Autocrine netrin function inhibits glioma cell motility and promotes focal adhesion formation
Deregulation of mechanisms that control cell motility plays a key role in tumor progression by promoting tumor cell dissemination. Secreted netrins and their receptors, Deleted in Colorectal Cancer (DCC), neogenin, and the UNC5 homologues, regulate cell and axon migration, cell adhesion, and tissue...
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| description | Deregulation of mechanisms that control cell motility plays a key role in tumor progression by promoting tumor cell dissemination. Secreted netrins and their receptors, Deleted in Colorectal Cancer (DCC), neogenin, and the UNC5 homologues, regulate cell and axon migration, cell adhesion, and tissue morphogenesis. Netrin and netrin receptor expression have previously been shown to be disrupted in invasive tumors, including glioblastoma. We determined that the human glioblastoma cell lines U87, U343, and U373 all express neogenin, UNC5 homologues, and netrin-1 or netrin-3, but only U87 cells express DCC. Using transfilter migration assays, we demonstrate DCC-dependent chemoattractant migration of U87 cells up a gradient of netrin-1. In contrast, U343 and U373 cells, which do not express DCC, were neither attracted nor repelled. Ectopic expression of DCC by U343 and U373 cells resulted in these cells becoming competent to respond to a gradient of netrin-1 as a chemoattractant, and also slowed their rate of spontaneous migration. Here, in addition to netrins' well-characterized chemotropic activity, we demonstrate an autocrine function for netrin-1 and netrin-3 in U87 and U373 cells that slows migration. We provide evidence that netrins promote the maturation of focal complexes, structures associated with cell movement, into focal adhesions. Consistent with this, netrin, DCC, and UNC5 homologues were associated with focal adhesions, but not focal complexes. Disrupting netrin or DCC function did not alter cell proliferation or survival. Our findings provide evidence that DCC can slow cell migration, and that neogenin and UNC5 homologues are not sufficient to substitute for DCC function in these cells. Furthermore, we identify a role for netrins as autocrine inhibitors of cell motility that promote focal adhesion formation. These findings suggest that disruption of netrin signalling may disable a mechanism that normally restrains inappropriate cell migration. |
| doi_str_mv | 10.1371/journal.pone.0025408 |
| format | Article |
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Secreted netrins and their receptors, Deleted in Colorectal Cancer (DCC), neogenin, and the UNC5 homologues, regulate cell and axon migration, cell adhesion, and tissue morphogenesis. Netrin and netrin receptor expression have previously been shown to be disrupted in invasive tumors, including glioblastoma. We determined that the human glioblastoma cell lines U87, U343, and U373 all express neogenin, UNC5 homologues, and netrin-1 or netrin-3, but only U87 cells express DCC. Using transfilter migration assays, we demonstrate DCC-dependent chemoattractant migration of U87 cells up a gradient of netrin-1. In contrast, U343 and U373 cells, which do not express DCC, were neither attracted nor repelled. Ectopic expression of DCC by U343 and U373 cells resulted in these cells becoming competent to respond to a gradient of netrin-1 as a chemoattractant, and also slowed their rate of spontaneous migration. Here, in addition to netrins' well-characterized chemotropic activity, we demonstrate an autocrine function for netrin-1 and netrin-3 in U87 and U373 cells that slows migration. We provide evidence that netrins promote the maturation of focal complexes, structures associated with cell movement, into focal adhesions. Consistent with this, netrin, DCC, and UNC5 homologues were associated with focal adhesions, but not focal complexes. Disrupting netrin or DCC function did not alter cell proliferation or survival. Our findings provide evidence that DCC can slow cell migration, and that neogenin and UNC5 homologues are not sufficient to substitute for DCC function in these cells. Furthermore, we identify a role for netrins as autocrine inhibitors of cell motility that promote focal adhesion formation. These findings suggest that disruption of netrin signalling may disable a mechanism that normally restrains inappropriate cell migration.</description><identifier>ISSN: 1932-6203</identifier><identifier>EISSN: 1932-6203</identifier><identifier>DOI: 10.1371/journal.pone.0025408</identifier><identifier>PMID: 21980448</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>Adhesion ; Apoptosis ; Autocrine Communication - drug effects ; Autocrine signalling ; Biology ; Brain cancer ; Brain tumors ; Cell adhesion ; Cell adhesion & migration ; Cell Line, Tumor ; Cell migration ; Cell Movement - drug effects ; Cell proliferation ; Cell survival ; Colorectal cancer ; Colorectal carcinoma ; Colorectal Neoplasms - genetics ; DCC protein ; Deregulation ; Disruption ; Ectopic expression ; Extracellular matrix ; Focal Adhesions - drug effects ; Focal Adhesions - metabolism ; Gene Deletion ; Gene Expression Regulation, Neoplastic - drug effects ; Glioblastoma ; Glioma ; Glioma - pathology ; Glioma cells ; Gliomas ; Growth factors ; Homology ; Humans ; Invasiveness ; Laminin - pharmacology ; Metastasis ; Molecular weight ; Morphogenesis ; Motility ; Nerve Growth Factors - deficiency ; Nerve Growth Factors - genetics ; Nerve Growth Factors - metabolism ; Nervous system ; Netrin Receptors ; Netrin-1 ; Neurology ; Neurosurgery ; Protein Transport - drug effects ; Proteins ; Receptors ; Receptors, Cell Surface - deficiency ; Receptors, Cell Surface - genetics ; Receptors, Cell Surface - metabolism ; Rodents ; Spinal cord ; Tumor Suppressor Proteins - deficiency ; Tumor Suppressor Proteins - genetics ; Tumor Suppressor Proteins - metabolism ; Tumorigenesis ; Tumors</subject><ispartof>PloS one, 2011-09, Vol.6 (9), p.e25408</ispartof><rights>COPYRIGHT 2011 Public Library of Science</rights><rights>2011 Jarjour et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License: https://creativecommons.org/licenses/by/4.0/ (the “License”), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. 