Abstract

Microvessel-on-a-Chip For Investigating Glioma-Vascular Interactions

Yan Yan Shery Huang, University Lecturer in Bioengineering, University of Cambridge

Gliomas, which are heterogeneous tumors made up of malignant glial cells, can often grow and progress without angiogenesis and thus escape anti-angiogenic therapies. One of the alternative mechanisms of tumor blood supply is vessel co-option, where cancer cells migrate along the pre-existing vessel of the host organ, preserving the blood-brain barrier (BBB). However, studying this phenomenon is currently limited mainly to animal models. With the push to reduce in vivo approaches, developing an experimental, tissue-on-a-chip model to encompass one or more tractable microenvironmental factors, will enable us to better understand their mechanistic roles in brain tumor progression. An extracellular matrix-integrated PDMS-based microfluidic chip with a rounded microvessel, mimicking the BBB, was generated using a human microvascular cell line (hCMEC/D3). In the chip, a vessel of ~100µm in diameter was interfaced with a 3D brain cancer cell culture (either U87, glioma neural stem or normal neural stem cells, embedded in a collagen-based ECM). The system was coupled with live-cell imaging and image analysis, which enabled tracking of cell-cell and cell-microenvironment interactions. Changes in gene expression and protein distribution in endothelial cells were successfully quantified, thus enabling the characterization of the influence of cancer cells population on the microvessel. Development and optimization of the device has given us the opportunity to study the influence of glioma cells on normal brain endothelium, when angiogenesis does not occur. Crucially, this can be done in controlled, user-defined environment unlike in animal models.