Desert Hedgehog/Patch2 axis contributes to vascular permeability and angiogenesis in glioblastoma
Glioblastoma multiforme (GBM) constitutes the most common and the most aggressive type of human tumors affecting the central nervous system. Prognosis remains dark due to the inefficiency of current treatments and the rapid relapse. Paralleling other human tumors, GBM contains a fraction of tumor in...
| Main Authors: | , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Frontiers Media S.A.
2015-11-01
|
| Series: | Frontiers in Pharmacology |
| Subjects: | |
| Online Access: | http://journal.frontiersin.org/Journal/10.3389/fphar.2015.00281/full |
| _version_ | 1818518400899481600 |
|---|---|
| author | Sandy eAzzi Lucas eTreps Heloise M Leclair Heloise M Leclair Hai-Mi eNgo Elizabeth eHarford-Wright Elizabeth eHarford-Wright Julie eGAVARD Julie eGAVARD |
| author_facet | Sandy eAzzi Lucas eTreps Heloise M Leclair Heloise M Leclair Hai-Mi eNgo Elizabeth eHarford-Wright Elizabeth eHarford-Wright Julie eGAVARD Julie eGAVARD |
| author_sort | Sandy eAzzi |
| collection | DOAJ |
| description | Glioblastoma multiforme (GBM) constitutes the most common and the most aggressive type of human tumors affecting the central nervous system. Prognosis remains dark due to the inefficiency of current treatments and the rapid relapse. Paralleling other human tumors, GBM contains a fraction of tumor initiating cells with the capacity to self-renew, initiate and maintain the tumor mass. These cells were found in close proximity to brain vasculature, suggesting functional interactions between brain tumor-initiating cells (BTICs) and endothelial cells within the so-called vascular niche. However, the mechanisms by which these cells impact on the endothelium plasticity and function remain unclear. Using culture of BTICs isolated from a cohort of 14 GBM patients, we show that BTIC secretome promotes brain endothelial cell remodeling in a VEGF-independent manner. Gene array analysis unmasked that BTIC-released factors drove the expression of Ptch2 in endothelial cells. Interestingly, BTICs produce Desert Hedgehog (DHH) ligand, enabling a paracrine DHH/Ptch2 signaling cascade that conveys elevated permeability and angiogenesis. Finally, DHH silencing in BTICs dramatically reduced tumor growth, as well as vascularization and intra-tumor permeability. Collectively, our data unveil a role for DHH in exacerbated tumor angiogenesis and permeability, which may ultimately favor glioblastoma growth, and thus place the DHH/Ptch2 nexus as a molecular target for novel therapies. |
| first_indexed | 2024-12-11T01:10:04Z |
| format | Article |
| id | doaj.art-8d2b138b216747958abc27e5267f7e86 |
| institution | Directory Open Access Journal |
| issn | 1663-9812 |
| language | English |
| last_indexed | 2024-12-11T01:10:04Z |
| publishDate | 2015-11-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Pharmacology |
| spelling | doaj.art-8d2b138b216747958abc27e5267f7e862022-12-22T01:26:04ZengFrontiers Media S.A.Frontiers in Pharmacology1663-98122015-11-01610.3389/fphar.2015.00281173261Desert Hedgehog/Patch2 axis contributes to vascular permeability and angiogenesis in glioblastomaSandy eAzzi0Lucas eTreps1Heloise M Leclair2Heloise M Leclair3Hai-Mi eNgo4Elizabeth eHarford-Wright5Elizabeth eHarford-Wright6Julie eGAVARD7Julie eGAVARD8Inserm U1016, CNRS UMR8104, University Paris DescartesInserm U1016, CNRS UMR8104, University Paris DescartesInserm U1016, CNRS UMR8104, University Paris DescartesInserm U892, CNRS UMR6299, University NantesInserm U1016, CNRS UMR8104, University Paris DescartesInserm U1016, CNRS UMR8104, University Paris DescartesInserm U892, CNRS UMR6299, University NantesInserm U1016, CNRS UMR8104, University Paris DescartesInserm U892, CNRS UMR6299, University NantesGlioblastoma