Advertisement

Cellular and Molecular Bioengineering

, Volume 12, Issue 5, pp 455–480 | Cite as

Tumor Cell Mechanosensing During Incorporation into the Brain Microvascular Endothelium

  • Marina A. Pranda
  • Kelsey M. Gray
  • Ariana Joy L. DeCastro
  • Gregory M. Dawson
  • Jae W. Jung
  • Kimberly M. StrokaEmail author
Article

Abstract

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.

Keywords

Breast cancer Hyaluronic acid Tight junctions Microvasculature 

Abbreviations

AFM

Atomic force microscopy

ANOVA

Analysis of variance

AR

Aspect ratio

BBB

Blood-brain barrier

BSA

Bovine serum albumin

DMEM

Dulbecco’s modified eagle’s medium

DMSO

Dimethyl sulfoxide

ECGS

Endothelial cell growth supplement

ECM

Extracellular matrix

FBS

Fetal bovine serum

GFP

Green fluorescent protein

HA

Hyaluronic acid

HBMEC

Human brain microvascular endothelial cell

JanaP

Junction Analyzer Program

LOX

Lysyl oxidase

PBS

Phosphate buffered saline

RPMI

Roswell Park Memorial Institute

STR

Short tandem repeat

TCM

Tumor conditioned media

TJ

Tight junctions

VE-cadherin

Vascular endothelial cadherin

VEGF

Vascular Endothelial Growth Factor

ZO-1

Zonula occludens-1

Notes

Acknowledgments

We thank Dr. Toshiyuki Yoneda for generously providing MDA-MB-231-BR cells. The University of Maryland Computer, Mathematical, and Natural Sciences imaging incubator is acknowledged for providing training and equipment for confocal imaging. Kyle Thomas at Yellow Basket, LLC (kyle@yellowbasket.io) is acknowledged for the JAnaP software development support. We also acknowledge Mary Doolin for help with editing custom Matlab code. We thank Dr. William Luscinskas from the Harvard Medical School for generously providing us with the VE-cadherin-GFP adenovirus.

Funding

Funding was provided by Burroughs Wellcome Fund (Career Award at the Scientific Interface). Additional funding was provided by the Ann G. Wylie Dissertation Fellowship from the University of Maryland Graduate School (to MAP), the Fischell Fellowship in Biomedical Engineering (to KMG), the Dr. Mabel S. Spencer Award for Excellence in Graduate Achievement (to KMG), the Clark Doctoral Fellowship (to AJD), the Fischell Department of Bioengineering, and the University of Maryland.

Author Contributions

KMS, MAP, and KMG designed the research. MAP and GMD performed experiments for Fig. 1. GMD analyzed all data for Fig. 1. AJLD performed all experiments and data analysis for Fig. 2, with guidance from MAP. MAP performed confocal microscopy for Fig. 3. KMG performed experiments and analysis for Figs. 4, 5, 6, S2, S3, and S4, with help in analysis from JWJ. KMG prepared Fig. S1. MAP performed experiments and analysis for Figs. 7a–7e. AJLD performed experiments for Figs. 7f–7h, with guidance from MAP, and MAP analyzed data for Figs. 7f–7h. MAP performed confocal microscopy for Fig. 8. MAP and AJLD performed experiments for Fig. 9. MAP performed experiments and all analysis for Fig. 10. MAP performed statistical analysis for Figs. 1, 2, 7, and 10. MAP formatted Figs. 1, 2, 3, 7, 8, 9, and 10. KMG performed statistical analysis and/or formatting for Figs. 4, 5, 6, S2, S3, and S4. MAP, KMG, and KMS wrote the manuscript. All authors edited the manuscript, and all authors reviewed and approved final version of the manuscript.

Conflict of interest

MAP, KMG, GMD, AJLD, JWJ, and KMS declare that they have no conflict of interest.

Human Studies

No human studies were carried out by the authors for this article.

Animal Studies

No animal studies were carried out by the authors for this article.

