Using Microfluidics to Investigate the Effects of Diet on Tumor Progression

Introduction:: Lifestyle factors, including diet, are known to increase or decrease the risk of developing cancer. However, once a tumor has been detected, it is unclear whether a patient’s diet affects tumor progression, the risk of metastasis, or the effectiveness of chemotherapy. Because of differences in their biology and metabolism, mouse models can provide only limited insight into the effects of diet on human tumors. Meanwhile, static cell culture models fail to mimic the constant concentration of nutrients maintained by interstitial fluid flow in the tumor microenvironment in vivo. Here, we used a three-dimensional (3D) microfluidic tumor model to replicate the interstitial fluid flow around a small avascular tumor to examine the effects of normal, post-prandial, and ketogenic conditions on tumor growth and cancer cell invasion.

Materials and Methods:: We used a 3D microfluidic tumor model that consisted of an aggregate of triple-negative breast cancer cells mimicking a small avascular tumor within a type I collagen gel. A hydrostatic pressure difference was maintained across the device to produce an interstitial fluid flow across around the tumor similar to flow rates observed in vivo. To assess the effects of different dietary conditions on tumor growth and cancer cell invasion, we took advantage of human plasma-like medium (HPLM), which contains many of the small metabolites found in human plasma. We used HPLM to mimic a normal diet and supplemented with beta-hydroxybutyric acid or insulin to mimic ketogenic or post-prandial conditions, respectively. Tumor growth and cancer cell invasion were assessed by quantitative image analysis of the tumors over several days.

Results, Conclusions, and Discussions:: Using a 3D microfluidic tumor model allowed us to investigate the growth and invasion of triple-negative breast cancer cells under normal, ketogenic, and post-prandial conditions. Although they did not alter proliferation rates in static 2D cultures, the different dietary conditions had a dramatic effect on tumor growth and cancer cell invasion in 3D under flow. Under normal HPLM conditions, tumors had smaller areas, invasions, and rates of invasion than those under the ketogenic or post-prandial conditions. These data suggest that patient diet may affect the earliest stages of the metastatic cascade by triple-negative breast cancer cells. Future work will define whether these dietary conditions affect response to chemotherapeutics.

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