multiforme (GBM) constitutes the most common and the most aggressive type of human tumors affecting the central nervous system. Prognosis remains dark due to the inefficiency of current treatments and the rapid relapse. Paralleling other human tumors, GBM contains a fraction of tumor initiating cells with the capacity to self-renew, initiate and maintain the tumor mass. These cells were found in close proximity to brain vasculature, suggesting functional interactions between brain tumor-initiating cells (BTICs) and endothelial cells within the so-called vascular niche. However, the mechanisms by which these cells impact on the endothelium plasticity and function remain unclear. Using culture of BTICs isolated from a cohort of 14 GBM patients, we show that BTIC secretome promotes brain endothelial cell remodeling in a VEGF-independent manner. Gene array analysis unmasked that BTIC-released factors drove the expression of Ptch2 in endothelial cells. Interestingly, BTICs produce Desert Hedgehog (DHH) ligand, enabling a paracrine DHH/Ptch2 signaling cascade that conveys elevated permeability and angiogenesis. Finally, DHH silencing in BTICs dramatically reduced tumor growth, as well as vascularization and intra-tumor permeability. Collectively, our data unveil a role for DHH in exacerbated tumor angiogenesis and permeability, which may ultimately favor glioblastoma growth, and thus place the DHH/Ptch2 nexus as a molecular target for novel therapies.http://journal.frontiersin.org/Journal/10.3389/fphar.2015.00281/fullGliomaPermeabilitytumor vasculatureBrain endothelial cellsHedghog |
| spellingShingle | Sandy eAzzi Lucas eTreps Heloise M Leclair Heloise M Leclair Hai-Mi eNgo Elizabeth eHarford-Wright Elizabeth eHarford-Wright Julie eGAVARD Julie eGAVARD Desert Hedgehog/Patch2 axis contributes to vascular permeability and angiogenesis in glioblastoma Frontiers in Pharmacology Glioma Permeability tumor vasculature Brain endothelial cells Hedghog |
| title | Desert Hedgehog/Patch2 axis contributes to vascular permeability and angiogenesis in glioblastoma |
| title_full | Desert Hedgehog/Patch2 axis contributes to vascular permeability and angiogenesis in glioblastoma |
| title_fullStr | Desert Hedgehog/Patch2 axis contributes to vascular permeability and angiogenesis in glioblastoma |
| title_full_unstemmed | Desert Hedgehog/Patch2 axis contributes to vascular permeability and angiogenesis in glioblastoma |
| title_short | Desert Hedgehog/Patch2 axis contributes to vascular permeability and angiogenesis in glioblastoma |
| title_sort | desert hedgehog patch2 axis contributes to vascular permeability and angiogenesis in glioblastoma |
| topic | Glioma Permeability tumor vasculature Brain endothelial cells Hedghog |
| url | http://journal.frontiersin.org/Journal/10.3389/fphar.2015.00281/full |
| work_keys_str_mv | AT sandyeazzi deserthedgehogpatch2axiscontributestovascularpermeabilityandangiogenesisinglioblastoma AT lucasetreps deserthedgehogpatch2axiscontributestovascularpermeabilityandangiogenesisinglioblastoma AT heloisemleclair deserthedgehogpatch2axiscontributestovascularpermeabilityandangiogenesisinglioblastoma AT heloisemleclair deserthedgehogpatch2axiscontributestovascularpermeabilityandangiogenesisinglioblastoma AT haimiengo deserthedgehogpatch2axiscontributestovascularpermeabilityandangiogenesisinglioblastoma AT elizabetheharfordwright deserthedgehogpatch2axiscontributestovascularpermeabilityandangiogenesisinglioblastoma AT elizabetheharfordwright deserthedgehogpatch2axiscontributestovascularpermeabilityandangiogenesisinglioblastoma AT julieegavard deserthedgehogpatch2axiscontributestovascularpermeabilityandangiogenesisinglioblastoma AT julieegavard deserthedgehogpatch2axiscontributestovascularpermeabilityandangiogenesisinglioblastoma |