Cancer drug discovery and preclinical drug screening mainly rely on animal models and static cell cultures, which can often not recapitulate the properties and dynamics of the human tumour microenvironment. This gap between experimental models and the pathological reality of tumours greatly contributes to the low success rate of cancer drugs in clinical trials. Now, reporting in Advanced Healthcare Materials, Sihong Wang and colleagues developed a microfluidic tumour-on-a-chip platform, which replicates the tumour microvasculature, includes tumour-associated stromal cells and allows high-throughput preclinical drug screening.
The tumour microenvironment is characterized by a leaky vasculature, a distinct extracellular matrix, and the presence of immune and stromal cells, in particular, cancer-associated fibroblasts (CAFs), which interact with cancer cells and remodel the matrix. This complex microenvironment not only impacts cancer cell behaviour but also affects drug delivery into cancer cells and, thus, is an important consideration for tumour models.
To mimic the dynamic nature of the tumour microenvironment and to enable high-throughput drug screening, Wang and colleagues designed a tumour-on-a-chip platform based on a three-layered polydimethylsiloxane microfluidic array. “Our layered tumour chip (L-TumorChip) provides a preclinical model that integrates the high-throughput capacity of lab-on-a-chip platforms with a dynamically perfused reconstructed tumour microenvironment comprised of key stromal components, including the tumour microvasculature, the tumour extracellular matrix and interactions between CAFs and tumour cells,” explains Wang.
The tumour compartment, which contains cancer and stromal cells embedded in matrigel, is covered by an endothelial layer cultured on a membrane with patterned micropores. This setup allows the entire chip to be perfused by a continuous flow of media, mimicking in vivo interstitial transport phenomena.
The cancer cells secrete cytokines that make the endothelial monolayer leaky, resembling the leaky features of tumour vasculature, and the presence of CAFs causes an increase in cancer cell proliferation, which is a known effect of these stromal cells in vivo.
The tumour-on-a-chip model can be used for the high-throughput screening of cancer drugs in different stromal conditions. As expected, treatment of breast cancer cells with the drug doxorubicin causes cancer cell apoptosis. Interestingly, the presence of an endothelial layer decreases the toxic effect of doxorubicin, and co-culture with stromal cells delays drug response, suggesting that stromal cells can reduce cancer cell apoptosis and/or prevent drug accumulation.
These findings highlight the impact of stromal cells and tumour vasculature on drug efficacy. “The L-TumorChip provides a balance between traditional 2D or 3D cultures and full-scale animal models, enabling high-throughput screening results that more closely reflect the outcome in clinical settings,” says Wang.
“The L-TumorChip provides a balance between traditional 2D or 3D cultures and full-scale animal models, enabling high-throughput screening results that more closely reflect the outcome in clinical settings”
However, the L-TumorChip does not yet fully represent the tumour microenvironment. “We are now planning to integrate immune cells into the flow of the system, which would make the chip even more clinically relevant,” concludes Wang.
Chi, C.-W. et al. High-throughput tumor-on-a-chip platform to study tumor–stroma interactions and drug pharmacokinetics. Adv. Healthc. Mater. https://doi.org/10.1002/adhm.202000880 (2020)
About this article
Cite this article
Horejs, C. A tumour chip for drug screening. Nat Rev Mater 5, 786 (2020). https://doi.org/10.1038/s41578-020-00258-9