Tumor Cell Mechanosensing During Incorporation into the Brain Microvascular Endothelium
| Autor: | Ariana Joy L. DeCastro, Marina A. Pranda, Gregory M. Dawson, Kimberly M. Stroka, Jae W. Jung, Kelsey M. Gray |
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| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
Tight junction biology Chemistry Cell CD44 Cell migration macromolecular substances 02 engineering and technology 021001 nanoscience & nanotechnology General Biochemistry Genetics and Molecular Biology Article Endothelial stem cell Extracellular matrix 03 medical and health sciences 030104 developmental biology medicine.anatomical_structure Modeling and Simulation Paracellular transport Biophysics medicine biology.protein Transcellular 0210 nano-technology |
| Zdroj: | Cell Mol Bioeng |
| ISSN: | 1865-5025 |
| Popis: | INTRODUCTION: Tumor metastasis to the brain occurs in approximately 20% of all cancer cases and often occurs due to tumor cells crossing the blood-brain barrier (BBB). The brain microenvironment is comprised of a soft hyaluronic acid (HA)-rich extracellular matrix with an elastic modulus of 0.1–1 kPa, whose crosslinking is often altered in disease states. METHODS: To explore the effects of HA crosslinking on breast tumor cell migration, we developed a biomimetic model of the human brain endothelium, consisting of brain microvascular endothelial cell (HBMEC) monolayers on HA and gelatin (HA/gelatin) films with different degrees of crosslinking, as established by varying the concentration of the crosslinker Extralink. RESULTS AND DISCUSSION: Metastatic breast tumor cell migration speed, diffusion coefficient, spreading area, and aspect ratio increased with decreasing HA crosslinking, a mechanosensing trend that correlated with tumor cell actin organization but not CD44 expression. Meanwhile, breast tumor cell incorporation into endothelial monolayers was independent of HA crosslinking density, suggesting that alterations in HA crosslinking density affect tumor cells only after they exit the vasculature. Tumor cells appeared to exploit both the paracellular and transcellular routes of trans-endothelial migration. Quantitative phenotyping of HBMEC junctions via a novel Python software revealed a VEGF-dependent decrease in punctate VE-cadherin junctions and an increase in continuous and perpendicular junctions when HBMECs were treated with tumor cell-secreted factors. CONCLUSIONS: Overall, our quantitative results suggest that a combination of biochemical and physical factors promote tumor cell migration through the BBB. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1007/s12195-019-00591-2) contains supplementary material, which is available to authorized users. |
| Databáze: | OpenAIRE |
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