Demonstration of Enhancement of Tumor Intravasation by Dicarbonyl Stress Using a Microfluidic Organ-on-chip

Cancer metastasis involves cell migration from their primary organ foci into vascular channels, followed by dissemination to prospective colonization sites. Vascular entry of tumor cells or intravasation involves their breaching stromal and endothelial extracellular matrix (ECM) and the endothelial barriers. How the kinetics of this breach are confounded by chronic inflammatory stresses seen in diabetes and aging remains ill-investigated. To study the problem, a histopathology-motivated, imaging-tractable, microfluidic multi-organ-on-chip platform is constructed, that seamlessly integrates a breast tumor-like compartment: invasive MDA-MB-231 in a 3D Collagen I scaffold, and a flow-implemented vascular channel: immortalized human aortic endothelia (TeloHAEC) on laminin-rich basement membrane (lrBM). The chip showcases the complexity of intravasation, wherein tumor cells and endothelia cooperate to form anastomotic structures, which facilitate cancer cell migration into the vascular channel. Upon entry, cancer cells adhere to and flow within the vascular channel. Exposure to methylglyoxal (MG), a dicarbonyl stressor associated with diabetic circulatory milieu increases cancer cell intravasation and adhesion through the vascular channel. This can be driven by MG-induced endothelial senescence and shedding, but also by the ability of MG to degrade lrBM and pathologically cross-link Collagen I, diminishing cell-ECM adhesion. Thus, dicarbonyl stress attenuates homeostatic barriers to cancer intravasation, exacerbating metastasis.