Abstract
Glioblastoma multiforme (GBM) is the most common primary malignant adult brain tumor and is associated with poor survival. Recently, stem-like cell populations have been identified in numerous malignancies including GBM. To identify genes whose expression is changed with differentiation, we compared transcript profiles from a GBM oncosphere line before and after differentiation. Bioinformatic analysis of the gene expression profiles identified podocalyxin-like protein (PODXL), a protein highly expressed in human embryonic stem cells, as a potential marker of undifferentiated GBM stem-like cells. The loss of PODXL expression upon differentiation of GBM stem-like cell lines was confirmed by quantitative real-time PCR and flow cytometry. Analytical flow cytometry of numerous GBM oncosphere lines demonstrated PODXL expression in all lines examined. Knockdown studies and flow cytometric cell sorting experiments demonstrated that PODXL is involved in GBM stem-like cell proliferation and oncosphere formation. Compared to PODXL-negative cells, PODXL-positive cells had increased expression of the progenitor/stem cell markers Musashi1, SOX2, and BMI1. Finally, PODXL expression directly correlated with increasing glioma grade and was a marker for poor outcome in patients with GBM. In summary, we have demonstrated that PODXL is expressed in GBM stem-like cells and is involved in cell proliferation and oncosphere formation. Moreover, high PODXL expression correlates with increasing glioma grade and decreased overall survival in patients with GBM.
Highlights
Glioblastoma multiforme (GBM), World Health Organization (WHO) grade IV astrocytoma, is the most common primary malignant adult brain tumor and is treated with a combination of surgery, radiation, and chemotherapy
The PODXL-positive population of cells had a significantly faster growth rate compared to the PODXL-negative population (p,0.0001, Figure 3B–C, E-F). These results demonstrate that PODXL is involved in proliferation of GBM stem-like cell lines
Our findings demonstrate that PODXL is involved in GBM stem-like cell proliferation and oncosphere formation and that high PODXL expression correlates with glioma grade and decreased overall survival in patients with GBMs
Summary
Glioblastoma multiforme (GBM), World Health Organization (WHO) grade IV astrocytoma, is the most common primary malignant adult brain tumor and is treated with a combination of surgery, radiation, and chemotherapy. These tumors remain incurable with a current median survival of 14.6 months [1]. GBM stem-like cells are heterogeneous populations that, like normal neural stem cells, are self-renewing and multi-potent. These cells can differentiate along both neuronal and glial lineages [2]. There is evidence these stemlike cells are resistant to chemotherapy and radiotherapy [4,5]
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