Supplementary material

12195_2019_591_MOESM1_ESM.pdf (336 kb)
Supplementary material 1 (PDF 336 kb)

References

  1. 1.
    Abbott, N. J., and A. Friedman. Overview and introduction: the blood-brain barrier in health and disease. Epilepsia 53(Suppl 6):1–6, 2012.CrossRefGoogle Scholar
  2. 2.
    Achrol, A. S., R. C. Rennert, C. Anders, R. Soffietti, M. S. Ahluwalia, L. Nayak, S. Peters, N. D. Arvold, G. R. Harsh, P. S. Steeg, and S. D. Chang. Brain metastases. Nat. Rev. Dis. Primers 5:5, 2019.CrossRefGoogle Scholar
  3. 3.
    Ajami, N. E., S. Gupta, M. R. Maurya, P. Nguyen, J. Y.-S. Li, J. Y.-J. Shyy, Z. Chen, S. Chien, and S. Subramaniam. Systems biology analysis of longitudinal functional response of endothelial cells to shear stress. Proc. Natl. Acad. Sci. 114:10990–10995, 2017.CrossRefGoogle Scholar
  4. 4.
    Akiri, G., E. Sabo, H. Dafni, Z. Vadasz, Y. Kartvelishvily, N. Gan, O. Kessler, T. Cohen, M. Resnick, M. Neeman, and G. Neufeld. Lysyl oxidase-related protein-1 promotes tumor fibrosis and tumor progression in vivo. Cancer Res. 63:1657–1666, 2003.Google Scholar
  5. 5.
    Ananthanarayanan, B., Y. Kim, and S. Kumar. Elucidating the mechanobiology of malignant brain tumors using a brain matrix-mimetic hyaluronic acid hydrogel platform. Biomaterials 32:7913–7923, 2011.CrossRefGoogle Scholar
  6. 6.
    Arshad, F., L. Wang, C. Sy, S. Avraham, and H. K. Avraham. Blood-brain barrier integrity and breast cancer metastasis to the brain. Patholog. Res. Int. 1–12:2010, 2011.Google Scholar
  7. 7.
    Arvanitis, C., S. Khuon, R. Spann, K. M. Ridge, T.-L. Chew, and L. Kreplak. Structure and biomechanics of the endothelial transcellular circumferential invasion array in tumor invasion. PLoS ONE 9:e89758, 2014.CrossRefGoogle Scholar
  8. 8.
    Avraham, H. K., S. Jiang, Y. Fu, H. Nakshatri, H. Ovadia, and S. Avraham. Angiopoietin-2 mediates blood-brain barrier impairment and colonization of triple-negative breast cancer cells in brain. J. Pathol. 232:369–381, 2014.CrossRefGoogle Scholar
  9. 9.
    Baeyens, N., C. Bandyopadhyay, B. G. Coon, S. Yun, and M. A. Schwartz. Endothelial fluid shear stress sensing in vascular health and disease. J. Clin. Invest. 126:821–828, 2016.CrossRefGoogle Scholar
  10. 10.
    Barnes, J. M., L. Przybyla, and V. M. Weaver. Tissue mechanics regulate brain development, homeostasis and disease. J. Cell Sci. 130:71–82, 2017.CrossRefGoogle Scholar
  11. 11.
    Bellail, A. C., S. B. Hunter, D. J. Brat, and E. G. Van Meir. Microregional extracellular matrix heterogeneity in brain modulates glioma cell invasion. Int. J. Biochem. Cell Biol. 36:1046–1069, 2004.CrossRefGoogle Scholar
  12. 12.
    Cai, J., W. G. Jiang, and R. E. Mansel. Phosphorylation and disorganization of vascular-endothelial cadherin in interaction between breast cancer and vascular endothelial cells. Int. J. Mol. Med. 4:191–195, 1999.Google Scholar
  13. 13.
    Chen, W., A. D. Hoffmann, H. Liu, and X. Liu. Organotropism: new insights into molecular mechanisms of breast cancer metastasis. Precis. Oncol. 2:4, 2018.CrossRefGoogle Scholar
  14. 14.
