Three-dimensional microfluidic model for tumor cell intravasation and endothelial barrier function
Author(s)Zervantonakisa, Ioannis K.; Hughes-Alford, Shannon Kay; Charest, Joseph L.; Condeelis, John S.; Gertler, Frank; Kamm, Roger Dale; ... Show more Show less
MetadataShow full item record
Entry of tumor cells into the blood stream is a critical step in cancer metastasis. Although significant progress has been made in visualizing tumor cell motility in vivo, the underlying mechanism of cancer cell intravasation remains largely unknown. We developed a microfluidic-based assay to recreate the tumor-vascular interface in three-dimensions, allowing for high resolution, real-time imaging, and precise quantification of endothelial barrier function. Studies are aimed at testing the hypothesis that carcinoma cell intravasation is regulated by biochemical factors from the interacting cells and cellular interactions with macrophages. We developed a method to measure spatially resolved endothelial permeability and show that signaling with macrophages via secretion of tumor necrosis factor alpha results in endothelial barrier impairment. Under these conditions intravasation rates were increased as validated with live imaging. To further investigate tumor-endothelial (TC-EC) signaling, we used highly invasive fibrosarcoma cells and quantified tumor cell migration dynamics and TC-EC interactions under control and perturbed (with tumor necrosis factor alpha) barrier conditions. We found that endothelial barrier impairment was associated with a higher number and faster dynamics of TC-EC interactions, in agreement with our carcinoma intravasation results. Taken together our results provide evidence that the endothelium poses a barrier to tumor cell intravasation that can be regulated by factors present in the tumor microenvironment.
DepartmentCharles Stark Draper Laboratory; David H. Koch Institute for Integrative Cancer Research at MIT; Massachusetts Institute of Technology. Department of Biological Engineering; Massachusetts Institute of Technology. Department of Biology; Massachusetts Institute of Technology. Department of Mechanical Engineering
Proceedings of the National Academy of Sciences of the United States of America
National Academy of Sciences (U.S.)
Zervantonakis, I. K. et al. “Three-dimensional Microfluidic Model for Tumor Cell Intravasation and Endothelial Barrier Function.” Proceedings of the National Academy of Sciences 109.34 (2012): 13515–13520.
Final published version