title: Matrix stiffening promotes a tumor vasculature phenotype.
abstract: Tumor microvasculature tends to be malformed, more permeable, and more tortuous than vessels in healthy tissue, effects that have been largely attributed to up-regulated VEGF expression. However, tumor tissue tends to stiffen during solid tumor progression, and tissue stiffness is known to alter cell behaviors including proliferation, migration, and cell-cell adhesion, which are all requisite for angiogenesis. Using in vitro, in vivo, and ex ovo models, we investigated the effects of matrix stiffness on vessel growth and integrity during angiogenesis. Our data indicate that angiogenic outgrowth, invasion, and neovessel branching increase with matrix cross-linking. These effects are caused by increased matrix stiffness independent of matrix density, because increased matrix density results in decreased angiogenesis. Notably, matrix stiffness up-regulates matrix metalloproteinase (MMP) activity, and inhibiting MMPs significantly reduces angiogenic outgrowth in stiffer cross-linked gels. To investigate the functional significance of altered endothelial cell behavior in response to matrix stiffness, we measured endothelial cell barrier function on substrates mimicking the stiffness of healthy and tumor tissue. Our data indicate that barrier function is impaired and the localization of vascular endothelial cadherin is altered as function of matrix stiffness. These results demonstrate that matrix stiffness, separately from matrix density, can alter vascular growth and integrity, mimicking the changes that exist in tumor vasculature. These data suggest that therapeutically targeting tumor stiffness or the endothelial cell response to tumor stiffening may help restore vessel structure, minimize metastasis, and aid in drug delivery.
authors.affiliation: Nancy E. and Peter C. Meinig School of Biomedical Engineering, Cornell University, Ithaca, NY 14853.
authors.forename: Francois
authors.initials: F
authors.lastname: Bordeleau
authors.affiliation: Nancy E. and Peter C. Meinig School of Biomedical Engineering, Cornell University, Ithaca, NY 14853.
authors.forename: Brooke N
authors.initials: BN
authors.lastname: Mason
authors.affiliation: Robert Frederick Smith School of Chemical and Biomolecular Engineering, Cornell University, Ithaca, NY 14853.
authors.forename: Emmanuel Macklin
authors.initials: EM
authors.lastname: Lollis
authors.affiliation: Nancy E. and Peter C. Meinig School of Biomedical Engineering, Cornell University, Ithaca, NY 14853.
authors.forename: Michael
authors.initials: M
authors.lastname: Mazzola
authors.affiliation: Nancy E. and Peter C. Meinig School of Biomedical Engineering, Cornell University, Ithaca, NY 14853.
authors.forename: Matthew R
authors.initials: MR
authors.lastname: Zanotelli
authors.affiliation: Nancy E. and Peter C. Meinig School of Biomedical Engineering, Cornell University, Ithaca, NY 14853.
authors.forename: Sahana
authors.initials: S
authors.lastname: Somasegar
authors.affiliation: Nancy E. and Peter C. Meinig School of Biomedical Engineering, Cornell University, Ithaca, NY 14853.
authors.forename: Joseph P
authors.initials: JP
authors.lastname: Califano
authors.affiliation: Nancy E. and Peter C. Meinig School of Biomedical Engineering, Cornell University, Ithaca, NY 14853.
authors.forename: Christine
authors.initials: C
authors.lastname: Montague
authors.affiliation: Nancy E. and Peter C. Meinig School of Biomedical Engineering, Cornell University, Ithaca, NY 14853.
authors.forename: Danielle J
authors.initials: DJ
authors.lastname: LaValley
authors.affiliation: Nancy E. and Peter C. Meinig School of Biomedical Engineering, Cornell University, Ithaca, NY 14853.
authors.forename: John
authors.initials: J
authors.lastname: Huynh
authors.affiliation: Division of Hematology and Medical Oncology, Department of Medicine, Weill Cornell Medical College, New York, NY 10065.
authors.forename: Nuria
authors.initials: N
authors.lastname: Mencia-Trinchant
authors.affiliation: Biomedical Sciences, Cornell University, Ithaca, NY 14853.
authors.forename: Yashira L
authors.initials: YL
authors.lastname: Negrón Abril
authors.affiliation: Division of Hematology and Medical Oncology, Department of Medicine, Weill Cornell Medical College, New York, NY 10065.
authors.forename: Duane C
authors.initials: DC
authors.lastname: Hassane
authors.affiliation: Nancy E. and Peter C. Meinig School of Biomedical Engineering, Cornell University, Ithaca, NY 14853.|Sibley School of Mechanical and Aerospace Engineering, Cornell University, Ithaca, NY 14853.
authors.forename: Lawrence J
authors.initials: LJ
authors.lastname: Bonassar
authors.affiliation: Nancy E. and Peter C. Meinig School of Biomedical Engineering, Cornell University, Ithaca, NY 14853.
authors.forename: Jonathan T
authors.initials: JT
authors.lastname: Butcher
authors.affiliation: Biomedical Sciences, Cornell University, Ithaca, NY 14853.
authors.forename: Robert S
authors.initials: RS
authors.lastname: Weiss
authors.affiliation: Nancy E. and Peter C. Meinig School of Biomedical Engineering, Cornell University, Ithaca, NY 14853; cak57@cornell.edu.
authors.forename: Cynthia A
authors.initials: CA
authors.lastname: Reinhart-King
mesh_terms: D000818:Animals; D001696:Biomechanical Phenomena; D002417:Cattle; D002478:Cells, Cultured; D002642:Chick Embryo; D003094:Collagen / Q000378:metabolism; D005109:Extracellular Matrix / Q000502:physiology*; D005260:Female; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D008325:Mammary Neoplasms, Experimental / Q000098:blood supply* / Q000473:pathology / Q000503:physiopathology*; D020782:Matrix Metalloproteinases / Q000378:metabolism; D051379:Mice; D055806:Microvessels / Q000473:pathology / Q000503:physiopathology*; D009361:Neoplasm Invasiveness / Q000473:pathology / Q000503:physiopathology; D009389:Neovascularization, Pathologic / Q000473:pathology / Q000503:physiopathology; D010641:Phenotype; D059016:Tumor Microenvironment / Q000502:physiology; D059289:Vascular Stiffness / Q000502:physiology
chemical_list: D003094:Collagen; D020782:Matrix Metalloproteinases
keywords: endothelial cells; extracellular matrix; glycation; tumor stiffness; vascular permeability