{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,12,12]],"date-time":"2025-12-12T07:55:34Z","timestamp":1765526134161,"version":"3.48.0"},"reference-count":27,"publisher":"Walter de Gruyter GmbH","issue":"3","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2018,9,25]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec id=\"j_dmpt-2018-0007_s_999_w2aab2b8c13b1b7b1aab1c16b1Aa\">\n                    <jats:title>Background:<\/jats:title>\n                    <jats:p>\n                      Central nervous system (CNS) hemangioblastoma (HB) is the most common tumor in the von Hippel Lindau (VHL) disorder, the hereditary tumor syndrome caused by the biallelic mutations of the\n                      <jats:italic>VHL<\/jats:italic>\n                      gene. The disrupted VHL and Elongin protein interaction on hypoxia-inducible factor-1\u03b1 (HIF-1\u03b1) induces a set of hypoxia-inducible genes, resulting in an unchecked endothelial cell proliferation that then leads to hemangioblastoma formation. However, recent studies have shown that disruptive germline mutations of\n                      <jats:italic>VHL<\/jats:italic>\n                      need not result in hemangioblastoma, though it can cause other manifestations of the VHL syndrome. Similarly, sporadic hemangioblastoma can occur rarely without a somatic biallelic\n                      <jats:italic>VHL<\/jats:italic>\n                      mutation. The VHL protein was earlier found to be associated with the deposition of matrix fibronectin (FN) protein in the renal extracellular matrix.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec id=\"j_dmpt-2018-0007_s_998_w2aab2b8c13b1b7b1aab1c16b2Aa\">\n                    <jats:title>Methods:<\/jats:title>\n                    <jats:p>The present study was designed to investigate the deposition of the matrix FN protein in VHL-associated hemangioblastoma.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec id=\"j_dmpt-2018-0007_s_997_w2aab2b8c13b1b7b1aab1c16b3Aa\">\n                    <jats:title>Results:<\/jats:title>\n                    <jats:p>Seven HB tumor samples from the VHL syndrome had lower expressions of tissue FN compared to the control cerebellum samples or the control blood vessel sample. On comparing the VHL and FN protein expressions in a timed endothelial tube assay, the VHL protein expression was absent during the initial phase of tube formation but started expressing after 6 h. The levels of matrix form of FN gradually increased along with the VHL expression during the maturation of tube formation. Tube formation was found to be enhanced with extraneously added soluble FN and inhibited by matrix FN. Similarly, tube formation was inhibited by a modified tripeptide (RGD) inhibitor of integrin (-\u03b1V\u03b23), namely, Cyclo-Ala-Arg-Gly-Asp-3-aminomethylbenzoyl.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec id=\"j_dmpt-2018-0007_s_996_w2aab2b8c13b1b7b1aab1c16b4Aa\">\n                    <jats:title>Conclusions:<\/jats:title>\n                    <jats:p>Our study implicates that the extracellular deposition and matrix formation of FN is important for vascular endothelial proliferation, and that its absence has roles in the development of hemangioblastoma in the VHL syndrome.