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Secreted netrins and their receptors, Deleted in Colorectal Cancer (DCC), neogenin, and the UNC5 homologues, regulate cell and axon migration, cell adhesion, and tissue morphogenesis. Netrin and netrin receptor expression have previously been shown to be disrupted in invasive tumors, including glioblastoma. We determined that the human glioblastoma cell lines U87, U343, and U373 all express neogenin, UNC5 homologues, and netrin-1 or netrin-3, but only U87 cells express DCC. Using transfilter migration assays, we demonstrate DCC-dependent chemoattractant migration of U87 cells up a gradient of netrin-1. In contrast, U343 and U373 cells, which do not express DCC, were neither attracted nor repelled. Ectopic expression of DCC by U343 and U373 cells resulted in these cells becoming competent to respond to a gradient of netrin-1 as a chemoattractant, and also slowed their rate of spontaneous migration. 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Secreted netrins and their receptors, Deleted in Colorectal Cancer (DCC), neogenin, and the UNC5 homologues, regulate cell and axon migration, cell adhesion, and tissue morphogenesis. Netrin and netrin receptor expression have previously been shown to be disrupted in invasive tumors, including glioblastoma. We determined that the human glioblastoma cell lines U87, U343, and U373 all express neogenin, UNC5 homologues, and netrin-1 or netrin-3, but only U87 cells express DCC. Using transfilter migration assays, we demonstrate DCC-dependent chemoattractant migration of U87 cells up a gradient of netrin-1. In contrast, U343 and U373 cells, which do not express DCC, were neither attracted nor repelled. Ectopic expression of DCC by U343 and U373 cells resulted in these cells becoming competent to respond to a gradient of netrin-1 as a chemoattractant, and also slowed their rate of spontaneous migration. Here, in addition to netrins' well-characterized chemotropic activity, we demonstrate an autocrine function for netrin-1 and netrin-3 in U87 and U373 cells that slows migration. We provide evidence that netrins promote the maturation of focal complexes, structures associated with cell movement, into focal adhesions. Consistent with this, netrin, DCC, and UNC5 homologues were associated with focal adhesions, but not focal complexes. Disrupting netrin or DCC function did not alter cell proliferation or survival. Our findings provide evidence that DCC can slow cell migration, and that neogenin and UNC5 homologues are not sufficient to substitute for DCC function in these cells. Furthermore, we identify a role for netrins as autocrine inhibitors of cell motility that promote focal adhesion formation. These findings suggest that disruption of netrin signalling may disable a mechanism that normally restrains inappropriate cell migration.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>21980448</pmid><doi>10.1371/journal.pone.0025408</doi><tpages>e25408</tpages><oa>free_for_read</oa></addata></record> |
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| recordid | cdi_plos_journals_1308927980 |
| source | MEDLINE; DOAJ Directory of Open Access Journals; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; PubMed Central; Free Full-Text Journals in Chemistry; Public Library of Science (PLoS) |
| subjects | Adhesion Apoptosis Autocrine Communication - drug effects Autocrine signalling Biology Brain cancer Brain tumors Cell adhesion Cell adhesion & migration Cell Line, Tumor Cell migration Cell Movement - drug effects Cell proliferation Cell survival Colorectal cancer Colorectal carcinoma Colorectal Neoplasms - genetics DCC protein Deregulation Disruption Ectopic expression Extracellular matrix Focal Adhesions - drug effects Focal Adhesions - metabolism Gene Deletion Gene Expression Regulation, Neoplastic - drug effects Glioblastoma Glioma Glioma - pathology Glioma cells Gliomas Growth factors Homology Humans Invasiveness Laminin - pharmacology Metastasis Molecular weight Morphogenesis Motility Nerve Growth Factors - deficiency Nerve Growth Factors - genetics Nerve Growth Factors - metabolism Nervous system Netrin Receptors Netrin-1 Neurology Neurosurgery Protein Transport - drug effects Proteins Receptors Receptors, Cell Surface - deficiency Receptors, Cell Surface - genetics Receptors, Cell Surface - metabolism Rodents Spinal cord Tumor Suppressor Proteins - deficiency Tumor Suppressor Proteins - genetics Tumor Suppressor Proteins - metabolism Tumorigenesis Tumors |
| title | Autocrine netrin function inhibits glioma cell motility and promotes focal adhesion formation |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-02-02T07%3A27%3A59IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-gale_plos_&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Autocrine%20netrin%20function%20inhibits%20glioma%20cell%20motility%20and%20promotes%20focal%20adhesion%20formation&rft.jtitle=PloS%20one&rft.au=Jarjour,%20Andrew%20A&rft.date=2011-09-28&rft.volume=6&rft.issue=9&rft.spage=e25408&rft.pages=e25408-&rft.issn=1932-6203&rft.eissn=1932-6203&rft_id=info:doi/10.1371/journal.pone.0025408&rft_dat=%3Cgale_plos_%3EA476877506%3C/gale_plos_%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=1308927980&rft_id=info:pmid/21980448&rft_galeid=A476877506&rft_doaj_id=oai_doaj_org_article_4f73c588eead43d5825edf45a10705ac&rfr_iscdi=true |