Angiogenic Gene Signature Derived from Subtype Specific Cell Models Segregate Proneural and Mesenchymal Glioblastoma
Intertumoral molecular heterogeneity in glioblastoma identifies four major subtypes based on expression of molecular markers. Among them, the two clinically interrelated subtypes, proneural and mesenchymal, are the most aggressive with proneural liable for conversion to mesenchymal upon therapy. Usi...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2017-07-01
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| Series: | Frontiers in Oncology |
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| Online Access: | http://journal.frontiersin.org/article/10.3389/fonc.2017.00146/full |
| _version_ | 1811312317492625408 |
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| author | Aman Sharma Aman Sharma Ajinkya Bendre Abir Mondal Dattatraya Muzumdar Naina Goel Anjali Shiras |
| author_facet | Aman Sharma Aman Sharma Ajinkya Bendre Abir Mondal Dattatraya Muzumdar Naina Goel Anjali Shiras |
| author_sort | Aman Sharma |
| collection | DOAJ |
| description | Intertumoral molecular heterogeneity in glioblastoma identifies four major subtypes based on expression of molecular markers. Among them, the two clinically interrelated subtypes, proneural and mesenchymal, are the most aggressive with proneural liable for conversion to mesenchymal upon therapy. Using two patient-derived novel primary cell culture models (MTA10 and KW10), we developed a minimal but unique four-gene signature comprising genes vascular endothelial growth factor A (VEGF-A), vascular endothelial growth factor B (VEGF-B) and angiopoietin 1 (ANG1), angiopoietin 2 (ANG2) that effectively segregated the proneural (MTA10) and mesenchymal (KW10) glioblastoma subtypes. The cell culture preclassified as mesenchymal showed elevated expression of genes VEGF-A, VEGF-B and ANG1, ANG2 as compared to the other cell culture model that mimicked the proneural subtype. The differentially expressed genes in these two cell culture models were confirmed by us using TCGA and Verhaak databases and we refer to it as a minimal multigene signature (MMS). We validated this MMS on human glioblastoma tissue sections with the use of immunohistochemistry on preclassified (YKL-40 high or mesenchymal glioblastoma and OLIG2 high or proneural glioblastoma) tumor samples (n = 30). MMS segregated mesenchymal and proneural subtypes with 83% efficiency using a simple histopathology scoring approach (p = 0.008 for ANG2 and p = 0.01 for ANG1). Furthermore, MMS expression negatively correlated with patient survival. Importantly, MMS staining demonstrated spatiotemporal heterogeneity within each subclass, adding further complexity to subtype identification in glioblastoma. In conclusion, we report a novel and simple sequencing-independent histopathology-based biomarker signature comprising genes VEGF-A, VEGF-B and ANG1, ANG2 for subtyping of proneural and mesenchymal glioblastoma. |
| first_indexed | 2024-04-13T10:35:10Z |
| format | Article |
| id | doaj.art-b8bd7889f65b4d3ab8c845aef6c434cd |
| institution | Directory Open Access Journal |
| issn | 2234-943X |
| language | English |
| last_indexed | 2024-04-13T10:35:10Z |
| publishDate | 2017-07-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Oncology |