    Cox, T. R., and J. T. Erler. Remodeling and homeostasis of the extracellular matrix: implications for fibrotic diseases and cancer. Dis. Model. Mech. 4:165–178, 2011.CrossRefGoogle Scholar
  15. 15.
    Destefano, J. G., J. J. Jamieson, R. M. Linville, and P. C. Searson. Benchmarking in vitro tissue-engineered blood-brain barrier models. Fluids Barriers CNS 15:32, 2018.CrossRefGoogle Scholar
  16. 16.
    DeStefano, J. G., Z. S. Xu, A. J. Williams, N. Yimam, and P. C. Searson. Effect of shear stress on iPSC-derived human brain microvascular endothelial cells (dhBMECs). Fluids Barriers CNS 14:20, 2017.CrossRefGoogle Scholar
  17. 17.
    Discher, D. E., P. Janmey, and Y.-L. Wang. Tissue cells feel and respond to the stiffness of their substrate. Science 310:1139–1143, 2005.CrossRefGoogle Scholar
  18. 18.
    Dorland, Y. L., and S. Huveneers. Cell-cell junctional mechanotransduction in endothelial remodeling. Cell. Mol. Life Sci. 74:279–292, 2017.CrossRefGoogle Scholar
  19. 19.
    Dun, M. D., R. J. Chalkley, S. Faulkner, S. Keene, K. A. Avery-Kiejda, R. J. Scott, L. G. Falkenby, M. J. Cairns, M. R. Larsen, R. A. Bradshaw, and H. Hondermarck. Proteotranscriptomic profiling of 231-BR breast cancer cells: identification of potential biomarkers and therapeutic targets for brain metastasis. Mol. Cell. Proteomics 14:2316–2330, 2015.CrossRefGoogle Scholar
  20. 20.
    Eddy, R. J., M. D. Weidmann, V. P. Sharma, and J. S. Condeelis. Tumor cell invadopodia: invasive protrusions that orchestrate metastasis. Trends Cell Biol. 27:595–607, 2017.CrossRefGoogle Scholar
  21. 21.
    Eichler, A. F., E. Chung, D. P. Kodack, J. S. Loeffler, D. Fukumura, and R. K. Jain. The biology of brain metastases-translation to new therapies. Nat. Rev. Clin. Oncol. 8:344–356, 2011.CrossRefGoogle Scholar
  22. 22.
    Fan, J., and B. M. Fu. Quantification of malignant breast cancer cell MDA-MB-231 transmigration across brain and lung microvascular endothelium. Ann. Biomed. Eng. 44:2189–2201, 2016.CrossRefGoogle Scholar
  23. 23.
    Fazakas, C., I. Wilhelm, P. Nagyoszi, A. E. Farkas, J. Haskó, J. Molnar, H. Bauer, H.-C. Bauer, F. Ayaydin, N. T. K. Dung, L. Siklós, and I. A. Krizbai. Transmigration of melanoma cells through the blood-brain barrier: role of endothelial tight junctions and melanoma-released serine proteases. PLoS ONE 6:e20758, 2011.CrossRefGoogle Scholar
  24. 24.
    Grammas, P., J. Martinez, and B. Miller. Cerebral microvascular endothelium and the pathogenesis of neurodegenerative diseases. Expert Rev. Mol. Med. 13:e19, 2011.CrossRefGoogle Scholar
  25. 25.
    Gray, K. M., D. B. Katz, E. G. Brown, and K. M. Stroka. Quantitative phenotyping of cell-cell junctions to evaluate ZO-1 presentation in brain endothelial cells. Ann. Biomed. Eng. 2019.  https://doi.org/10.1007/s10439-019-02266-5.CrossRefGoogle Scholar
  26. 26.
    Hagedorn, E. J., J. W. Ziel, M. A. Morrissey, L. M. Linden, Z. Wang, Q. Chi, S. A. Johnson, and D. R. Sherwood. The netrin receptor DCC focuses invadopodia-driven basement membrane transmigration in vivo. J. Cell Biol. 201:903–913, 2013.CrossRefGoogle Scholar
  27. 27.
