Activation of hypoxia signaling induces phenotypic transformation of glioma cells: implications for bevacizumab antiangiogenic therapy

Abstract

Glioblastoma (GBM) is the most common and deadly primary brain tumor in adults. Bevacizumab, a humanized monoclonal antibody against vascular endothelial growth factor (VEGF), can attenuate tumor-associated edema and improve patient symptoms but based on magnetic resonance imaging, is associated with non-enhancing tumor progression and possibly gliosarcoma differentiation. To gain insight into these findings, we investigated the role of hypoxia and epithelial-mesenchymal transition (EMT)-associated proteins in GBM. Tumor markers of hypoxia and EMT were upregulated in bevacizumab-treated tumors from GBM patients compared to untreated counterparts. Exposure of glioma cells to 1% oxygen tension increased cell proliferation, expression of EMT-associated proteins and enhanced cell migration in vitro. These phenotypic changes were significantly attenuated by pharmacologic knockdown of hypoxia-inducible Factor 1α (HIF1α) or HIF2α, indicating that HIFs represent a therapeutic target for mesenchymal GBM cells. These findings provide insights into potential development of novel therapeutic targeting of angiogenesis-specific pathways in GBM.

Gold nanoparticles attenuate metastasis by tumor vasculature normalization and epithelial–mesenchymal transition inhibition

“…One of these factors is hypoxia. 28,29 Several studies have demonstrated that prolonged anti-angiogenic therapy increased the expression of mesenchymal phenotypes, [30][31][32][33] and this may be due to hypoxia induced by excessive anti-angiogenesis. Other studies have also shown that hypoxia and hypoxia-inducible factor-1 alpha (HIF-1α) promote EMT in several tumor types.…”

Assessment of tumor oxygenation and its impact on treatment response in bevacizumab-treated recurrent glioblastoma

“…4 These treatment-related effects may in part be explained by intratumoral hypoxia resulting from BEV-induced vessel pruning and subsequent activation of compensatory survival pathways that would be expected to negatively impact BEV response by negating any early transient benefits attributable to reductions in vascular permeability and contrast enhancing tumor. 3 Indeed, the effects of antiangiogenic agents on tumor oxygenation status remain controversial, with evidence supporting either vascular regression, which is associated with increased intratumoral hypoxia, 5,6 or a so-called ''normalization'' of the tumor vasculature, resulting in improved tumor oxygenation and cytotoxic chemotherapy sensitivity. [7][8][9] The tumor microcirculation is characterized by abnormal capillary bed topology, elevated edema pressure, and microthromboses, all of which give rise to shunting of oxygenated blood through the tissue.…”

Resveratrol inhibits hypoxia-induced glioma cell migration and invasion by the p-STAT3/miR-34a axis

“…Glioblastoma has strong activity of migration and invasion [2], which is associated to low oxygen condition of tumor microenvironment [4][5][6]. Thus it's essential to find a way to block hypoxia-induced migration and invasion.…”

“…This aggressive phenotype is possibly relevant to hypoxia, which is one of the most remarkably characteristics of glioma microenvironment and might play a crucial role in glioma growth, development, and angiogenesis [3]. It has been documented that hypoxia also induces migration and invasion of glioma cells [4][5][6], which involves a series of transduction pathways and signal molecules.…”