Abstract
Glioblastoma (GBM) is the most lethal primary brain tumor with few treatment options. The survival of glioma-initiating cells (GICs) is one of the major factors contributing to treatment failure. GICs frequently produce and respond to their own growth factors that support cell proliferation and survival. In this study, we aimed to identify critical autocrine factors mediating GIC survival and to evaluate the anti-GBM effect of antagonizing these factors. Proteomic analysis was performed using conditioned media from two different patient-derived GBM tumor spheres under a growth factor-depleted status. Then, the antitumor effects of inhibiting an identified autocrine factor were evaluated by bioinformatic analysis and molecular validation. Proteins secreted by sphere-forming GICs promote cell proliferation/survival and detoxify reactive oxygen species (ROS). Among these proteins, we focused on midkine (MDK) as a clinically significant and pathologically relevant autocrine factor. Antagonizing MDK reduced the survival of GBM tumor spheres through the promotion of cell cycle arrest and the consequent apoptotic cell death caused by oxidative stress-induced DNA damage. We also identified PCBP4, a novel molecular predictor of resistance to anti-MDK treatment. Collectively, our results indicate that MDK inhibition is an important therapeutic option by suppressing GIC survival through the induction of ROS-mediated cell cycle arrest and apoptosis.
Highlights
Glioblastoma (GBM) is the most lethal cancer in the adult brain with a dismal prognosis[1]
In this study, we conducted a comprehensive analysis of the cytokine milieu of Glioma-initiating cells (GICs) by performing liquid chromatography-mass spectrometry (LC-MS)-based proteome analysis using conditioned media from two different GBM tumor spheres with sustained growth under growth factor-free conditions
Our data suggest that GICs may protect themselves from reactive oxygen species (ROS) by secreting numerous proteins associated with redox homeostasis (Fig. 1)
Summary
Glioblastoma (GBM) is the most lethal cancer in the adult brain with a dismal prognosis[1]. Clinical approaches to target genetic alterations have shown limited clinical responses, which emphasizes the need for the Glioma-initiating cells (GICs), an undifferentiated stemlike cell subpopulation, frequently resemble classical neurospheres (termed GBM tumor spheres ) and show self-renewal and oncogenic transforming properties, which are crucially important in therapeutic resistance and tumor recurrence after treatment[3]. Intensive studies have revealed the molecular mechanisms underlying the survival of GICs, few molecules have been identified as effective therapeutic targets to abolish this subpopulation[4]. Han et al Experimental & Molecular Medicine (2019) 51:147 associated signaling cascades[5,6]. Antagonizing these autocrine factors secreted by GICs may be a therapeutic option via the interruption of GIC maintenance
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