    Hamilla, S. M., K. M. Stroka, and H. Aranda-Espinoza. VE-Cadherin-independent cancer cell incorporation into the vascular endothelium precedes transmigration. PLoS ONE 9:e109748, 2014.CrossRefGoogle Scholar
  28. 28.
    Hielscher, A., K. Ellis, C. Qiu, J. Porterfield, and S. Gerecht. Fibronectin deposition participates in extracellular matrix assembly and vascular morphogenesis. PLoS ONE 11:e0147600, 2016.CrossRefGoogle Scholar
  29. 29.
    Hoshino, A., et al. Tumour exosome integrins determine organotropic metastasis. Nature 527:329–335, 2015.CrossRefGoogle Scholar
  30. 30.
    Jamieson, J. J., P. C. Searson, and S. Gerecht. Engineering the human blood-brain barrier in vitro. J. Biol. Eng. 11:37, 2017.CrossRefGoogle Scholar
  31. 31.
    Kass, L., J. T. Erler, M. Dembo, and V. M. Weaver. Mammary epithelial cell: Influence of extracellular matrix composition and organization during development and tumorigenesis. Int. J. Biochem. Cell Biol. 3(39):1987–1994, 2007.CrossRefGoogle Scholar
  32. 32.
    Katt, M. E., R. M. Linville, L. N. Mayo, Z. S. Xu, and P. C. Searson. Functional brain-specific microvessels from iPSC-derived human brain microvascular endothelial cells: the role of matrix composition on monolayer formation. Fluids Barriers CNS 15:7, 2018.CrossRefGoogle Scholar
  33. 33.
    Kienast, Y., L. Von Baumgarten, M. Fuhrmann, W. E. F. Klinkert, R. Goldbrunner, J. Herms, and F. Winkler. Real-time imaging reveals the single steps of brain metastasis formation. Nat. Med. 16:116–122, 2010.CrossRefGoogle Scholar
  34. 34.
    Kim, Y., and S. Kumar. CD44-mediated adhesion to hyaluronic acid contributes to mechanosensing and invasive motility. Mol. Cancer Res. 12:1416–1429, 2014.CrossRefGoogle Scholar
  35. 35.
    Kohn, J. C. C., D. W. W. Zhou, F. Bordeleau, A. L. L. Zhou, B. N. N. Mason, M. J. J. Mitchell, M. R. R. King, and C. A. A. Reinhart-King. Cooperative effects of matrix stiffness and fluid shear stress on endothelial cell behavior. Biophys. J. 108:471–478, 2015.CrossRefGoogle Scholar
  36. 36.
    Lee, H. J., M. F. Diaz, K. M. Price, J. A. Ozuna, S. Zhang, E. M. Sevick-Muraca, J. P. Hagan, and P. L. Wenzel. Fluid shear stress activates YAP1 to promote cancer cell motility. Nat. Commun. 8:14122, 2017.CrossRefGoogle Scholar
  37. 37.
    Lee, T.-H., H. Karsenty Avraham, S. Jiang, and S. Avraham. Vascular endothelial growth factor modulates the transendothelial migration of MDA-MB-231 breast cancer cells through regulation of brain microvascular endothelial cell permeability. J. Biol. Chem. 278:5277–5284, 2003.CrossRefGoogle Scholar
  38. 38.
    Lee, K. Y., Y.-J. Kim, H. Yoo, S. H. Lee, J. B. Park, and H. J. Kim. Human brain endothelial cell-derived COX-2 facilitates extravasation of breast cancer cells across the blood-brain barrier. Anticancer Res. 31:4307–4313, 2011.Google Scholar
  39. 39.
    Leong, H. S., A. E. Robertson, K. Stoletov, S. J. Leith, C. A. Chin, A. E. Chien, M. N. Hague, A. Ablack, K. Carmine-Simmen, V. A. Mcpherson, C. O. Postenka, E. A. Turley, S. A. Courtneidge, A. F. Chambers, and J. D. Lewis. Article invadopodia are required for cancer cell extravasation and are a therapeutic target for metastasis. Cell Rep. 8:1558–1570, 2014.CrossRefGoogle Scholar
