Targeting Src family kinases inhibits bevacizumab-induced glioma cell invasion.
Anti-VEGF antibody therapy with bevacizumab provides significant clinical benefit in patients with recurrent glioblastoma multiforme (GBM). Unfortunately, progression on bevacizumab therapy is often associated with a diffuse disease recurrence pattern, which limits subsequent therapeutic options. Th...
| Main Authors: | , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Public Library of Science (PLoS)
2013-01-01
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| Series: | PLoS ONE |
| Online Access: | http://europepmc.org/articles/PMC3572988?pdf=render |
| _version_ | 1818399468117032960 |
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| author | Deborah Huveldt Laura J Lewis-Tuffin Brett L Carlson Mark A Schroeder Fausto Rodriguez Caterina Giannini Evanthia Galanis Jann N Sarkaria Panos Z Anastasiadis |
| author_facet | Deborah Huveldt Laura J Lewis-Tuffin Brett L Carlson Mark A Schroeder Fausto Rodriguez Caterina Giannini Evanthia Galanis Jann N Sarkaria Panos Z Anastasiadis |
| author_sort | Deborah Huveldt |
| collection | DOAJ |
| description | Anti-VEGF antibody therapy with bevacizumab provides significant clinical benefit in patients with recurrent glioblastoma multiforme (GBM). Unfortunately, progression on bevacizumab therapy is often associated with a diffuse disease recurrence pattern, which limits subsequent therapeutic options. Therefore, there is an urgent need to understand bevacizumab's influence on glioma biology and block it's actions towards cell invasion. To explore the mechanism(s) of GBM cell invasion we have examined a panel of serially transplanted human GBM lines grown either in short-term culture, as xenografts in mouse flank, or injected orthotopically in mouse brain. Using an orthotopic xenograft model that exhibits increased invasiveness upon bevacizumab treatment, we also tested the effect of dasatinib, a broad spectrum SFK inhibitor, on bevacizumab-induced invasion.We show that 1) activation of Src family kinases (SFKs) is common in GBM, 2) the relative invasiveness of 17 serially transplanted GBM xenografts correlates strongly with p120 catenin phosphorylation at Y228, a Src kinase site, and 3) SFK activation assessed immunohistochemically in orthotopic xenografts, as well as the phosphorylation of downstream substrates occurs specifically at the invasive tumor edge. Further, we show that SFK signaling is markedly elevated at the invasive tumor front upon bevacizumab administration, and that dasatinib treatment effectively blocked the increased invasion induced by bevacizumab.Our data are consistent with the hypothesis that the increased invasiveness associated with anti-VEGF therapy is due to increased SFK signaling, and support testing the combination of dasatinib with bevacizumab in the clinic. |
| first_indexed | 2024-12-14T07:21:09Z |
| format | Article |
| id | doaj.art-8019741ab28644f0b91fe851b0421d34 |
| institution | Directory Open Access Journal |
| issn | 1932-6203 |
| language | English |
| last_indexed | 2024-12-14T07:21:09Z |
| publishDate | 2013-01-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS ONE |
| spelling | doaj.art-8019741ab28644f0b91fe851b0421d342022-12-21T23:11:37ZengPublic Library of Science (PLoS)PLoS ONE1932-62032013-01-0182e5650510.1371/journal.pone.0056505Targeting Src family kinases inhibits bevacizumab-induced glioma cell invasion.Deborah HuveldtLaura J Lewis-TuffinBrett L CarlsonMark A SchroederFausto RodriguezCaterina GianniniEvanthia GalanisJann N SarkariaPanos Z AnastasiadisAnti-VEGF antibody therapy with bevacizumab provides significant clinical benefit in patients with recurrent glioblastoma multiforme (GBM). Unfortunately, progression on bevacizumab therapy is often associated with a diffuse disease recurrence pattern, which limits subsequent therapeutic options. Therefore, there is an urgent need to understand bevacizumab's influence on glioma biology and block it's actions towards cell invasion. To explore the mechanism(s) of GBM cell invasion we have examined a panel of serially transplanted human GBM lines grown either in short-term culture, as xenografts in mouse flank, or injected orthotopically in mouse brain. Using an orthotopic xenograft model that exhibits increased invasiveness upon bevacizumab treatment, we also tested the effect of dasatinib, a broad spectrum SFK inhibitor, on bevacizumab-induced invasion.We show that 1) activation of Src family kinases (SFKs) is common in GBM, 2) the relative invasiveness of 17 serially transplanted GBM xenografts correlates strongly with p120 catenin phosphorylation at Y228, a Src kinase site, and 3) SFK activation assessed immunohistochemically in orthotopic xenografts, as well as the phosphorylation of downstream substrates occurs specifically at the invasive tumor edge. Further, we show that SFK signaling is markedly elevated at the invasive tumor front upon bevacizumab administration, and that dasatinib treatment effectively blocked the increased invasion induced by bevacizumab.Our data are consistent with the hypothesis that the increased invasiveness associated with anti-VEGF therapy is due to increased SFK signaling, and support testing the combination of dasatinib with bevacizumab in the clinic.http://europepmc.org/articles/PMC3572988?pdf=render |
| spellingShingle | Deborah Huveldt Laura J Lewis-Tuffin Brett L Carlson Mark A Schroeder Fausto Rodriguez Caterina Giannini Evanthia Galanis Jann N Sarkaria Panos Z Anastasiadis Targeting Src family kinases inhibits bevacizumab-induced glioma cell invasion. PLoS ONE |
| title | Targeting Src family kinases inhibits bevacizumab-induced glioma cell invasion. |
| title_full | Targeting Src family kinases inhibits bevacizumab-induced glioma cell invasion. |
| title_fullStr | Targeting Src family kinases inhibits bevacizumab-induced glioma cell invasion. |
| title_full_unstemmed | Targeting Src family kinases inhibits bevacizumab-induced glioma cell invasion. |
| title_short | Targeting Src family kinases inhibits bevacizumab-induced glioma cell invasion. |
| title_sort | targeting src family kinases inhibits bevacizumab induced glioma cell invasion |
| url | http://europepmc.org/articles/PMC3572988?pdf=render |
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