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1515\/dmpt-2018-0007","type":"journal-article","created":{"date-parts":[[2018,5,30]],"date-time":"2018-05-30T18:18:06Z","timestamp":1527704286000},"page":"127-134","source":"Crossref","is-referenced-by-count":1,"title":["Exploring the role of defective fibronectin matrix assembly in the VHL-associated CNS hemangioblastoma"],"prefix":"10.1515","volume":"33","author":[{"given":"Narendranath","family":"Vikkath","sequence":"first","affiliation":[{"name":"Department of Neurosurgery, Research Associate, Amrita Vishwa Vidyapeetham, Amrita Institute of Medical Sciences and Research Centre , Kochi-41, Kerala , India , Email:"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0888-8094","authenticated-orcid":false,"given":"Prasanth","family":"Ariyannur","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, Amrita School of Medicine, Amrita Vishwa Vidyapeetham, Amrita Institute of Medical Sciences and Research Centre , Kochi, Kerala , India"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Krishnakumar N.","family":"Menon","sequence":"additional","affiliation":[{"name":"Amrita Center for Nanosciences and Molecular Medicine, Amrita Institute of Medical Sciences and Research Centre , Kochi, Kerala , India"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Bindhu","family":"MR","sequence":"additional","affiliation":[{"name":"Department of Pathology, Amrita Institute of Medical Sciences and Research Centre , Kochi, Kerala , India"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ashok","family":"Pillai","sequence":"additional","affiliation":[{"name":"Professor, Department of Neurosurgery , Amrita Institute of Medical Sciences and Research Centre , Kochi-41, Kerala , India"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"374","published-online":{"date-parts":[[2018,5,29]]},"reference":[{"key":"2025121207095712748_j_dmpt-2018-0007_ref_001_w2aab2b8c13b1b7b1ab2b1b1Aa","doi-asserted-by":"crossref","unstructured":"Kim WY, Kaelin WG. Role of VHL gene mutation in human cancer. J Clin Oncol 2004;22:4991\u20135004.","DOI":"10.1200\/JCO.2004.05.061"},{"key":"2025121207095712748_j_dmpt-2018-0007_ref_002_w2aab2b8c13b1b7b1ab2b1b2Aa","doi-asserted-by":"crossref","unstructured":"Leung RS, Biswas SV, Duncan M, Rankin S. Imaging features of von Hippel-Lindau disease. Radiographics 2008;28:65\u201379.","DOI":"10.1148\/rg.281075052"},{"key":"2025121207095712748_j_dmpt-2018-0007_ref_003_w2aab2b8c13b1b7b1ab2b1b3Aa","doi-asserted-by":"crossref","unstructured":"Vikkath N, Valiyaveedan S, Nampoothiri S, Radhakrishnan N, Pillai GS, Nair V, et al. Genotype-phenotype analysis of von Hippel-Lindau syndrome in fifteen Indian families. Fam Cancer 2015;14:585\u201394.","DOI":"10.1007\/s10689-015-9806-z"},{"key":"2025121207095712748_j_dmpt-2018-0007_ref_004_w2aab2b8c13b1b7b1ab2b1b4Aa","doi-asserted-by":"crossref","unstructured":"Wierzbicka-Patynowski I, Schwarzbauer JE. The ins and outs of fibronectin matrix assembly. J Cell Sci 2003;116(Pt 16):3269\u201376.","DOI":"10.1242\/jcs.00670"},{"key":"2025121207095712748_j_dmpt-2018-0007_ref_005_w2aab2b8c13b1b7b1ab2b1b5Aa","doi-asserted-by":"crossref","unstructured":"Schwarzbauer JE, Sechler JL. Fibronectin fibrillogenesis: a paradigm for extracellular matrix assembly. Curr Opin Cell Biol 1999;11:622\u20137.","DOI":"10.1016\/S0955-0674(99)00017-4"},{"key":"2025121207095712748_j_dmpt-2018-0007_ref_006_w2aab2b8c13b1b7b1ab2b1b6Aa","doi-asserted-by":"crossref","unstructured":"Ohh M, Yauch RL, Lonergan KM, Whaley JM, Stemmer-Rachamimov AO, Louis DN, et al. The von Hippel-Lindau tumor suppressor protein is required for proper assembly of an extracellular fibronectin matrix. Mol Cell 1998;1:959\u201368.","DOI":"10.1016\/S1097-2765(00)80096-9"},{"key":"2025121207095712748_j_dmpt-2018-0007_ref_007_w2aab2b8c13b1b7b1ab2b1b7Aa","doi-asserted-by":"crossref","unstructured":"Ji Q, Burk RD. Downregulation of integrins by von Hippel-Lindau (VHL) tumor suppressor protein is independent of VHL-directed hypoxia-inducible factor alpha degradation. Biochem Cell Biol 2008;86:227\u201334.","DOI":"10.1139\/O08-035"},{"key":"2025121207095712748_j_dmpt-2018-0007_ref_008_w2aab2b8c13b1b7b1ab2b1b8Aa","doi-asserted-by":"crossref","unstructured":"Tang N, Mack F, Haase VH, Simon MC, Johnson RS. pVHL function is essential for endothelial extracellular matrix