Abstract
Cells in a tumor microenvironment are exposed to spatial and temporal variations in oxygen tension due to hyperproliferation and immature vascularization. Such spatiotemporal oxygen heterogeneity affects the behavior of cancer cells, leading to cancer growth and metastasis, and thus, it is essential to clarify the cellular responses of cancer cells to oxygen tension. Herein, we describe a new double-layer microfluidic device allowing the control of oxygen tension and the behavior of cancer cells under spatiotemporal oxygen heterogeneity. Two parallel gas channels were located above the media and gel channels to enhance gas exchange, and a gas-impermeable polycarbonate film was embedded in the device to prevent the diffusion of atmospheric oxygen. Variations in oxygen tension in the device with the experimental parameters and design variables were investigated computationally and validated by using oxygen-sensitive nanoparticles. The present device can generate a uniform hypoxic condition at oxygen levels down to 0.3% O2, as well as a linear oxygen gradient from 3% O2 to 17% O2 across the gel channel within 15 min. Moreover, human breast cancer cells suspended in type I collagen gel were introduced in the gel channel to observe their response under controlled oxygen tension. Hypoxic exposure activated the proliferation and motility of the cells, which showed a local maximum increase at 5% O2. Under the oxygen gradient condition, the increase in the cell number was relatively high in the central mild hypoxia region. These findings demonstrate the utility of the present device to study cellular responses in an oxygen-controlled microenvironment.
Highlights
Low oxygen tension is a major stimulus affecting cell behavior and cell–cell interactions[1] and is commonly found in both physiological and pathological conditions
We found that the cells are activated after hypoxic exposure, promoting their migration and proliferation, and that the cells tend to migrate toward an area of mild hypoxia when cultured under an oxygen gradient
The present double-layer microfluidic device provides superior performance to our previously published system in terms of generating scitation.org/journal/apb a controlled oxygen level and a rapid response rate, which are indispensable to reproduce the in vivo spatiotemporal heterogeneity of oxygen tension
Summary
Low oxygen tension (hypoxia) is a major stimulus affecting cell behavior and cell–cell interactions[1] and is commonly found in both physiological and pathological conditions. Pathological events can further decrease oxygen concentration to levels below 1%, as observed in tumor microenvironments.[3] The hyperproliferation of cells and immature vascularization in the tumor microenvironment lead to a hypoxic condition with a non-uniform spatial distribution of oxygen tension[4] and a temporal variation of oxygen tension due to ischemia and reperfusion.[5,6] the cells. It is important to understand cancer cell responses to a wide range of oxygen tensions with different spatiotemporal variations,[25,26] but currently, little is known regarding the oxygen dependency of cancer cell behavior Hypoxic microenvironments allow cancer cells to proliferate at the primary site and disseminate, invading the surrounding tissues, blood vessels, and lymph vessels and metastasizing toward secondary sites.[8,9] Cancer cell migration depends on mechanical stimuli, such as interstitial flow[10,11] and ECM stiffness,[12] and chemical stimuli.[13,14] Hypoxic stress represents a chemical signal that can alter cancer cell metabolism and activity related to proliferation, invasion, and migration.[15–20] Acute, cyclic hypoxic stress enhances tumor metastasis.[21,22] In addition, hypoxic conditions in the tumor microenvironment induce resistance to anti-cancer drugs.[23,24] It is important to understand cancer cell responses to a wide range of oxygen tensions with different spatiotemporal variations,[25,26] but currently, little is known regarding the oxygen dependency of cancer cell behavior
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