Transmembrane Protein TMEM230, a Target of Glioblastoma Therapy
Glioblastomas (GBM) are the most aggressive tumors originating in the brain. Histopathologic features include circuitous, disorganized, and highly permeable blood vessels with intermittent blood flow. These features contribute to the inability to direct therapeutic agents to tumor cells. Known targe...
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Frontiers Media S.A.
2021
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oai:doaj.org-article:75f0ce9fbf4943ef8b3abd80f17950d92021-11-17T09:00:36ZTransmembrane Protein TMEM230, a Target of Glioblastoma Therapy1662-510210.3389/fncel.2021.703431https://doaj.org/article/75f0ce9fbf4943ef8b3abd80f17950d92021-11-01T00:00:00Zhttps://www.frontiersin.org/articles/10.3389/fncel.2021.703431/fullhttps://doaj.org/toc/1662-5102Glioblastomas (GBM) are the most aggressive tumors originating in the brain. Histopathologic features include circuitous, disorganized, and highly permeable blood vessels with intermittent blood flow. These features contribute to the inability to direct therapeutic agents to tumor cells. Known targets for anti-angiogenic therapies provide minimal or no effect in overall survival of 12–15 months following diagnosis. Identification of novel targets therefore remains an important goal for effective treatment of highly vascularized tumors such as GBM. We previously demonstrated in zebrafish that a balanced level of expression of the transmembrane protein TMEM230/C20ORF30 was required to maintain normal blood vessel structural integrity and promote proper vessel network formation. To investigate whether TMEM230 has a role in the pathogenesis of GBM, we analyzed its prognostic value in patient tumor gene expression datasets and performed cell functional analysis. TMEM230 was found necessary for growth of U87-MG cells, a model of human GBM. Downregulation of TMEM230 resulted in loss of U87 migration, substratum adhesion, and re-passaging capacity. Conditioned media from U87 expressing endogenous TMEM230 induced sprouting and tubule-like structure formation of HUVECs. Moreover, TMEM230 promoted vascular mimicry-like behavior of U87 cells. Gene expression analysis of 702 patients identified that TMEM230 expression levels distinguished high from low grade gliomas. Transcriptomic analysis of patients with gliomas revealed molecular pathways consistent with properties observed in U87 cell assays. Within low grade gliomas, elevated TMEM230 expression levels correlated with reduced overall survival independent from tumor subtype. Highest level of TMEM230 correlated with glioblastoma and ATP-dependent microtubule kinesin motor activity, providing a direction for future therapeutic intervention. Our studies support that TMEM230 has both glial tumor and endothelial cell intracellular and extracellular functions. Elevated levels of TMEM230 promote glial tumor cell migration, extracellular scaffold remodeling, and hypervascularization and abnormal formation of blood vessels. Downregulation of TMEM230 expression may inhibit both low grade glioma and glioblastoma tumor progression and promote normalization of abnormally formed blood vessels. TMEM230 therefore is both a promising anticancer and antiangiogenic therapeutic target for inhibiting GBM tumor cells and tumor-driven angiogenesis.Cinzia CocolaCinzia CocolaValerio MagnaghiEdoardo AbeniParide PelucchiValentina MartinoLaura VilardoEleonora PiscitelliArianna ConsiglioGiorgio GrilloEttore MoscaRoberta GualtierottiDaniela MazzaccaroGina La SalaChiara Di PietroMira PalizbanSabino LiuniGiuseppina DePedroStefano MoraraGiovanni NanoGiovanni NanoJames KehlerBurkhard GreveAlessio NogheroAlessio NogheroDaniela MarazzitiFederico BussolinoFederico BussolinoGianfranco BellipanniIgea D’AgnanoMartin GötteIleana ZucchiRolland ReinboldFrontiers Media S.A.articlecargo vesicle transportangiogenesis and normalization of vascular networktumor cell migration and adhesionanticancer and antiangiogenic therapygliomakinesin motor proteinsNeurosciences. Biological psychiatry. NeuropsychiatryRC321-571ENFrontiers in Cellular Neuroscience, Vol 15 (2021) |
| institution |
DOAJ |
| collection |
DOAJ |
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EN |
| topic |
cargo vesicle transport angiogenesis and normalization of vascular network tumor cell migration and adhesion anticancer and antiangiogenic therapy glioma kinesin motor proteins Neurosciences. Biological psychiatry. Neuropsychiatry RC321-571 |
| spellingShingle |