  40. 40.
    Levental, K. R., H. Yu, L. Kass, J. N. Lakins, M. Egeblad, J. T. Erler, S. F. T. Fong, K. Csiszar, A. Giaccia, W. Weninger, M. Yamauchi, D. L. Gasser, and V. M. Weaver. Matrix crosslinking forces tumor progression by enhancing integrin signaling. Cell 139:891–906, 2009.CrossRefGoogle Scholar
  41. 41.
    Li, B., W.-D. Zhao, Z.-M. Tan, W.-G. Fang, L. Zhu, and Y.-H. Chen. Involvement of Rho/ROCK signalling in small cell lung cancer migration through human brain microvascular endothelial cells. FEBS Lett. 580:4252–4260, 2006.CrossRefGoogle Scholar
  42. 42.
    Mader, C. C., M. Oser, M. A. O. Magalhaes, J. J. Bravo-Cordero, J. Condeelis, A. J. Koleske, and H. Gil-Henn. An EGFR-Src-Arg-cortactin pathway mediates functional maturation of invadopodia and breast cancer cell invasion. J. Cancer Res. 71:OF1–OF12, 2011.CrossRefGoogle Scholar
  43. 43.
    Martin, T. A., and W. G. Jiang. Loss of tight junction barrier function and its role in cancer metastasis. Biochim. Biophys. Acta Biomembr. 1788:872–891, 2009.CrossRefGoogle Scholar
  44. 44.
    McFarlane, S., J. A. Coulter, P. Tibbits, A. O’Grady, C. McFarlane, N. Montgomery, A. Hill, H. O. McCarthy, L. S. Young, E. W. Kay, C. M. Isacke, and D. J. J. Waugh. CD44 increases the efficiency of distant metastasis of breast cancer. Oncotarget 6:11465–11476, 2015.Google Scholar
  45. 45.
    Mouw, J. K., G. Ou, and V. M. Weaver. Extracellular matrix assembly: a multiscale deconstruction. Nat. Publ. Gr. 15:771, 2014.Google Scholar
  46. 46.
    Narkhede, A. A., J. H. Crenshaw, R. M. Manning, and S. S. Rao. The influence of matrix stiffness on the behavior of brain metastatic breast cancer cells in a biomimetic hyaluronic acid hydrogel platform. J. Biomed. Mater. Res. A 106:1832–1841, 2018.CrossRefGoogle Scholar
  47. 47.
    Nayak, L., E. Q. Lee, and P. Y. Wen. Epidemiology of brain metastases. Curr. Oncol. Rep. 14:48–54, 2012.CrossRefGoogle Scholar
  48. 48.
    Northcott, J. M., I. S. Dean, J. K. Mouw, and V. M. Weaver. Feeling stress: the mechanics of cancer progression and aggression. Front. Cell Dev. Biol. 6:17, 2018.CrossRefGoogle Scholar
  49. 49.
    Novak, U., and A. H. Kaye. Extracellular matrix and the brain: components and function. J. Clin. Neurosci. 7:280–290, 2000.CrossRefGoogle Scholar
  50. 50.
    Onken, M. D., J. Li, and J. A. Cooper. Uveal melanoma cells utilize a novel Route for transendothelial migration. PLoS ONE 9:e115472, 2014.CrossRefGoogle Scholar
  51. 51.
    Onken, M. D., O. L. Mooren, S. Mukherjee, S. T. Shahan, J. Li, and J. A. Cooper. Endothelial monolayers and transendothelial migration depend on mechanical properties of the substrate. Cytoskeleton 71:695–706, 2014.CrossRefGoogle Scholar
  52. 52.
    Pogoda, K., R. Bucki, F. J. Byfield, K. Cruz, T. Lee, C. Marcinkiewicz, and P. A. Janmey. Soft substrates containing hyaluronan mimic the effects of increased stiffness on morphology, motility, and proliferation of glioma cells. Biomacromolecules 18:3040–3051, 2017.CrossRefGoogle Scholar
