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      Matrix stiffening promotes a tumor vasculature phenotype

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          Significance

          Dysregulation of both vascular architecture and function is a hallmark of numerous diseases, including cancer. This dysregulation is currently largely attributed to up-regulated proangiogenic growth factors. Here, we show that the stiffness of the underlying extracellular matrix also plays a central role in promoting angiogenesis and a characteristic tumor-like vasculature both in vitro and in vivo. The matrix stiffness-mediated angiogenesis is dependent on increased matrix metalloprotease activity. In addition, increased matrix cross-linking disrupts endothelial cell–cell junctional integrity and results in leakier vasculature. These results suggest that altered tissue mechanics, which are characteristic of solid tumors, directly influence vascular phenotype and, subsequently, may impair therapeutic delivery and efficacy.

          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.

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          Most cited references42

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          Drug resistance and the solid tumor microenvironment.

          Resistance of human tumors to anticancer drugs is most often ascribed to gene mutations, gene amplification, or epigenetic changes that influence the uptake, metabolism, or export of drugs from single cells. Another important yet little-appreciated cause of anticancer drug resistance is the limited ability of drugs to penetrate tumor tissue and to reach all of the tumor cells in a potentially lethal concentration. To reach all viable cells in the tumor, anticancer drugs must be delivered efficiently through the tumor vasculature, cross the vessel wall, and traverse the tumor tissue. In addition, heterogeneity within the tumor microenvironment leads to marked gradients in the rate of cell proliferation and to regions of hypoxia and acidity, all of which can influence the sensitivity of the tumor cells to drug treatment. In this review, we describe how the tumor microenvironment may be involved in the resistance of solid tumors to chemotherapy and discuss potential strategies to improve the effectiveness of drug treatment by modifying factors relating to the tumor microenvironment.
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            Endothelial cell migration during angiogenesis.

            Endothelial cell migration is essential to angiogenesis. This motile process is directionally regulated by chemotactic, haptotactic, and mechanotactic stimuli and further involves degradation of the extracellular matrix to enable progression of the migrating cells. It requires the activation of several signaling pathways that converge on cytoskeletal remodeling. Then, it follows a series of events in which the endothelial cells extend, contract, and throw their rear toward the front and progress forward. The aim of this review is to give an integrative view of the signaling mechanisms that govern endothelial cell migration in the context of angiogenesis.
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              Vascular effects of advanced glycation endproducts: Clinical effects and molecular mechanisms.

              The enhanced generation and accumulation of advanced glycation endproducts (AGEs) have been linked to increased risk for macrovascular and microvascular complications associated with diabetes mellitus. AGEs result from the nonenzymatic reaction of reducing sugars with proteins, lipids, and nucleic acids, potentially altering their function by disrupting molecular conformation, promoting cross-linking, altering enzyme activity, reducing their clearance, and impairing receptor recognition. AGEs may also activate specific receptors, like the receptor for AGEs (RAGE), which is present on the surface of all cells relevant to atherosclerotic processes, triggering oxidative stress, inflammation and apoptosis. Understanding the pathogenic mechanisms of AGEs is paramount to develop strategies against diabetic and cardiovascular complications.
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                Author and article information

                Journal
                Proc Natl Acad Sci U S A
                Proc. Natl. Acad. Sci. U.S.A
                pnas
                pnas
                PNAS
                Proceedings of the National Academy of Sciences of the United States of America
                National Academy of Sciences
                0027-8424
                1091-6490
                17 January 2017
                29 December 2016
                29 December 2016
                : 114
                : 3
                : 492-497
                Affiliations
                [1] aNancy E. and Peter C. Meinig School of Biomedical Engineering, Cornell University , Ithaca, NY 14853;
                [2] bRobert Frederick Smith School of Chemical and Biomolecular Engineering, Cornell University , Ithaca, NY 14853;
                [3] cDivision of Hematology and Medical Oncology, Department of Medicine, Weill Cornell Medical College , New York, NY 10065;
                [4] dBiomedical Sciences, Cornell University , Ithaca, NY 14853;
                [5] eSibley School of Mechanical and Aerospace Engineering, Cornell University , Ithaca, NY 14853
                Author notes
                2To whom correspondence should be addressed. Email: cak57@ 123456cornell.edu .

                Edited by Lance L. Munn, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA, and accepted by Editorial Board Member Rakesh K. Jain December 2, 2016 (received for review August 23, 2016)

                Author contributions: F.B., B.N.M., D.J.L., D.C.H., L.J.B., J.T.B., R.S.W., and C.A.R.-K. designed research; F.B., B.N.M., E.M.L., M.M., M.R.Z., S.S., J.P.C., C.M., J.H., N.M.-T., Y.L.N.A., and D.C.H. performed research; F.B., B.N.M., E.M.L., M.R.Z., S.S., J.P.C., C.M., D.J.L., J.H., and D.C.H. analyzed data; and F.B., B.N.M., E.M.L., D.C.H., and C.A.R.-K. wrote the paper.

                1F.B. and B.N.M. contributed equally to this article.

                Article
                PMC5255592 PMC5255592 5255592 201613855
                10.1073/pnas.1613855114
                5255592
                28034921
                3a6ba748-2c4c-4e72-9216-31a0ef1b38cd

                Freely available online through the PNAS open access option.

                History
                Page count
                Pages: 6
                Funding
                Funded by: HHS | NIH | National Heart, Lung, and Blood Institute (NHBLI) 100000050
                Award ID: HL127499
                Funded by: HHS | NIH | National Cancer Institute (NCI) 100000054
                Award ID: CA163255
                Funded by: NSF | ENG | Division of Chemical, Bioengineering, Environmental, and Transport Systems (CBET) 100000146
                Award ID: 1055502
                Funded by: NSF | ENG | Division of Civil, Mechanical and Manufacturing Innovation (CMMI) 100000147
                Award ID: 1435755
                Funded by: HHS | NIH | National Institute of General Medical Sciences (NIGMS) 100000057
                Award ID: GM008500
                Categories
                Biological Sciences
                Cell Biology
                Physical Sciences
                Applied Physical Sciences

                tumor stiffness,endothelial cells,vascular permeability,glycation,extracellular matrix

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