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

Xu H, Rahimpour S, Nesvick CL, Zhang X, Ma J, Zhang M, Zhang G, Wang L, Yang C, Hong CS, Germanwala AV, Elder JB, Ray-Chaudhury A, Yao Y, Gilbert MR, Lonser RR, Heiss JD, Brady RO, Mao Y, Qin J, Zhuang Z - Oncotarget (2015)

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Division of Biotechnology, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian, China.

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.

No MeSH data available.


Related in: MedlinePlus

Knockdown of HIF targets by siRNA and pharmacologic agents in U87 glioblastoma cellsQuantitative real-time PCR (qRT-PCR) was used to quantify mRNA expression of the HIF targets GLUT1, VEGFA, EDN1 and EPO following exposure to various oxygen concentrations for 24 (left) or 48 (right) hours. The y-axis reflects relative mRNA expression (standard errors of the means [S.E.M.]).
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Figure 2: Knockdown of HIF targets by siRNA and pharmacologic agents in U87 glioblastoma cellsQuantitative real-time PCR (qRT-PCR) was used to quantify mRNA expression of the HIF targets GLUT1, VEGFA, EDN1 and EPO following exposure to various oxygen concentrations for 24 (left) or 48 (right) hours. The y-axis reflects relative mRNA expression (standard errors of the means [S.E.M.]).

Mentions: Given that antiangiogenic therapy can be associated with induction of a hypoxic phenotype and development of gliosarcoma, we hypothesized that exposure to hypoxia would enhance proliferation and mesenchymal change in GBM cell lines. U87 and U251 human GBM cells and C6 rat glioma cells were cultured in 21%, 1% or 0.2% oxygen for 24 or 48 hours. Expression of the HIF target genes coding for erythropoietin (EPO), vascular endothelial growth factor A (VEGFA), endothelin 1 (EDN1) and glucose transporter 1 (GLUT1) were markedly increased in both a time- and oxygen concentration-dependent manner, demonstrating robust activation of hypoxia signaling (Fig. 2, Fig. S1). Alternatively, expression of HIF targets was reduced by knockdown of HIF1α or HIF2α using small interfering RNA (siRNA) or pharmacologic inhibition (demonstrative of a robust blockade of HIF transcriptional activity).


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

Xu H, Rahimpour S, Nesvick CL, Zhang X, Ma J, Zhang M, Zhang G, Wang L, Yang C, Hong CS, Germanwala AV, Elder JB, Ray-Chaudhury A, Yao Y, Gilbert MR, Lonser RR, Heiss JD, Brady RO, Mao Y, Qin J, Zhuang Z - Oncotarget (2015)

Knockdown of HIF targets by siRNA and pharmacologic agents in U87 glioblastoma cellsQuantitative real-time PCR (qRT-PCR) was used to quantify mRNA expression of the HIF targets GLUT1, VEGFA, EDN1 and EPO following exposure to various oxygen concentrations for 24 (left) or 48 (right) hours. The y-axis reflects relative mRNA expression (standard errors of the means [S.E.M.]).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4494911&req=5

Figure 2: Knockdown of HIF targets by siRNA and pharmacologic agents in U87 glioblastoma cellsQuantitative real-time PCR (qRT-PCR) was used to quantify mRNA expression of the HIF targets GLUT1, VEGFA, EDN1 and EPO following exposure to various oxygen concentrations for 24 (left) or 48 (right) hours. The y-axis reflects relative mRNA expression (standard errors of the means [S.E.M.]).
Mentions: Given that antiangiogenic therapy can be associated with induction of a hypoxic phenotype and development of gliosarcoma, we hypothesized that exposure to hypoxia would enhance proliferation and mesenchymal change in GBM cell lines. U87 and U251 human GBM cells and C6 rat glioma cells were cultured in 21%, 1% or 0.2% oxygen for 24 or 48 hours. Expression of the HIF target genes coding for erythropoietin (EPO), vascular endothelial growth factor A (VEGFA), endothelin 1 (EDN1) and glucose transporter 1 (GLUT1) were markedly increased in both a time- and oxygen concentration-dependent manner, demonstrating robust activation of hypoxia signaling (Fig. 2, Fig. S1). Alternatively, expression of HIF targets was reduced by knockdown of HIF1α or HIF2α using small interfering RNA (siRNA) or pharmacologic inhibition (demonstrative of a robust blockade of HIF transcriptional activity).

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Division of Biotechnology, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian, China.

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.

No MeSH data available.


Related in: MedlinePlus