  53. 53.
    Prestwich, G. D., and C. O. N. Spectus. Evaluating drug efficacy and toxicology in three dimensions: using synthetic extracellular matrices in drug discovery. Acc. Chem. Res. 41:139–148, 2008.CrossRefGoogle Scholar
  54. 54.
    Reymond, N., P. Riou, and A. J. Ridley. Rho GTPases and cancer cell transendothelial migration. Methods Mol. Biol. 827:123–142, 2012.CrossRefGoogle Scholar
  55. 55.
    Roberts, H. C., T. P. L. Roberts, R. C. Brasch, and W. P. Dillon. Quantitative measurement of microvascular permeability in human brain tumors achieved using dynamic contrast-enhanced mr imaging: correlation with histologic grade. AJNR Am. J. Neuroradiol. 21:891–899, 2000.Google Scholar
  56. 56.
    Rodriguez, P. L., S. Jiang, Y. Fu, S. Avraham, and H. K. Avraham. The proinflammatory peptide substance P promotes blood-brain barrier breaching by breast cancer cells through changes in microvascular endothelial cell tight junctions. Int. J. Cancer 134:1034–1044, 2014.CrossRefGoogle Scholar
  57. 57.
    Roh-Johnson, M., J. J. Bravo-Cordero, A. Patsialou, V. P. Sharma, P. Guo, H. Liu, L. Hodgson, and J. Condeelis. Macrophage contact induces RhoA GTPase signaling to trigger tumor cell intravasation. Oncogene 33:4203–4212, 2014.CrossRefGoogle Scholar
  58. 58.
    Sarrió, D., S. M. Rodriguez-Pinilla, D. Hardisson, A. Cano, G. Moreno-Bueno, and J. Palacios. Epithelial-mesenchymal transition in breast cancer relates to the basal-like phenotype. Cancer Res. 68:989–997, 2008.CrossRefGoogle Scholar
  59. 59.
    Shaw, S. K., P. S. Bamba, B. N. Perkins, and F. W. Luscinskas. Real-time imaging of vascular endothelial-cadherin during leukocyte transmigration across endothelium. J. Immunol. 167:2323–2330, 2001.CrossRefGoogle Scholar
  60. 60.
    Shumakovich, M. A., C. P. Mencio, J. S. Siglin, R. A. Moriarty, H. M. Geller, and K. M. Stroka. Astrocytes from the brain microenvironment alter migration and morphology of metastatic breast cancer cells. FASEB J. 31:5049–5067, 2017.CrossRefGoogle Scholar
  61. 61.
    Sibony-Benyamini, H., and H. Gil-Henn. Invadopodia: the leading force. Eur. J. Cell Biol. 91:896–901, 2012.CrossRefGoogle Scholar
  62. 62.
    Stroka, K. M., and H. Aranda-Espinoza. Neutrophils display biphasic relationship between migration and substrate stiffness. Cell Motil. Cytoskelet. 66:328–341, 2009.CrossRefGoogle Scholar
  63. 63.
    Stroka, K. M., H. N. Hayenga, and H. Aranda-Espinoza. Human neutrophil cytoskeletal dynamics and contractility actively contribute to trans-endothelial migration. PLoS ONE 8:61377, 2013.CrossRefGoogle Scholar
  64. 64.
    Stroka, K. M., B. Sheng Wong, M. Shriver, J. M. Phillip, D. Wirtz, A. Kontrogianni-Konstantopoulos, and K. Konstantopoulos. Loss of giant obscurins alters breast epithelial cell mechanosensing of matrix stiffness. Oncotarget 5:54004–54020, 2016.Google Scholar
  65. 65.
    Tornavaca, O., M. Chia, N. Dufton, L. O. Almagro, D. E. Conway, A. M. Randi, M. A. Schwartz, K. Matter, and M. S. Balda. ZO-1 controls endothelial adherens junctions, cell-cell tension, angiogenesis, and barrier formation. J. Cell Biol. 208:821–838, 2015.CrossRefGoogle Scholar