| spelling | doaj.art-b8bd7889f65b4d3ab8c845aef6c434cd2022-12-22T02:50:05ZengFrontiers Media S.A.Frontiers in Oncology2234-943X2017-07-01710.3389/fonc.2017.00146274963Angiogenic Gene Signature Derived from Subtype Specific Cell Models Segregate Proneural and Mesenchymal GlioblastomaAman Sharma0Aman Sharma1Ajinkya Bendre2Abir Mondal3Dattatraya Muzumdar4Naina Goel5Anjali Shiras6National Centre for Cell Science (NCCS), SP Pune University Campus, Pune, IndiaExoCan Healthcare Technologies Pvt Ltd, Venture Centre, NCL Innovation Park, Pune, IndiaNational Centre for Cell Science (NCCS), SP Pune University Campus, Pune, IndiaNational Centre for Cell Science (NCCS), SP Pune University Campus, Pune, IndiaSeth G.S. Medical College, KEM Hospital, Mumbai, IndiaSeth G.S. Medical College, KEM Hospital, Mumbai, IndiaNational Centre for Cell Science (NCCS), SP Pune University Campus, Pune, IndiaIntertumoral molecular heterogeneity in glioblastoma identifies four major subtypes based on expression of molecular markers. Among them, the two clinically interrelated subtypes, proneural and mesenchymal, are the most aggressive with proneural liable for conversion to mesenchymal upon therapy. Using two patient-derived novel primary cell culture models (MTA10 and KW10), we developed a minimal but unique four-gene signature comprising genes vascular endothelial growth factor A (VEGF-A), vascular endothelial growth factor B (VEGF-B) and angiopoietin 1 (ANG1), angiopoietin 2 (ANG2) that effectively segregated the proneural (MTA10) and mesenchymal (KW10) glioblastoma subtypes. The cell culture preclassified as mesenchymal showed elevated expression of genes VEGF-A, VEGF-B and ANG1, ANG2 as compared to the other cell culture model that mimicked the proneural subtype. The differentially expressed genes in these two cell culture models were confirmed by us using TCGA and Verhaak databases and we refer to it as a minimal multigene signature (MMS). We validated this MMS on human glioblastoma tissue sections with the use of immunohistochemistry on preclassified (YKL-40 high or mesenchymal glioblastoma and OLIG2 high or proneural glioblastoma) tumor samples (n = 30). MMS segregated mesenchymal and proneural subtypes with 83% efficiency using a simple histopathology scoring approach (p = 0.008 for ANG2 and p = 0.01 for ANG1). Furthermore, MMS expression negatively correlated with patient survival. Importantly, MMS staining demonstrated spatiotemporal heterogeneity within each subclass, adding further complexity to subtype identification in glioblastoma. In conclusion, we report a novel and simple sequencing-independent histopathology-based biomarker signature comprising genes VEGF-A, VEGF-B and ANG1, ANG2 for subtyping of proneural and mesenchymal glioblastoma.http://journal.frontiersin.org/article/10.3389/fonc.2017.00146/fullangiogenesisintertumoral heterogeneityangiopoietinsglioma stem cellsbiomarker |
| spellingShingle | Aman Sharma Aman Sharma Ajinkya Bendre Abir Mondal Dattatraya Muzumdar Naina Goel Anjali Shiras Angiogenic Gene Signature Derived from Subtype Specific Cell Models Segregate Proneural and Mesenchymal Glioblastoma Frontiers in Oncology angiogenesis intertumoral heterogeneity angiopoietins glioma stem cells biomarker |
| title | Angiogenic Gene Signature Derived from Subtype Specific Cell Models Segregate Proneural and Mesenchymal Glioblastoma |
| title_full | Angiogenic Gene Signature Derived from Subtype Specific Cell Models Segregate Proneural and Mesenchymal Glioblastoma |
| title_fullStr | Angiogenic Gene Signature Derived from Subtype Specific Cell Models Segregate Proneural and Mesenchymal Glioblastoma |
| title_full_unstemmed | Angiogenic Gene Signature Derived from Subtype Specific Cell Models Segregate Proneural and Mesenchymal Glioblastoma |
| title_short | Angiogenic Gene Signature Derived from Subtype Specific Cell Models Segregate Proneural and Mesenchymal Glioblastoma |
| title_sort | angiogenic gene signature derived from subtype specific cell models segregate proneural and mesenchymal glioblastoma |
| topic | angiogenesis intertumoral heterogeneity angiopoietins glioma stem cells biomarker |
| url | http://journal.frontiersin.org/article/10.3389/fonc.2017.00146/full |
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