TWIST1 promotes invasion through mesenchymal change in human glioblastoma
<p>Abstract</p> <p>Background</p> <p>Tumor cell invasion into adjacent normal brain is a mesenchymal feature of GBM and a major factor contributing to their dismal outcomes. Therefore, better understandings of mechanisms that promote mesenchymal change in GBM are of gre...
| Main Authors: | , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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BMC
2010-07-01
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| Series: | Molecular Cancer |
| Online Access: | http://www.molecular-cancer.com/content/9/1/194 |
| _version_ | 1818081605258838016 |
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| author | Wakimoto Hiroaki Glackin Carlotta A Maxwell John-Patrick Oxford Robert G Khorasani Leila Beyer Richard Petit Audrey Mikheev Andrei M Mikheeva Svetlana A González-Herrero Inés Sánchez-García Isidro Silber John R Horner Philip J Rostomily Robert C |
| author_facet | Wakimoto Hiroaki Glackin Carlotta A Maxwell John-Patrick Oxford Robert G Khorasani Leila Beyer Richard Petit Audrey Mikheev Andrei M Mikheeva Svetlana A González-Herrero Inés Sánchez-García Isidro Silber John R Horner Philip J Rostomily Robert C |
| author_sort | Wakimoto Hiroaki |
| collection | DOAJ |
| description | <p>Abstract</p> <p>Background</p> <p>Tumor cell invasion into adjacent normal brain is a mesenchymal feature of GBM and a major factor contributing to their dismal outcomes. Therefore, better understandings of mechanisms that promote mesenchymal change in GBM are of great clinical importance to address invasion. We previously showed that the bHLH transcription factor TWIST1 which orchestrates carcinoma metastasis through an epithelial mesenchymal transition (EMT) is upregulated in GBM and promotes invasion of the SF767 GBM cell line <it>in vitro</it>.</p> <p>Results</p> <p>To further define TWIST1 functions in GBM we tested the impact of TWIST1 over-expression on invasion <it>in vivo </it>and its impact on gene expression. We found that TWIST1 significantly increased SNB19 and T98G cell line invasion in orthotopic xenotransplants and increased expression of genes in functional categories associated with adhesion, extracellular matrix proteins, cell motility and locomotion, cell migration and actin cytoskeleton organization. Consistent with this TWIST1 reduced cell aggregation, promoted actin cytoskeletal re-organization and enhanced migration and adhesion to fibronectin substrates. Individual genes upregulated by TWIST1 known to promote EMT and/or GBM invasion included SNAI2, MMP2, HGF, FAP and FN1. Distinct from carcinoma EMT, TWIST1 did not generate an E- to N-cadherin "switch" in GBM cell lines. The clinical relevance of putative TWIST target genes SNAI2 and fibroblast activation protein alpha (FAP) identified <it>in vitro </it>was confirmed by their highly correlated expression with TWIST1 in 39 human tumors. The potential therapeutic importance of inhibiting TWIST1 was also shown through a decrease in cell invasion <it>in vitro </it>and growth of GBM stem cells.</p> <p>Conclusions</p> <p>Together these studies demonstrated that TWIST1 enhances GBM invasion in concert with mesenchymal change not involving the canonical cadherin switch of carcinoma EMT. Given the recent recognition that mesenchymal change in GBMs is associated with increased malignancy, these findings support the potential therapeutic importance of strategies to subvert TWIST1-mediated mesenchymal change.</p> |
| first_indexed | 2024-12-10T19:08:52Z |
| format | Article |
| id | doaj.art-45e20ca43a094b1fb7b7e74573f9efe8 |
| institution | Directory Open Access Journal |
| issn | 1476-4598 |
| language | English |
| last_indexed | 2024-12-10T19:08:52Z |
| publishDate | 2010-07-01 |
| publisher | BMC |
| record_format | Article |
| series | Molecular Cancer |
| spelling | doaj.art-45e20ca43a094b1fb7b7e74573f9efe82022-12-22T01:36:49ZengBMCMolecular Cancer1476-45982010-07-019119410.1186/1476-4598-9-194TWIST1 promotes invasion through mesenchymal change in human glioblastomaWakimoto HiroakiGlackin Carlotta AMaxwell John-PatrickOxford Robert GKhorasani LeilaBeyer RichardPetit AudreyMikheev Andrei MMikheeva Svetlana AGonzález-Herrero InésSánchez-García IsidroSilber John RHorner Philip JRostomily Robert C<p>Abstract</p> <p>Background</p> <p>Tumor cell invasion into adjacent normal brain is a mesenchymal feature of GBM and a major factor contributing to their dismal outcomes. Therefore, better understandings of mechanisms that promote mesenchymal change in GBM are of great clinical importance to address invasion. We previously showed that the bHLH transcription factor TWIST1 which orchestrates carcinoma metastasis through an epithelial mesenchymal transition (EMT) is upregulated in GBM and promotes invasion of the SF767 GBM cell line <it>in vitro</it>.</p> <p>Results</p> <p>To further define TWIST1 functions in GBM we tested the impact of TWIST1 over-expression on invasion <it>in vivo </it>and its impact on gene expression. We found that TWIST1 significantly increased SNB19 and T98G cell line invasion in orthotopic xenotransplants and increased expression of genes in functional categories associated with adhesion, extracellular matrix proteins, cell motility and locomotion, cell migration and actin cytoskeleton organization. Consistent with this TWIST1 reduced cell aggregation, promoted actin cytoskeletal re-organization and enhanced migration and adhesion to fibronectin substrates. Individual genes upregulated by TWIST1 known to promote EMT and/or GBM invasion included SNAI2, MMP2, HGF, FAP and FN1. Distinct from carcinoma EMT, TWIST1 did not generate an E- to N-cadherin "switch" in GBM cell lines. The clinical relevance of putative TWIST target genes SNAI2 and fibroblast activation protein alpha (FAP) identified <it>in vitro </it>was confirmed by their highly correlated expression with TWIST1 in 39 human tumors. The potential therapeutic importance of inhibiting TWIST1 was also shown through a decrease in cell invasion <it>in vitro </it>and growth of GBM stem cells.</p> <p>Conclusions</p> <p>Together these studies demonstrated that TWIST1 enhances GBM invasion in concert with mesenchymal change not involving the canonical cadherin switch of carcinoma EMT. Given the recent recognition that mesenchymal change in GBMs is associated with increased malignancy, these findings support the potential therapeutic importance of strategies to subvert TWIST1-mediated mesenchymal change.</p>http://www.molecular-cancer.com/content/9/1/194 |
| spellingShingle | Wakimoto Hiroaki Glackin Carlotta A Maxwell John-Patrick Oxford Robert G Khorasani Leila Beyer Richard Petit Audrey Mikheev Andrei M Mikheeva Svetlana A González-Herrero Inés Sánchez-García Isidro Silber John R Horner Philip J Rostomily Robert C TWIST1 promotes invasion through mesenchymal change in human glioblastoma Molecular Cancer |
| title | TWIST1 promotes invasion through mesenchymal change in human glioblastoma |
| title_full | TWIST1 promotes invasion through mesenchymal change in human glioblastoma |
| title_fullStr | TWIST1 promotes invasion through mesenchymal change in human glioblastoma |
| title_full_unstemmed | TWIST1 promotes invasion through mesenchymal change in human glioblastoma |
| title_short | TWIST1 promotes invasion through mesenchymal change in human glioblastoma |
| title_sort | twist1 promotes invasion through mesenchymal change in human glioblastoma |
| url | http://www.molecular-cancer.com/content/9/1/194 |
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