deposition. Mol Cell Biol 2006;26:2519\u201330.","DOI":"10.1128\/MCB.26.7.2519-2530.2006"},{"key":"2025121207095712748_j_dmpt-2018-0007_ref_009_w2aab2b8c13b1b7b1ab2b1b9Aa","doi-asserted-by":"crossref","unstructured":"Baudin B, Bruneel A, Bosselut N, Vaubourdolle M. A protocol for isolation and culture of human umbilical vein endothelial cells. Nat Protoc 2007;2:481\u20135.","DOI":"10.1038\/nprot.2007.54"},{"key":"2025121207095712748_j_dmpt-2018-0007_ref_010_w2aab2b8c13b1b7b1ab2b1c10Aa","doi-asserted-by":"crossref","unstructured":"Richards FM, Webster AR, McMahon R, Woodward ER, Rose S, Maher ER. Molecular genetic analysis of von Hippel-Lindau disease. J Intern Med 1998;243:527\u201333.","DOI":"10.1046\/j.1365-2796.1998.00334.x"},{"key":"2025121207095712748_j_dmpt-2018-0007_ref_011_w2aab2b8c13b1b7b1ab2b1c11Aa","doi-asserted-by":"crossref","unstructured":"Bradford MM. A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Anal Bioanal Chem 1976;72:248\u201354.","DOI":"10.1006\/abio.1976.9999"},{"key":"2025121207095712748_j_dmpt-2018-0007_ref_012_w2aab2b8c13b1b7b1ab2b1c12Aa","doi-asserted-by":"crossref","unstructured":"Min JH, Yang H, Ivan M, Gertler F, Kaelin WG, Jr., Pavletich NP. Structure of an HIF-1alpha-pVHL complex: hydroxyproline recognition in signaling. Science 2002;296:1886\u20139.","DOI":"10.1126\/science.1073440"},{"key":"2025121207095712748_j_dmpt-2018-0007_ref_013_w2aab2b8c13b1b7b1ab2b1c13Aa","doi-asserted-by":"crossref","unstructured":"Arnaoutova I, Kleinman HK. In vitro angiogenesis: endothelial cell tube formation on gelled basement membrane extract. Nat Protoc 2010;5:628\u201335.","DOI":"10.1038\/nprot.2010.6"},{"key":"2025121207095712748_j_dmpt-2018-0007_ref_014_w2aab2b8c13b1b7b1ab2b1c14Aa","doi-asserted-by":"crossref","unstructured":"Morla A, Zhang Z, Ruoslahti E. Superfibronectin is a functionally distinct form of fibronectin. Nature 1994;367:193\u20136.","DOI":"10.1038\/367193a0"},{"key":"2025121207095712748_j_dmpt-2018-0007_ref_015_w2aab2b8c13b1b7b1ab2b1c15Aa","doi-asserted-by":"crossref","unstructured":"Arnaoutova I, George J, Kleinman HK, Benton G. The endothelial cell tube formation assay on basement membrane turns 20: state of the science and the art. Angiogenesis 2009;12:267\u201374.","DOI":"10.1007\/s10456-009-9146-4"},{"key":"2025121207095712748_j_dmpt-2018-0007_ref_016_w2aab2b8c13b1b7b1ab2b1c16Aa","doi-asserted-by":"crossref","unstructured":"Yi M, Ruoslahti E. A fibronectin fragment inhibits tumor growth, angiogenesis, and metastasis. Proc Natl Acad Sci USA 2001;98:620\u20134.","DOI":"10.1073\/pnas.98.2.620"},{"key":"2025121207095712748_j_dmpt-2018-0007_ref_017_w2aab2b8c13b1b7b1ab2b1c17Aa","doi-asserted-by":"crossref","unstructured":"Brooks PC, Montgomery AM, Rosenfeld M, Reisfeld RA, Hu T, Klier G, et al. Integrin alpha v beta 3 antagonists promote tumor regression by inducing apoptosis of angiogenic blood vessels. Cell 1994;79:1157\u201364.","DOI":"10.1016\/0092-8674(94)90007-8"},{"key":"2025121207095712748_j_dmpt-2018-0007_ref_018_w2aab2b8c13b1b7b1ab2b1c18Aa","doi-asserted-by":"crossref","unstructured":"Gnarra JR, Ward JM, Porter FD, Wagner JR, Devor DE, Grinberg A, et al. Defective placental vasculogenesis causes embryonic lethality in VHL-deficient mice. Proc Natl Acad Sci USA 1997;94:9102\u20137.","DOI":"10.1073\/pnas.94.17.9102"},{"key":"2025121207095712748_j_dmpt-2018-0007_ref_019_w2aab2b8c13b1b7b1ab2b1c19Aa","doi-asserted-by":"crossref","unstructured":"Wang H, Shepard M, Zhang C, Dong L, Walker DT, Guedez L, et al. Deletion of the von Hippel-Lindau gene in hemangioblasts causes hemangioblastoma-like lesions in murine retina. Cancer Res 2018;78:1266\u201374.","DOI":"10.1158\/0008-5472.CAN-17-1718"},{"key":"2025121207095712748_j_dmpt-2018-0007_ref_020_w2aab2b8c13b1b7b1ab2b1c20Aa","doi-asserted-by":"crossref","unstructured":"Zhuang Z, Frerich JM, Huntoon K, Yang C, Merrill MJ, Abdullaev Z, et al. Tumor derived vasculogenesis in von Hippel-Lindau disease-associated tumors. Sci Rep 2014;4:4102.","DOI":"10.1038\/srep04102"},{"key":"2025121207095712748_j_dmpt-2018-0007_ref_021_w2aab2b8c13b1b7b1ab2b1c21Aa","doi-asserted-by":"crossref","unstructured":"Senger DR, Davis GE. Angiogenesis. Cold Spring Harbor perspectives in biology. 