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Metalloproteinases ADAM10 and ADAM17 mediate migration and differentiation in glioblastoma sphere-forming cells.

Metalloproteinases ADAM10 and ADAM17 mediate migration and differentiation in glioblastoma sphere-forming cells.
Metalloproteinases ADAM10 and ADAM17 mediate migration and differentiation in glioblastoma sphere-forming cells.
Glioblastoma is the most common form of primary malignant brain tumour. These tumours are highly proliferative and infiltrative resulting in a median patient survival of only 14 months from diagnosis. The current treatment regimens are ineffective against the small population of cancer stem cells residing in the tumourigenic niche; however, a new therapeutic approach could involve the removal of these cells from the microenvironment that maintains the cancer stem cell phenotype. We have isolated multipotent sphere-forming cells from human high grade glioma (glioma sphere-forming cells (GSCs)) to investigate the adhesive and migratory properties of these cells in vitro. We have focused on the role of two closely related metalloproteinases ADAM10 and ADAM17 due to their high expression in glioblastoma and GSCs and their ability to activate cytokines and growth factors. Here, we report that ADAM10 and ADAM17 inhibition selectively increases GSC, but not neural stem cell, migration and that the migrated GSCs exhibit a differentiated phenotype. We also observed a correlation between nestin, a stem/progenitor marker, and fibronectin, an extracellular matrix protein, expression in high grade glioma tissues. GSCs adherence on fibronectin is mediated by ?5?1 integrin, where fibronectin further promotes GSC migration and is an effective candidate for in vivo cancer stem cell migration out of the tumourigenic niche. Our results suggest that therapies against ADAM10 and ADAM17 may promote cancer stem cell migration away from the tumourigenic niche resulting in a differentiated phenotype that is more susceptible to treatment.
0893-7648
1-13
Siney, Elodie J.
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Holden, Alexander
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Casselden, Elizabeth
1f235c1a-ad52-43cc-9902-9b89a0a0f7bb
Bulstrode, Harry
7d977124-acda-4e5f-91b5-183105c297f7
Thomas, Gareth J.
2ff54aa9-a766-416b-91ee-cf1c5be74106
Willaime-Morawek, Sandrine
24a2981f-aa9e-4bf6-ad12-2ccf6b49f1c0
Siney, Elodie J.
8be7cefb-b63f-4c92-a275-b0495e75e4b2
Holden, Alexander
3e92b14f-a1bf-45ff-9d54-bf32a32f3e4e
Casselden, Elizabeth
1f235c1a-ad52-43cc-9902-9b89a0a0f7bb
Bulstrode, Harry
7d977124-acda-4e5f-91b5-183105c297f7
Thomas, Gareth J.
2ff54aa9-a766-416b-91ee-cf1c5be74106
Willaime-Morawek, Sandrine
24a2981f-aa9e-4bf6-ad12-2ccf6b49f1c0

Siney, Elodie J., Holden, Alexander and Casselden, Elizabeth et al. (2016) Metalloproteinases ADAM10 and ADAM17 mediate migration and differentiation in glioblastoma sphere-forming cells. Molecular Neurobiology, 1-13. (doi:10.1007/s12035-016-0053-6). (PMID:27541285)

Record type: Article

Abstract

Glioblastoma is the most common form of primary malignant brain tumour. These tumours are highly proliferative and infiltrative resulting in a median patient survival of only 14 months from diagnosis. The current treatment regimens are ineffective against the small population of cancer stem cells residing in the tumourigenic niche; however, a new therapeutic approach could involve the removal of these cells from the microenvironment that maintains the cancer stem cell phenotype. We have isolated multipotent sphere-forming cells from human high grade glioma (glioma sphere-forming cells (GSCs)) to investigate the adhesive and migratory properties of these cells in vitro. We have focused on the role of two closely related metalloproteinases ADAM10 and ADAM17 due to their high expression in glioblastoma and GSCs and their ability to activate cytokines and growth factors. Here, we report that ADAM10 and ADAM17 inhibition selectively increases GSC, but not neural stem cell, migration and that the migrated GSCs exhibit a differentiated phenotype. We also observed a correlation between nestin, a stem/progenitor marker, and fibronectin, an extracellular matrix protein, expression in high grade glioma tissues. GSCs adherence on fibronectin is mediated by ?5?1 integrin, where fibronectin further promotes GSC migration and is an effective candidate for in vivo cancer stem cell migration out of the tumourigenic niche. Our results suggest that therapies against ADAM10 and ADAM17 may promote cancer stem cell migration away from the tumourigenic niche resulting in a differentiated phenotype that is more susceptible to treatment.

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10.1007_s12035-016-0053-6.pdf - Version of Record
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More information

Accepted/In Press date: 9 August 2016
e-pub ahead of print date: 19 August 2016
Organisations: Clinical & Experimental Sciences

Identifiers

Local EPrints ID: 399742
URI: https://eprints.soton.ac.uk/id/eprint/399742
ISSN: 0893-7648
PURE UUID: d54dc89e-521d-4a5e-b743-c8121191a308
ORCID for Sandrine Willaime-Morawek: ORCID iD orcid.org/0000-0002-1121-6419

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Date deposited: 26 Aug 2016 10:53
Last modified: 10 Dec 2019 01:41

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