Abstract
Glioblastoma (GBM) is the most common and deadliest primary adult brain tumor. Invasion, resistance to therapy, and tumor recurrence in GBM can be attributed in part to brain tumor-initiating cells (BTICs). BTICs isolated from various patient-derived xenografts showed high expression of the poorly characterized Apelin early ligand A (APELA) gene. Although originally considered to be a non-coding gene, the APELA gene encodes a protein that binds to the Apelin receptor and promotes the growth of human embryonic stem cells and the formation of the embryonic vasculature. We found that both APELA mRNA and protein are expressed at high levels in a subset of brain tumor patients, and that APELA is also expressed in putative stem cell niche in GBM tumor tissue. Analysis of APELA and the Apelin receptor gene expression in brain tumor datasets showed that high APELA expression was associated with poor patient survival in both glioma and glioblastoma, and APELA expression correlated with glioma grade. In contrast, gene expression of the Apelin receptor or Apelin was not found to be associated with patient survival, or glioma grade. Consequently, APELA may play an important role in glioblastoma tumorigenesis and may be a future therapeutic target.
Highlights
Glioblastoma (GBM) is the most lethal intracranial neoplasm in adults and has a median survival of only 14–18 months [1]
We found that Apelin early ligand A (APELA) gene expression was markedly upregulated in brain tumor-initiating cells (BTICs) isolated from a number of
Analysis of brain tumor expression datasets showed that high APELA
Summary
Glioblastoma (GBM) is the most lethal intracranial neoplasm in adults and has a median survival of only 14–18 months [1]. The cellular heterogeneity of GBM has been attributed to a subpopulation of brain tumor-initiating cells (BTICs), which express stem cell markers, can self-renew and undergo differentiation into multiple cell types [3,4,5]. BTICs have high tumor-initiating capacity and therapeutic resistance that can drive tumorigenesis and tumor recurrence after therapy [6]. APELA functions both as an endogenous ligand necessary for the growth of human embryonic stem cells [9] and in the formation of the embryonic vasculature [10]. Both Apelin and APELA bind to the Apelin receptor to transduce their distinct
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