Elucidation of the Roles of Tumor Integrin 1 in the Extravasation Stage of the Metastasis Cascade
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Author(s)
Chen, Michelle B.
Lamar, John
Li, Ran
Hynes, Richard O.
Kamm, Roger Dale
Date Issued
March 2016
Journal
Cancer Research
Publisher
American Association for Cancer Research (AACR)
Citation
Chen, M. B. et al. “Elucidation of the Roles of Tumor Integrin 1 in the Extravasation Stage of the Metastasis Cascade.” Cancer Research 76, 9 (March 2016): 2513–2524 © 2016 American Association for Cancer Research
Version
Author's final manuscript
Abstract
Tumor integrin β1 (ITGB1) contributes to primary tumor growth and metastasis, but its specific roles in extravasation have not yet been clearly elucidated. In this study, we engineered a three-dimensional microfluidic model of the human microvasculature to recapitulate the environment wherein extravasation takes place and assess the consequences of β1 depletion in cancer cells. Combined with confocal imaging, these tools allowed us to decipher the detailed morphology of transmigrating tumor cells and associated endothelial cells in vitro at high spatio-temporal resolution not easily achieved in conventional transmigration assays. Dynamic imaging revealed that β1-depleted cells lacked the ability to sustain protrusions into the subendothelial matrix in contrast with control cells. Specifically, adhesion via α3β1 and α6β1 to subendothelial laminin was a critical prerequisite for successful transmigration. β1 was required to invade past the endothelial basement membrane, whereas its attenuation in a syngeneic tumor model resulted in reduced metastatic colonization of the lung, an effect not observed upon depletion of other integrin alpha and beta subunits. Collectively, our findings in this novel model of the extravasation microenvironment revealed a critical requirement for β1 in several steps of extravasation, providing new insights into the mechanisms underlying metastasis.
MIT Department
Massachusetts Institute of Technology. Department of Biological Engineering
Massachusetts Institute of Technology. Department of Biology
Massachusetts Institute of Technology. Department of Mechanical Engineering
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DOI of Published Version
https://doi.org/10.1158/0008-5472.CAN-15-1325
