Three-dimensional microfluidic model for tumor cell intravasation and endothelial barrier function

Ioannis K. Zervantonakis, Shannon K. Hughes-Alford, Joseph L. Charest, John S. Condeelis, Frank B. Gertler, Roger D. Kamm

Research output: Contribution to journalArticle

392 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)13515-13520
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume109
Issue number34
DOIs
StatePublished - Aug 21 2012

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Microfluidics
Endothelial Cells
Neoplasms
Cell Movement
Tumor Necrosis Factor-alpha
Macrophages
Carcinoma
Tumor Microenvironment
Fibrosarcoma
Cell Communication
Endothelium
Blood Vessels
Permeability
Blood Cells
Neoplasm Metastasis

Keywords

  • 3D microfluidics
  • Cancer migration
  • Cancer-endothelial cell interactions
  • In vitro
  • Transmigration

ASJC Scopus subject areas

  • General

Cite this

Three-dimensional microfluidic model for tumor cell intravasation and endothelial barrier function. / Zervantonakis, Ioannis K.; Hughes-Alford, Shannon K.; Charest, Joseph L.; Condeelis, John S.; Gertler, Frank B.; Kamm, Roger D.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 109, No. 34, 21.08.2012, p. 13515-13520.

Research output: Contribution to journalArticle

Zervantonakis, Ioannis K. ; Hughes-Alford, Shannon K. ; Charest, Joseph L. ; Condeelis, John S. ; Gertler, Frank B. ; Kamm, Roger D. / Three-dimensional microfluidic model for tumor cell intravasation and endothelial barrier function. In: Proceedings of the National Academy of Sciences of the United States of America. 2012 ; Vol. 109, No. 34. pp. 13515-13520.
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