Flow‐regulated endothelial glycocalyx determines metastatic cancer cell activity
Open Access
- 13 March 2020
- journal article
- research article
- Published by Wiley in The FASEB Journal
- Vol. 34 (5), 6166-6184
- https://doi.org/10.1096/fj.201901920r
Abstract
Cancer metastasis and secondary tumor initiation largely depend on circulating tumor cell (CTC) and vascular endothelial cell (EC) interactions by incompletely understood mechanisms. Endothelial glycocalyx (GCX) dysfunction may play a significant role in this process. GCX structure depends on vascular flow patterns, which are irregular in tumor environments. This work presents evidence that disturbed flow (DF) induces GCX degradation, leading to CTC homing to the endothelium, a first step in secondary tumor formation. A 2-fold greater attachment of CTCs to human ECs was found to occur under DF conditions, compared to uniform flow (UF) conditions. These results corresponded to an approximately 50% decrease in wheat germ agglutinin (WGA)-labeled components of the GCX under DF conditions, vs UF conditions, with undifferentiated levels of CTC-recruiting E-selectin under DF vs UF conditions. Confirming the role of the GCX, neuraminidase induced the degradation of WGA-labeled GCX under UF cell culture conditions or in Balb/C mice and led to an over 2-fold increase in CTC attachment to ECs or Balb/C mouse lungs, respectively, compared to untreated conditions. These experiments confirm that flow-induced GCX degradation can enable metastatic CTC arrest. This work, therefore, provides new insight into pathways of secondary tumor formation.Keywords
Funding Information
- National Institutes of Health (K01 HL125499, 1R01HL124315‐01A1)
- National Science Foundation (DGE‐1451070, CMMI‐1846962)
- American Heart Association (18PRE33960461)
This publication has 86 references indexed in Scilit:
- Heparan Sulfate Regrowth Profiles Under Laminar Shear Flow Following Enzymatic DegradationCellular and Molecular Bioengineering, 2013
- Lest we forget the endothelial glycocalyx in sepsisCritical Care, 2012
- Structure and Composition of Pulmonary Arteries, Capillaries, and VeinsComprehensive Physiology, 2012
- Imaging the Endothelial Glycocalyx In Vitro by Rapid Freezing/Freeze Substitution Transmission Electron MicroscopyArteriosclerosis, Thrombosis, and Vascular Biology, 2011
- Normalization of the Vasculature for Treatment of Cancer and Other DiseasesPhysiological Reviews, 2011
- Relating Function to Branching Geometry: A Micro-CT Study of the Hepatic Artery, Portal Vein, and Biliary TreeCells Tissues Organs, 2011
- Molecular Stiffness of SelectinsOnline Journal of Public Health Informatics, 2011
- Partial carotid ligation is a model of acutely induced disturbed flow, leading to rapid endothelial dysfunction and atherosclerosisAmerican Journal of Physiology-Heart and Circulatory Physiology, 2009
- The endothelial glycocalyx: composition, functions, and visualizationPflügers Archiv - European Journal of Physiology, 2007
- Tumour-cell invasion and migration: diversity and escape mechanismsNature Reviews Cancer, 2003