Abstract
The physical microenvironment of tumours is characterized by heterotypic cell interactions and physiological gradients of nutrients, waste products and oxygen. This tumour microenvironment has a major impact on the biology of cancer cells and their response to chemotherapeutic agents. Despite this, most in vitro cancer research still relies primarily on cells grown in 2D and in isolation in nutrient- and oxygen-rich conditions. Here, a microfluidic device is presented that is easy to use and enables modelling and study of the tumour microenvironment in real-time. The versatility of this microfluidic platform allows for different aspects of the microenvironment to be monitored and dissected. This is exemplified here by real-time profiling of oxygen and glucose concentrations inside the device as well as effects on cell proliferation and growth, ROS generation and apoptosis. Heterotypic cell interactions were also studied. The device provides a live ‘window’ into the microenvironment and could be used to study cancer cells for which it is difficult to generate tumour spheroids. Another major application of the device is the study of effects of the microenvironment on cellular drug responses. Some data is presented for this indicating the device’s potential to enable more physiological in vitro drug screening.
Highlights
The physical microenvironment of tumours is characterized by heterotypic cell interactions and physiological gradients of nutrients, waste products and oxygen
A characteristic feature of solid tumours is their unique physiological and biological microenvironment, which consists of multiple cell types and gradients of oxygen tension, nutrients and waste products which vary as a function of distance from a supporting blood vessel[1,2,3,4,5]
One of the models that is currently used is the three dimensional multicellular spheroid, this model has a number of key limitations: (i) some cell lines do not form spheroids; (ii) spheroid size can be controlled, cell density within a spheroid cannot; (iii) controlling the extracellular matrix (ECM) within a spheroid is not possible; and (iv) direct visualization of cells within the microenvironment created by the spheroid is difficult in real-time due to the thickness of the viable rim of the spheroid[10,12]
Summary
The physical microenvironment of tumours is characterized by heterotypic cell interactions and physiological gradients of nutrients, waste products and oxygen. This article presents an easy-to-operate microdevice which can mimic the three dimensional architecture of multicellular spheroids, whilst at the same time generating a visible, live “tumour slice” that allows easy monitoring of cells in different regions of the microenvironment in real-time as well as their response to different drugs. This model has the potential to assess the ability of drugs to penetrate through several cell layers which can be a major barrier to effective drug treatment[25]. The potential of this technology for analysing the impact of microenvironmental parameters on drug response is exemplified by the differential cellular response to several well-known drugs in different parts of the microdevice
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