The Role of Hypoxia and Cancer Stem Cells in Development of Glioblastoma

SIMPLE SUMMARY: As one of most malignant tumors in brain, glioblastoma (GBM) is lack of effective treatment and the prognosis of GBM patients is still very poor despite accumulated progresses. Hypoxia is an essential factor for the initiation and progression of GBM, especially for the glioma stem like cells (GSCs). Hypoxia induced many target genes which form a complicated molecular interacting network, influencing a lot of tumor behaviors by regulating key signal pathways. In addition, hypoxia has great impact on the interplayed niches of GCSs. Here, by systematically reviewing the role of hypoxia on the maintenance of GSCs and the development of GBM, and analyzing the related molecular mechanisms, we integrated the hypoxia related tumor features of GBM. This summary helps to deepen our knowledge of the tumorigenic mechanisms of GBM, and can help to develop novel therapeutic strategies targeting hypoxia to improve the survival of GBM patients. ABSTRACT: Glioblastoma multiform (GBM) is recognized as the most malignant brain tumor with a high level of hypoxia, containing a small population of glioblastoma stem like cells (GSCs). These GSCs have the capacity of self-renewal, proliferation, invasion and recapitulating the parent tumor, and are major causes of radio-and chemoresistance of GBM. Upregulated expression of hypoxia inducible factors (HIFs) in hypoxia fundamentally contributes to maintenance and progression of GSCs. Therefore, we thoroughly reviewed the currently acknowledged roles of hypoxia-associated GSCs in development of GBM. In detail, we recapitulated general features of GBM, especially GSC-related features, and delineated essential responses resulted from interactions between GSC and hypoxia, including hypoxia-induced signatures, genes and pathways, and hypoxia-regulated metabolic alterations. Five hypothesized GSC niches are discussed and integrated into one comprehensive concept: hypoxic peri-arteriolar niche of GSCs. Autophagy, another protective mechanism against chemotherapy, is also closely related to hypoxia and is a potential therapeutic target for GBM. In addition, potential causes of therapeutic resistance (chemo-, radio-, surgical-, immuno-), and chemotherapeutic agents which can improve the therapeutic effects of chemo-, radio-, or immunotherapy are introduced and discussed. At last, as a potential approach to reverse the hypoxic microenvironment in GBM, hyperbaric oxygen therapy (HBOT) might be an adjuvant therapy to chemo-and radiotherapy after surgery. In conclusion, we focus on demonstrating the important role of hypoxia on development of GBM, especially by affecting the function of GSCs. Important advantages have been made to understand the complicated responses induced by hypoxia in GBM. Further exploration of targeting hypoxia and GSCs can help to develop novel therapeutic strategies to improve the survival of GBM patients.