Article: Bordeleau, F; Mason, BN; Lollis, EM; Mazzola, M; Zanotelli, MR; Somasegar, S; Califano, JP; Montague, C; LaValley, DJ; Huynh, J; Mencia-Trinchant, N; Abril, YLN; Hassane, DC; Bonassar, LJ; Butcher, JT; Weiss, RS; Reinhart-King, CA; “Matrix Stiffening Promotes a Tumor Vasculature Phenotype”, Proceedings of the National Academy of Sciences of the United States of America, 114 (3): 492-497
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 crosslinked 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, minimizemetastasis, and aid in drug delivery.
Funding Acknowledgement: NIH [R01-HL127499, R01-CA163255, T32 GM008500, S10OD016191, S10OD018516]; National Science Foundation (NSF) [1055502, 1435755]; Cancer Research Society; NSF Graduate Research Fellowship in Science, Technology, Engineering and Mathematics; The Morgan Family Fellowship; NSF Graduate Teaching Fellows in K-12 Education Fellowship; New York State Stem Cell Science [CO29155]
Funding Text: This work was supported in part by NIH Grant R01-HL127499 (to C.A.R.-K.), National Science Foundation (NSF) awards 1055502 and 1435755 (to C.A.R.-K.), and NIH Grant R01-CA163255 (to R.S.W.). F.B. is the recipient of a Scholarship for the Next Generation of Scientists from the Cancer Research Society. B.N.M. is the recipient of an NSF Graduate Research Fellowship in Science, Technology, Engineering and Mathematics, The Morgan Family Fellowship, and an NSF Graduate Teaching Fellows in K-12 Education Fellowship. Y.L.N.A. is the recipient of NIH Training Grant T32 GM008500. Imaging data were acquired in the Cornell Biotechnology Resource Center Imaging Facility using the shared, NIH-funded (Grant S10OD016191) VisualSonics high-resolution ultrasound platform and the New York State Stem Cell Science (Grant CO29155)- and NIH (Grant S10OD018516)-funded Zeiss LSM880 confocal/multiphoton microscope.