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Autocrine netrin function inhibits glioma cell motility and promotes focal adhesion formation

Jarjour, Andrew A ; Durko, Margaret ; Luk, Tamarah L ; Marçal, Nathalie ; Shekarabi, Masoud ; Kennedy, Timothy E Colon-Ramos, Daniel A.

PloS one, 2011-09, Vol.6 (9), p.e25408 [Periódico revisado por pares]

United States: Public Library of Science

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Título:
Autocrine netrin function inhibits glioma cell motility and promotes focal adhesion formation
Autor: Jarjour, Andrew A ; Durko, Margaret ; Luk, Tamarah L ; Marçal, Nathalie ; Shekarabi, Masoud ; Kennedy, Timothy E
Colon-Ramos, Daniel A.
Assuntos: 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
É parte de: PloS one, 2011-09, Vol.6 (9), p.e25408
Notas: Conceived and designed the experiments: AAJ MD TLL TEK. Performed the experiments: AAJ MD TLL NM MS. Analyzed the data: AAJ MD TLL NM TEK. Wrote the paper: AAJ TEK.
Current address: Edinburgh Centre for Multiple Sclerosis Research, Scottish Centre for Regenerative Medicine, The University of Edinburgh, Edinburgh, United Kingdom
Descrição: 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.
Editor: United States: Public Library of Science
Idioma: Inglês

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Autocrine netrin function inhibits glioma cell motility and promotes focal adhesion formation

Jarjour, Andrew A ; Durko, Margaret ; Luk, Tamarah L ; Marçal, Nathalie ; Shekarabi, Masoud ; Kennedy, Timothy E Colon-Ramos, Daniel A.

United States: Public Library of Science

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