An Oxygen-Concentration-Controllable Multiorgan Microfluidic Platform for Studying Hypoxia-Induced Lung Cancer-Liver Metastasis and Screening Drugs

Various cancer metastasis models based on organ-on-a-chip platforms have been established to study molecular mechanisms and screen drugs. However, current platforms can neither reveal hypoxia-induced cancer metastasis mechanisms nor allow drug screening under a hypoxia environment on a multiorgan level. We have developed a three-dimensional-culture multiorgan microfluidic (3D-CMOM) platform in which the dissolved oxygen concentration can be precisely controlled. An organ-level lung cancer and liver linkage model was established under normoxic/hypoxic conditions. A transcriptomics analysis of the hypoxia-induced lung cancer cells (A549 cells) on the platform indicated that the hypoxia-inducible factor 1 alpha (HIF-1 alpha) pathway could elevate epithelial-mesenchymal transition (EMT) transcription factors (Snail 1 and Snail 2), which could promote cancer metastasis. Then, protein detection demonstrated that HIF-1 alpha and EMT transcription factor expression levels were positively correlated with the secretion of cancer metastasis damage factors alpha-fetoprotein (AFP), alkaline phosphatase (ALP), and gamma-glutamyl transpeptidase (gamma-GT) from liver cells. Furthermore, the cancer treatment effects of HIF-1 alpha inhibitors (tirapazamine, SYP-5, and IDF-11774) were evaluated using the platform. The treatment effect of SYP-5 was enhanced under the hypoxic conditions with fewer side effects, similar to the findings of TPZ. We can envision its wide application in future investigations of cancer metastasis and screening of drugs under hypoxic conditions with the potential to replace animal experiments.

Automated summary

A three-dimensional-culture multiorgan microfluidic platform was developed to study cancer metastasis mechanisms and drug screening. The research showed that hypoxia-induced lung cancer cells could promote metastasis through the HIF-1 alpha pathway, and inhibiting HIF-1 alpha effectively treated lung cancer under hypoxic conditions. The platform has the potential to replace animal experiments and become an important tool for future cancer research and drug screening.