Vascularized cancer on a chip: The effect of perfusion on growth and drug delivery of tumor spheroid

Nashimoto, Yuji; Okada, Ryu; Hanada, Sanshiro; Arima, Yuichiro; Nishiyama, Koichi; Miura, Takashi; Yokokawa, Ryuji

doi:10.1016/j.biomaterials.2019.119547

Cited by 248 publications

(252 citation statements)

References 37 publications

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“…Recently, examining the relationship between blood vessels and tumor spheroids in 3D in vitro devices has attracted attention because the models have offered more realistic environments (e.g., dimensionality, fluid flow (luminal/interstitial), physical deformation, and ECM stiffness) to simulate in vivo human body than conventional cell culture on 2D plastic. For instance, therapeutic efficacies of anti-cancer drugs were assessed in tumor spheroid models under controlled fluid flow in an engineered tumor vascular network (Nashimoto et al, 2020). In this study, the anti-cancer drugs under the flow did not show dose-dependency that has been observed under the static condition.…”

Section: Introductionmentioning

confidence: 74%

“…In this study, the anti-cancer drugs under the flow did not show dose-dependency that has been observed under the static condition. In addition, the proliferation of tumor cells in the spheroids were more accelerated under the flow perfusion (Nashimoto et al, 2020). In another study, differentiation and migration of vascular endothelial cells were observed under pro-angiogenic growth factor treatments, and permeability of the angiogenic sprouts within the collagen matrix was measured (van Duinen et al, 2019).…”

Section: Introductionmentioning

confidence: 97%

“…Multicellular tumor spheroids have been used to model human solid tumors because of their morphological and biological similarities to in vivo human tumors. Indeed, compared to two-dimensional (2D) tumor cell culture models, three-dimensional (3D) multicellular tumor spheroids could provide more realistic cell-cell, cell-extracellular matrix (ECM) interactions with multiple stromal cells, which are the essential characteristics of the heterogeneous tumor microenvironment (TME) (Chung, Ahn, Son, Kim, & Jeon, 2017;Hirschhaeuser et al, 2010;Ko et al, 2019;Nashimoto et al, 2020). In particular, spheroids models have been useful because they could display morphological and size changes in 3D when the cancer cells' traits are transformed in the ECM under anti-cancer drug treatments (Antoni, Burckel, Josset, & Noel, 2015).…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

In vitromodeling of tumor spheroid interactions to perfused blood vessels

Kwak

Lee

2020

Preprint

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Tumor angiogenesis, the formation of new blood vessels from existing blood vessels in and around the tumor stroma, is orchestrated by multiple biological factors in the tumor microenvironment, including tumor stromal cells, extracellular matrices, and secreted growth factors. Here, we present the processes to define and optimize the biological conditions for robust interactions between tumor spheroids and engineered blood vessels in a microfluidic organ-on-a-chip device in vitro. Within the device, vascular lumen formation and vessel sprouting in human umbilical vein endothelial cell based engineered blood vessels are observed in a variety of extracellular matrices (collagen, Matrigel, and fibrin), containing metastatic breast tumor cells (MDA-MB-231), and tumor stromal cells (mesenchymal stem cells, and human lung fibroblasts) to show the crosstalk between the tumor spheroids and the perfused blood vasculatures in vitro.

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Section: Introductionmentioning

confidence: 74%

Section: Introductionmentioning

confidence: 97%

Section: Introductionmentioning

confidence: 99%

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In vitromodeling of tumor spheroid interactions to perfused blood vessels

Kwak

Lee

2020

Preprint

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“…However, most of these MCTSs lack endothelial and stromal cells, which play an important role in aggressive behaviours of tumour cells, such as angiogenesis and invasion [15]. Recently, microfluidic devices have been developed to recapitulate TME with perfusable vascular networks that exhibit angiogenesis [16][17][18][19]. However, because microfluidic devices are difficult to mass-produce, and their liquid handling for cell culture and drug testing in the devices is relatively complicated compared to those in microwell plates, their use in high-throughput screening (HTS) of anticancer drug efficacy is limited.…”

Section: Introductionmentioning

confidence: 99%

3D Bioprinted Vascularized Tumour for Drug Testing

Han

Kim

Chen

et al. 2020

IJMS

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An in vitro screening system for anti-cancer drugs cannot exactly reflect the efficacy of drugs in vivo, without mimicking the tumour microenvironment (TME), which comprises cancer cells interacting with blood vessels and fibroblasts. Additionally, the tumour size should be controlled to obtain reliable and quantitative drug responses. Herein, we report a bioprinting method for recapitulating the TME with a controllable spheroid size. The TME was constructed by printing a blood vessel layer consisting of fibroblasts and endothelial cells in gelatine, alginate, and fibrinogen, followed by seeding multicellular tumour spheroids (MCTSs) of glioblastoma cells (U87 MG) onto the blood vessel layer. Under MCTSs, sprouts of blood vessels were generated and surrounding MCTSs thereby increasing the spheroid size. The combined treatment involving the anti-cancer drug temozolomide (TMZ) and the angiogenic inhibitor sunitinib was more effective than TMZ alone for MCTSs surrounded by blood vessels, which indicates the feasibility of the TME for in vitro testing of drug efficacy. These results suggest that the bioprinted vascularized tumour is highly useful for understanding tumour biology, as well as for in vitro drug testing.

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“…For example, in 2013, a microfluidic device was developed with a self-organized perfusable vascular network [14]. We have previously integrated a spheroid culture system with the self-organized capillary network to improve the culture conditions of spheroids [15, 16].…”

Section: Introductionmentioning

confidence: 99%

A new microcirculation culture method with a self-organized capillary network

Sugihara

Yamaguchi

Usui

et al. 2020

Preprint

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25A lack of microcirculation has been one of the most significant obstacles for three-26 dimensional culture systems of organoids and embryonic tissues. Here, we 27 developed a simple and reliable method to implement a perfusable capillary 28 network in vitro. The method employed the self-organization of endothelial cells 29 to generate a capillary network and a static pressure difference for culture medium 30 circulation, which can be easily introduced to standard biological laboratories and 31 enables long-term cultivation of vascular structures. Using this culture system, we 32 perfused the lumen of the self-organized capillary network and observed a flow-33 induced vascular remodeling process, cell shape changes, and collective cell 34 migration. We also observed an increase in cell proliferation around the synthetic 35 vasculature induced by flow, indicating functional perfusion of the culture 36 medium. We also reconstructed extravasation of tumor and inflammatory cells, 37 and circulation inside spheroids including endothelial cells and human lung 38 fibroblasts. In conclusion, this system is a promising tool to elucidate the 39 mechanisms of various biological processes related to vascular flow.

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Vascularized cancer on a chip: The effect of perfusion on growth and drug delivery of tumor spheroid

Cited by 248 publications

References 37 publications

In vitromodeling of tumor spheroid interactions to perfused blood vessels

In vitromodeling of tumor spheroid interactions to perfused blood vessels

3D Bioprinted Vascularized Tumour for Drug Testing

A new microcirculation culture method with a self-organized capillary network

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