Abstract
The majority of all cancers metastasize initially through the lymphatic system. Despite this, the mechanisms of lymphogenous metastasis remain poorly understood and understudied compared to hematogenous metastasis. Over the past few decades, microfluidic devices have been used to model pathophysiological processes and drug interactions in numerous contexts. These devices carry many advantages over traditional 2D in vitro systems, allowing for better replication of in vivo microenvironments. This review highlights prominent fluidic devices used to model the stages of cancer metastasis via the lymphatic system, specifically within lymphangiogenesis, vessel permeability, tumor cell chemotaxis, transendothelial migration, lymphatic circulation, and micrometastases within the lymph nodes. In addition, we present perspectives for the future roles that microfluidics might play within these settings and beyond.
Highlights
THE RISE OF MICROFLUIDICSThe discrepancies between scientific data gathered in vitro and in vivo vs clinical settings suggest that new models are warranted to recapitulate human pathophysiological processes.[1]
Despite their great potential and versatility, microfluidic devices have not been fully harnessed to study the intricacies of lymphogenous metastasis
While there are an abundance of microfluidic devices studying metastasis in the context of the bloodstream, few devices exist that incorporate lymphatics as part of or the focus of their model
Summary
The discrepancies between scientific data gathered in vitro and in vivo vs clinical settings suggest that new models are warranted to recapitulate human pathophysiological processes.[1]. The Swartz Lab created a multichambered, high-throughput flow device capable of replicating interstitial flow pressures through a 3D extracellular matrix.[61] This PDMS device allowed live imaging of morphogenesis of lymphatic and blood endothelial cells while incorporating tumor microenvironment (TME) components with cocultures of tumor cells and fibroblasts. This study was instrumental in elucidating the role of macrophagesecreted TNF-α in endothelial monolayer permeability and tumor intravasation potential Building on this, another group created artificial microvasculature from cylindrical channels lined with endothelial cells to study cancer cell migration and intravasation into perfusable vessels.[94]. Xiong et al created a simplified version that used transwell inserts coated with an LEC monolayer to study vectorial migration and intravasation of immune cells and breast cancer cell lines.[102] This more recent model was designed to be more readily accessible and easier to use for other research labs to study TEM. There currently are multiple “lymph node on a chip” devices existing outside of the applications of cancer.[117–119] outside of the scope of this review, incorporating cancer cells within lymph node on chip microenvironments may elucidate the mechanisms behind cancer cell seeding and survival
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