Autocrine semaphorin 3A signaling promotes glioblastoma dispersal.

Full Abstract

Glioblastoma multiforme (GBM) is the most malignant glioma type with diffuse borders due to extensive tumor cell infiltration. Therefore, understanding the mechanism of GBM cell dispersal is critical for developing effective therapies to limit infiltration. We identified neuropilin-1 as a mediator of cancer cell invasion by a functional proteomic screen and showed its role in GBM cells. Neuropilin-1 is a receptor for semaphorin3A (Sema3A), a secreted chemorepellent that facilitates axon guidance during neural development. Although neuropilin-1 expression in GBMs was previously shown, its role as a Sema3A receptor remained elusive. Using fluorophore-assisted light inactivation and RNA interference , we showed that neuropilin-1 is required for GBM cell migration. We also showed that GBM cells secrete Sema3A endogenously, and RNA interference-mediated downregulation of Sema3A inhibits migration and alters cell morphology that is dependent on Rac1 activity. Sema3A depletion also reduces dispersal, which is recovered by supplying Sema3A exogenously. Extracellular application of Sema3A decreases cell-substrate adhesion in a neuropilin-1-dependent manner. Using immunohistochemistry, we showed that Sema3A is overexpressed in a subset of human GBMs compared with the non-neoplastic brain. Together, these findings implicate Sema3A as an autocrine signal for neuropilin-1 to promote GBM dispersal by modulating substrate adhesion and suggest that targeting Sema3A-neuropilin-1 signaling may limit GBM infiltration.

Author information

Author/s: Bagci, T (T); Wu, J K (JK); Pfannl, R (R); Ilag, L L (LL); Jay, D G (DG);

Affiliation: Department of Neuroscience, Tufts University School of Medicine, Boston, MA 2111, USA.

Grants: R01 CA 116642 (Agency:NCI NIH HHS)

Journal and publication information

Publication Type: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't

Journal: Oncogene (Oncogene), published in England. (Language: eng)

Reference: 2009-Oct; vol 28 (issue 40) : pp 3537-50

Dates: Created 2009/10/08; Completed 2009/10/22;

PMID: 19684614, status: MEDLINE (last retrieval date: 10/22/2009, IMS Date: )

Sourced from the National Library of Medicine. Abstract text and other information may be subject to copyright.

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MeSH headings (categories)

This article was linked to the MESH Headings shown below.

Autocrine Communication - physiology
Brain Chemistry
Brain Neoplasms - pathology
Cell Adhesion
Cell Line, Tumor
Cell Movement
Glioblastoma - pathology

Glioblastoma - pathology
Humans
Neoplasm Invasiveness
Neuropilin-1 - physiology
Proteomics
Semaphorin-3A - analysis; physiology
rac1 GTP-Binding Protein - physiology

Associated Chemicals: RAC1 protein, human (0) ; SEMA3A protein, human (0) ; Semaphorin-3A (0) ; Neuropilin-1 (144713-63-3) ; rac1 GTP-Binding Protein (EC 3.6.5.2)

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