Abstract
A microfluidic device capable of precise chemical control is helpful to mimic tumor microenvironments in vitro, which are closely associated with malignant progression, including metastasis. Cancer cells under a concentration gradient of oxygen and other sustenance materials inside a tumor in vivo have recently been reported to increase the probability of metastasis. The influence of glucose concentration on cancer cells has not been measured well, whereas that of oxygen concentration has been thoroughly examined using microfluidic devices. This is because glucose concentrations can be controlled using microfluidic concentration gradient generators, which trade off temporal stability of the glucose concentration and shear stress on the cells; by contrast, oxygen concentration can be easily controlled without microfluidic device-induced shear stresses. To study cell division and migration responses as a function of glucose concentration, we developed a microfluidic device to observe cell behaviors under various chemical conditions. The device has small-cross-section microchannels for generating a concentration gradient and a large-cross-section chamber for cell culture. With this design, the device can achieve both a cell culture with sufficiently low shear stress on cell activity and a stable glucose concentration gradient. Experiments revealed that a low glucose concentration increased the total migration length of HeLa cells and that HeLa cells under a glucose concentration gradient exhibit random motion rather than chemotaxis.
Highlights
Understanding cancer cell metastasis is important because the survival rate of patients with metastasis is drastically lower than that of patients without metastasis in almost all cancers
In the initial step of the metastatic process, cancer cells gain higher migration capabilities [4,5] by losing adhesion to neighboring cells through epithelial-mesenchymal transitions which are induced by multiple mechanisms including a hypoxic environment [6,7,8,9,10]
Tumors have low oxygen concentrations owing to their abnormal structure and distribution of tumor blood vessels, through which sustenance such as oxygen and glucose are supplied [11]
Summary
Understanding cancer cell metastasis is important because the survival rate of patients with metastasis is drastically lower than that of patients without metastasis in almost all cancers. The behavior of cancer cells under low oxygen concentrations has been actively studied; hypoxic cancer cells have been found to be epigenetically changed, contributing to their high migration capability [13] and induction of angiogenesis [14]. Glucose may be a crucial factor for cancer cell metastasis [15,16,17], because glucose concentration is low in chronic hypoxic regions in tumors.
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