Transmembrane Protein TMEM230, a Target of Glioblastoma Therapy

Abstract

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.

Transmembrane Protein TMEM230, Regulator of Glial Cell Vascular Mimicry and Endothelial Cell Angiogenesis in High-Grade Heterogeneous Infiltrating Gliomas and Glioblastoma

“…The addition of secreted factors generated from glial cells in which TMEM230 expression was upregulated to human umbilical vein endothelial cell (HUVEC) cultures resulted in endothelial cell sprouting and blood-vessel-like structure formation. Collectively, our previous studies have supported that expression of TMEM230 promotes the infiltration of various cell types [5], including microglia, macrophages, endothelial cells, and immune cells.…”

“…Sustained over-expression of TMEM230 in endothelial cells also promoted loss of normal blood vessel structure and function by inducing loss of cellto-cell contacts [6]. Recently, we demonstrated that TMEM230 induces vascular mimicry by secretion of glial and macrophage cellular proteins and glycan-digesting enzymes and glycoproteins that have microchannel-and scar-forming capacity [5]. The addition of secreted factors generated from glial cells in which TMEM230 expression was upregulated to human umbilical vein endothelial cell (HUVEC) cultures resulted in endothelial cell sprouting and blood-vessel-like structure formation.…”

“…The destruction of blood vessels and the formation of microchannels and scar tissue promote the loss of normal vascular activities and drug delivery for cancer treatment. We previously demonstrated that the transmembrane protein TMEM230 regulates both tissue vascularization by inducing endothelial cell sprouting and vessel formation and vascular mimicry by regulating glial-and macrophage-cellgenerating microchannels [5]. TMEM230 is an evolutionarily conserved multifunctional protein expressed in various cell types such as tubule-forming glandular cells and endothelial cells [5,6].…”

“…We previously demonstrated that the transmembrane protein TMEM230 regulates both tissue vascularization by inducing endothelial cell sprouting and vessel formation and vascular mimicry by regulating glial-and macrophage-cellgenerating microchannels [5]. TMEM230 is an evolutionarily conserved multifunctional protein expressed in various cell types such as tubule-forming glandular cells and endothelial cells [5,6]. TMEM230 has both intracellular and extracellular trafficking and secretion activities.…”

NCDN is a Potential Biomarker and Therapeutic Target for Glioblastoma

“…Upregulation of HOTAIRM1 expression in GBM cells promotes cell migration and invasion, suggesting that targeting HOTAIRM1 is also a possible therapeutic strategy for GBM 35 . Elevated transmembrane protein TMEM230 in GBM can promote tumor cell migration, extracellular stent remodeling, and excessive blood vessels and abnormal formation of blood vessels, so TMEM230 has the potential be a therapeutic target for inhibition of GBM tumor cells and anti-angiogenesis 36 . PDRG1 is abnormally highly expressed in GBM, promoting the migration and proliferation of GBM cells through the MEK/ERK/CD44 pathway 37 .…”