same time imaging multicellular structures at a large scale. In this study, a confocal microscopy‐based HCS platform in optical multiwell plates that enables the quantitative morphological profiling of populations of nonuniform spheroids obtained from HT‐29 human colorectal cancer cells is described. This platform is then utilized to demonstrate a quantitative dissection of the penetration of synthetic nanoparticles (NP) in multicellular 3D spheroids at multiple levels of scale. A pilot RNA interference‐based screening validates this methodology and identifies a subset of RAB GTPases that regulate NP trafficking in these spheroids. This technology is suitable for high‐content phenotyping in 3D cell‐based screening, providing a framework for nanomedicine drug development as applied to translational oncology.

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Three‑dimensional cell culture: A powerful tool in tumor research and drug discovery (Review)

Cited by 245 publications

References 88 publications

Facile One Step Formation and Screening of Tumor Spheroids Using Droplet‐Microarray Platform

Facile One Step Formation and Screening of Tumor Spheroids Using Droplet‐Microarray Platform

In vitro lung cancer multicellular tumor spheroid formation using a microfluidic device

A High‐Throughput Automated Confocal Microscopy Platform for Quantitative Phenotyping of Nanoparticle Uptake and Transport in Spheroids

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