cargo vesicle transport angiogenesis and normalization of vascular network tumor cell migration and adhesion anticancer and antiangiogenic therapy glioma kinesin motor proteins Neurosciences. Biological psychiatry. Neuropsychiatry RC321-571 Cinzia Cocola Cinzia Cocola Valerio Magnaghi Edoardo Abeni Paride Pelucchi Valentina Martino Laura Vilardo Eleonora Piscitelli Arianna Consiglio Giorgio Grillo Ettore Mosca Roberta Gualtierotti Daniela Mazzaccaro Gina La Sala Chiara Di Pietro Mira Palizban Sabino Liuni Giuseppina DePedro Stefano Morara Giovanni Nano Giovanni Nano James Kehler Burkhard Greve Alessio Noghero Alessio Noghero Daniela Marazziti Federico Bussolino Federico Bussolino Gianfranco Bellipanni Igea D’Agnano Martin Götte Ileana Zucchi Rolland Reinbold Transmembrane Protein TMEM230, a Target of Glioblastoma Therapy |
| description |
Glioblastomas (GBM) are the most aggressive tumors originating in the brain. Histopathologic features include circuitous, disorganized, and highly permeable blood vessels with intermittent blood flow. These features contribute to the inability to direct therapeutic agents to tumor cells. Known targets for anti-angiogenic therapies provide minimal or no effect in overall survival of 12–15 months following diagnosis. Identification of novel targets therefore remains an important goal for effective treatment of highly vascularized tumors such as GBM. We previously demonstrated in zebrafish that a balanced level of expression of the transmembrane protein TMEM230/C20ORF30 was required to maintain normal blood vessel structural integrity and promote proper vessel network formation. To investigate whether TMEM230 has a role in the pathogenesis of GBM, we analyzed its prognostic value in patient tumor gene expression datasets and performed cell functional analysis. TMEM230 was found necessary for growth of U87-MG cells, a model of human GBM. Downregulation of TMEM230 resulted in loss of U87 migration, substratum adhesion, and re-passaging capacity. Conditioned media from U87 expressing endogenous TMEM230 induced sprouting and tubule-like structure formation of HUVECs. Moreover, TMEM230 promoted vascular mimicry-like behavior of U87 cells. Gene expression analysis of 702 patients identified that TMEM230 expression levels distinguished high from low grade gliomas. Transcriptomic analysis of patients with gliomas revealed molecular pathways consistent with properties observed in U87 cell assays. Within low grade gliomas, elevated TMEM230 expression levels correlated with reduced overall survival independent from tumor subtype. Highest level of TMEM230 correlated with glioblastoma and ATP-dependent microtubule kinesin motor activity, providing a direction for future therapeutic intervention. Our studies support that TMEM230 has both glial tumor and endothelial cell intracellular and extracellular functions. Elevated levels of TMEM230 promote glial tumor cell migration, extracellular scaffold remodeling, and hypervascularization and abnormal formation of blood vessels. Downregulation of TMEM230 expression may inhibit both low grade glioma and glioblastoma tumor progression and promote normalization of abnormally formed blood vessels. TMEM230 therefore is both a promising anticancer and antiangiogenic therapeutic target for inhibiting GBM tumor cells and tumor-driven angiogenesis. |
| format |
article |
| author |
Cinzia Cocola Cinzia Cocola Valerio Magnaghi Edoardo Abeni Paride Pelucchi Valentina Martino Laura Vilardo Eleonora Piscitelli Arianna Consiglio Giorgio Grillo Ettore Mosca Roberta Gualtierotti Daniela Mazzaccaro Gina La Sala Chiara Di Pietro Mira Palizban Sabino Liuni Giuseppina DePedro Stefano Morara Giovanni Nano Giovanni Nano James Kehler Burkhard Greve Alessio Noghero Alessio Noghero Daniela Marazziti Federico Bussolino Federico Bussolino Gianfranco Bellipanni Igea D’Agnano Martin Götte Ileana Zucchi Rolland Reinbold |
| author_facet |
Cinzia Cocola Cinzia Cocola Valerio Magnaghi Edoardo Abeni Paride Pelucchi Valentina Martino Laura Vilardo Eleonora Piscitelli Arianna Consiglio Giorgio Grillo Ettore Mosca Roberta Gualtierotti Daniela Mazzaccaro Gina La Sala Chiara Di Pietro Mira Palizban Sabino Liuni Giuseppina DePedro Stefano Morara Giovanni Nano Giovanni Nano James Kehler Burkhard Greve Alessio Noghero Alessio Noghero Daniela Marazziti Federico Bussolino Federico Bussolino Gianfranco Bellipanni Igea D’Agnano Martin Götte Ileana Zucchi Rolland Reinbold |
| author_sort |
Cinzia Cocola |
| title |
Transmembrane Protein TMEM230, a Target of Glioblastoma Therapy |
| title_short |
Transmembrane Protein TMEM230, a Target of Glioblastoma Therapy |
| title_full |
Transmembrane Protein TMEM230, a Target of Glioblastoma Therapy |
| title_fullStr |
Transmembrane Protein TMEM230, a Target of Glioblastoma Therapy |
| title_full_unstemmed |
Transmembrane Protein TMEM230, a Target of Glioblastoma Therapy |
| title_sort |
transmembrane protein tmem230, a target of glioblastoma therapy |
| publisher |
Frontiers Media S.A. |
| publishDate |
2021 |
| url |
https://doaj.org/article/75f0ce9fbf4943ef8b3abd80f17950d9 |
| work_keys_str_mv |
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