Abstract
Solid tumors in advanced cancer often feature a structurally and functionally abnormal vasculature through tumor angiogenesis, which contributes to cancer progression, metastasis, and therapeutic resistances. Hypoxia is considered a major driver of angiogenesis in tumor microenvironments. However, there remains a lack of in vitro models that recapitulate both the vasculature and hypoxia in the same model with physiological resemblance to the tumor microenvironment, while allowing for high-content spatiotemporal analyses for mechanistic studies and therapeutic evaluations. We have previously constructed a hypoxia microdevice that utilizes the metabolism of cancer cells to generate an oxygen gradient in the cancer cell layer as seen in solid tumor sections. Here, we have engineered a new composite microdevice-microfluidics platform that recapitulates a vascularized hypoxic tumor. Endothelial cells were seeded in a collagen channel formed by viscous fingering, to generate a rounded vascular lumen surrounding a hypoxic tumor section composed of cancer cells embedded in a 3-D hydrogel extracellular matrix. We demonstrated that the new device can be used with microscopy-based high-content analyses to track the vascular phenotypes, morphology, and sprouting into the hypoxic tumor section over a 7-day culture, as well as the response to different cancer/stromal cells. We further evaluated the integrity/leakiness of the vascular lumen in molecular delivery, and the potential of the platform to study the movement/trafficking of therapeutic immune cells. Therefore, our new platform can be used as a model for understanding tumor angiogenesis and therapeutic delivery/efficacy in vascularized hypoxic tumors.
Highlights
A characteristic feature of solid tumors in advanced cancers is the complex yet functionally abnormal network of blood vessels formed through tumor angiogenesis, which is considered one of the hallmarks of cancer [1]
The endothelialized microchannel mimics the blood vessels surrounding tumor nests in real tumors, which allows for the study of angiogenesis in response to tumor hypoxia, as well as the delivery of oxygenated medium, nutrients, drugs, and/or therapeutic cells (Figure 1A)
The PDMS microfluidic channel was bonded onto a glass slide by oxygen plasma treatment and inserted with the oxygen diffusion barrier cap in the final assembled device (Figure 1D, without cells)
Summary
A characteristic feature of solid tumors in advanced cancers is the complex yet functionally abnormal network of blood vessels formed through tumor angiogenesis, which is considered one of the hallmarks of cancer [1]. Angiogenesis is delicately balanced by pro- and anti-angiogenic factors [2]. The balance is shifted toward a chronic pro-angiogenic state, largely driven by the state of oxygen deficiency or hypoxia in cancer cells [3,4]. Endothelial cells may directly regulate the anti-tumor immune responses [13] Despite these advances, it remains difficult to study the cellular mechanisms of tumor-vasculature interplay or to evaluate the therapeutic efficacies of drugs and cell-based immunotherapies in such complex microenvironments in vivo
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