2011;3:a005090.","DOI":"10.1101\/cshperspect.a005090"},{"key":"2025121207095712748_j_dmpt-2018-0007_ref_022_w2aab2b8c13b1b7b1ab2b1c22Aa","doi-asserted-by":"crossref","unstructured":"Stickle NH, Chung J, Klco JM, Hill RP, Kaelin WG, Jr., Ohh M. pVHL modification by NEDD8 is required for fibronectin matrix assembly and suppression of tumor development. Mol Cell Biol 2004;24:3251\u201361.","DOI":"10.1128\/MCB.24.8.3251-3261.2004"},{"key":"2025121207095712748_j_dmpt-2018-0007_ref_023_w2aab2b8c13b1b7b1ab2b1c23Aa","doi-asserted-by":"crossref","unstructured":"George EL, Georges-Labouesse EN, Patel-King RS, Rayburn H, Hynes RO. Defects in mesoderm, neural tube and vascular development in mouse embryos lacking fibronectin. Development 1993;119:1079\u201391.","DOI":"10.1242\/dev.119.4.1079"},{"key":"2025121207095712748_j_dmpt-2018-0007_ref_024_w2aab2b8c13b1b7b1ab2b1c24Aa","doi-asserted-by":"crossref","unstructured":"Ilic D, Kovacic B, McDonagh S, Jin F, Baumbusch C, Gardner DG, et al. Focal adhesion kinase is required for blood vessel morphogenesis. Circ Res 2003;92:300\u20137.","DOI":"10.1161\/01.RES.0000055016.36679.23"},{"key":"2025121207095712748_j_dmpt-2018-0007_ref_025_w2aab2b8c13b1b7b1ab2b1c25Aa","doi-asserted-by":"crossref","unstructured":"Ilic D, Kovacic B, Johkura K, Schlaepfer DD, Tomasevic N, Han Q, et al. FAK promotes organization of fibronectin matrix and fibrillar adhesions. J Cell Sci 2004;117(Pt 2):177\u201387.","DOI":"10.1242\/jcs.00845"},{"key":"2025121207095712748_j_dmpt-2018-0007_ref_026_w2aab2b8c13b1b7b1ab2b1c26Aa","doi-asserted-by":"crossref","unstructured":"Francis SE, Goh KL, Hodivala-Dilke K, Bader BL, Stark M, Davidson D, et al. Central roles of alpha5beta1 integrin and fibronectin in vascular development in mouse embryos and embryoid bodies. Arterioscler Thromb Vasc Biol 2002;22:927\u201333.","DOI":"10.1161\/01.ATV.0000016045.93313.F2"},{"key":"2025121207095712748_j_dmpt-2018-0007_ref_027_w2aab2b8c13b1b7b1ab2b1c27Aa","doi-asserted-by":"crossref","unstructured":"George EL, Baldwin HS, Hynes RO. Fibronectins are essential for heart and blood vessel morphogenesis but are dispensable for initial specification of precursor cells. Blood 1997;90:3073\u201381.","DOI":"10.1182\/blood.V90.8.3073"}],"container-title":["Drug Metabolism and Personalized Therapy"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/www.degruyter.com\/view\/j\/dmdi.2018.33.issue-3\/dmpt-2018-0007\/dmpt-2018-0007.xml","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.degruyterbrill.com\/document\/doi\/10.1515\/dmpt-2018-0007\/xml","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.degruyterbrill.com\/document\/doi\/10.1515\/dmpt-2018-0007\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,12,12]],"date-time":"2025-12-12T07:51:59Z","timestamp":1765525919000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.degruyterbrill.com\/document\/doi\/10.1515\/dmpt-2018-0007\/html"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2018,5,29]]},"references-count":27,"journal-issue":{"issue":"3","published-online":{"date-parts":[[2018,8,2]]},"published-print":{"date-parts":[[2018,9,25]]}},"alternative-id":["10.1515\/dmpt-2018-0007"],"URL":"https:\/\/doi.org\/10.1515\/dmpt-2018-0007","relation":{},"ISSN":["2363-8915","2363-8907"],"issn-type":[{"type":"electronic","value":"2363-8915"},{"type":"print","value":"2363-8907"}],"subject":[],"published":{"date-parts":[[2018,5,29]]}}}