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

Abstract

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 1α (HIF-1α) 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-1α and EMT transcription factor expression levels were positively correlated with the secretion of cancer metastasis damage factors alphafetoprotein (AFP), alkaline phosphatase (ALP), and gamma-glutamyl transpeptidase (γ-GT) from liver cells. Furthermore, the cancer treatment effects of HIF-1α 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.

Application Progress of Organoids in Colorectal Cancer

“…By precisely regulating the oxygen concentration in each chamber and monitoring the oxygen concentration level with sensors on the chip, the anoxic environment is achieved in the lung tumor organoids chamber of the upstream. The downstream chamber imitates the oxygen environment of the normal liver organoids, which realizes the cancer metastasis induced by the oxygen-deficient environment on the chip and can be used to the antitumor drug screening under the oxygen-deficient environment ( Zheng et al, 2021 ). More and more tumor organoids generate the TME by microfluidic chips and coculture technology.…”

“…The microfluidic chip can also be used for the construction of multi-organoid models. The microfluidic chip of lung tumor organoids and liver organoids linkage model has been successfully constructed and conducted drug screening at a multi-organ level ( Zheng et al, 2021 ). In the future, further studies are needed for the integration model of multiple organoids, which will better contribute to the development of new drugs and drug toxicology.…”

Microfluidic-based in vitro thrombosis model for studying microplastics toxicity

“…The ubiquity of microplastics (MPs, including nanoplastics smaller than 1 μm) in the global biosphere has led to increasing concerns about their impact on health. [1][2][3][4][5][6] Recent evidence indicates that humans constantly inhale and ingest MPs. After uptake, in many cases particles will come into contact with the blood system.…”

Polydopamine-coated UiO-66 nanoparticles loaded with perfluorotributylamine/tirapazamine for hypoxia-activated osteosarcoma therapy

“…However, a single use of TPZ can elicit only a marginal effect on tumor growth because a limited amount of BTZ is generated from TPZ due to restricted penetration into the tumor and insufficient tumor hypoxia [ 12 ]. Accordingly, many studies have focused on creating a penetrable and hypoxic intratumor microenvironment to enhance the toxicity of hypoxia-sensitive prodrugs [ 13 – 15 ]. Perfluorotributylamine (PFA) is a clinically approved perfluorocarbon that can enhance tumor permeability and deoxygenation due to its platelet inhibition and oxygen-absorbing effects.…”