  66. 66.
    Turitto, V. T. Blood viscosity, mass transport, and thrombogenesis. Prog. Hemost. Thromb. 6:139–177, 1982.Google Scholar
  67. 67.
    Vallenius, T. Actin stress fibre subtypes in mesenchymal-migrating cells. Open Biol. 3:130001, 2013.CrossRefGoogle Scholar
  68. 68.
    Vanderhooft, J. L., M. Alcoutlabi, J. J. Magda, and G. D. Prestwich. Rheological properties of cross-linked hyaluronan-gelatin hydrogels for tissue engineering. Macromol. Biosci. 2009.  https://doi.org/10.1002/mabi.200800141.CrossRefGoogle Scholar
  69. 69.
    Wrobel, J. K., and M. Toborek. Blood–brain barrier remodeling during brain metastasis formation. Mol. Med. 22:32–40, 2016.CrossRefGoogle Scholar
  70. 70.
    Yankaskas, C. L., K. N. Thompson, C. D. Paul, M. I. Vitolo, P. Mistriotis, A. Mahendra, V. K. Bajpai, D. J. Shea, K. M. Manto, A. C. Chai, N. Varadarajan, A. Kontrogianni-Konstantopoulos, S. S. Martin, and K. Konstantopoulos. A microfluidic assay for the quantification of the metastatic propensity of breast cancer specimens. Nat. Biomed. Eng. 2019.  https://doi.org/10.1038/s41551-019-0400-9.CrossRefGoogle Scholar
  71. 71.
    Ye, M., H. M. Sanchez, M. Hultz, Z. Yang, M. Bogorad, A. D. Wong, and P. C. Searson. Brain microvascular endothelial cells resist elongation due to curvature and shear stress. Sci. Rep. 4:4681, 2014.CrossRefGoogle Scholar
  72. 72.
    Yeung, T., P. C. Georges, L. A. Flanagan, B. Marg, M. Ortiz, M. Funaki, N. Zahir, W. Ming, V. Weaver, and P. A. Janmey. Effects of substrate stiffness on cell morphology, cytoskeletal structure, and adhesion. Cell Motil. Cytoskelet. 60:24–34, 2005.CrossRefGoogle Scholar
  73. 73.
    Yoneda, T., P. J. Williams, T. Hiraga, M. Niewolna, and R. Nishimura. A bone-seeking clone exhibits different biological properties from the MDA-MB-231 parental human breast cancer cells and a brain-seeking clone in vivo and in vitro. J. Bone Miner. Res. 16:1486–1495, 2001.CrossRefGoogle Scholar
  74. 74.
    Zhang, P., C. Fu, H. Bai, E. Song, and Y. Song. CD44 variant, but not standard CD44 isoforms, mediate disassembly of endothelial VE-cadherin junction on metastatic melanoma cells. FEBS Lett. 588:4573–4582, 2014.CrossRefGoogle Scholar
  75. 75.
    Zheng Shu, X., Y. Liu, F. S. Palumbo, Y. Luo, and G. D. Prestwich. In situ crosslinkable hyaluronan hydrogels for tissue engineering. Biomaterials 25:1339–1348, 2004.CrossRefGoogle Scholar

Copyright information

© Biomedical Engineering Society 2019

Authors and Affiliations

  1. 1.Fischell Department of BioengineeringUniversity of Maryland, College ParkCollege ParkUSA
  2. 2.Department of BiologyUniversity of Maryland, College ParkCollege ParkUSA
  3. 3.Biophysics ProgramUniversity of Maryland, College ParkCollege ParkUSA
  4. 4.Center for Stem Cell Biology and Regenerative MedicineUniversity of Maryland – BaltimoreBaltimoreUSA
  5. 5.Marlene and Stewart Greenebaum Comprehensive Cancer CenterUniversity of Maryland – BaltimoreBaltimoreUSA
  6. 6.Fischell Department of BioengineeringUniversity of Maryland, College ParkCollege ParkUSA

Personalised recommendations