The Effect of Dynamic, In Vivo-like Oxaliplatin on HCT116 Spheroids in a Cancer-on-Chip Model Is Representative of the Response in Xenografts

Abstract

The cancer xenograft model in which human cancer cells are implanted in a mouse is one of the most used preclinical models to test the efficacy of novel cancer drugs. However, the model is imperfect; animal models are ethically burdened, and the imperfect efficacy predictions contribute to high clinical attrition of novel drugs. If microfluidic cancer-on-chip models could recapitulate key elements of the xenograft model, then these models could substitute the xenograft model and subsequently surpass the xenograft model by reducing variation, increasing sensitivity and scale, and adding human factors. Here, we exposed HCT116 colorectal cancer spheroids to dynamic, in vivo-like, concentrations of oxaliplatin, including a 5 day drug-free period, on-chip. Growth inhibition on-chip was comparable to existing xenograft studies. Furthermore, immunohistochemistry showed a similar response in proliferation and apoptosis markers. While small volume changes in xenografts are hard to detect, in the chip-system, we could observe a temporary growth delay. Lastly, histopathology and a pharmacodynamic model showed that the cancer spheroid-on-chip was representative of the proliferating outer part of a HCT116 xenograft, thereby capturing the major driver of the drug response of the xenograft. Hence, the cancer-on-chip model recapitulated the response of HCT116 xenografts to oxaliplatin and provided additional drug efficacy information.

Simulating the Effect of Gut Microbiome on Cancer Cell Growth Using a Microfluidic Device

“…Previously several microfluidics devices have been developed to study the cancer progression [ 30 , 31 ] and drug testing [ 32 , 33 ], but only a few models are available that tested the co-culturing of bacteria and cancer cells in hypoxic conditions. Here we developed a simplistic co-culturing microfluidics model that allows the maintenance of hypoxic conditions and maintains media flow to mimic gut physiological conditions.…”

“…Most recently, there have been some attempts to show that cancer progression is associated with a microbiome while using a colorectal tumor chip [ 30 , 31 ] or during the testing drug efficacy [ 32 , 33 ]. Additionally, Gregorio et al attempted to create an anaerobic cultural condition by generating an oxygen gradient along the thickness of the small intestine of the human tumor [ 34 ].…”

Editorial for the Special Issue on Micro/Nanofluidic and Lab-on-a-Chip Devices for Biomedical Applications

“…Through these experiments, it was possible to verify that microbeads tend to stick to the side surface of the villi, which can explain the relationship between fluid flow and the settlement of gut bacteria on the villi. Komen and colleagues [ 7 ], on the other hand, established an alternative to cancer xenografts due to ethical considerations and a lack of accuracy to predict physiological responses. The authors created a microfluidic device integrated with a U-shaped well for having a single spheroid and exposed it to a dynamic environment and to an in vivo-like concentration of oxaliplatin, a medication commonly used to treat colorectal cancer, and compared it to an in-vivo cancer xenograft.…”