Hypoxia can induce c‐Met expression in glioma cells and enhance SF/HGF‐induced cell migration

Eckerich, Carmen; Zapf, Svenja; Fillbrandt, Regina; Loges, Sonja; Westphal, Manfred; Lamszus, Katrin

doi:10.1002/ijc.22679

Cited by 120 publications

(106 citation statements)

References 47 publications

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“…Recent studies have shown that HIF-1α is widely found in all histiocytes, as well as in peripheral leukocytes (3,15,16). Moreover, increased HIF-1α expression occurs in a variety of solid tumor cells and stromal cells, which may be related to their migration and adhesion (17,18). In the current study, HIF-1α mRNA and protein expression in acute leukemia hBMSCs were significantly increased compared to control, suggesting that HIF-1α may have been involved in the formation of the leukemia bone marrow hypoxic microenvironment.…”

Section: Discussionmentioning

confidence: 99%

Silencing HIF-1α reduces the adhesion and secretion functions of acute leukemia hBMSCs

Zeng¹,

Liu²,

Chen³

et al. 2012

Braz J Med Biol Res

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Hypoxia inducible factor-1α (HIF-1α) is an important transcription factor, which plays a critical role in the formation of solid tumor and its microenvironment. The objective of the present study was to evaluate the expression and function of HIF-1α in human leukemia bone marrow stromal cells (BMSCs) and to identify the downstream targets of HIF-1α. HIF-1α expression was detected at both the RNA and protein levels using real-time PCR and immunohistochemistry, respectively. Vascular endothelial growth factor (VEGF) and stromal cell-derived factor-1α (SDF-1α) were detected in stromal cells by enzyme-linked immunosorbent assay. HIF-1α was blocked by constructing the lentiviral RNAi vector system and infecting the BMSCs. The Jurkat cell/BMSC co-cultured system was constructed by putting the two cells into the same suitable cultured media and conditions. Cell adhesion and secretion functions of stromal cells were evaluated after transfection with the lentiviral RNAi vector of HIF-1α. Increased HIF-1α mRNA and protein was detected in the nucleus of the acute myeloblastic and acute lymphoblastic leukemia compared with normal BMSCs. The lentiviral RANi vector for HIF-1α was successfully constructed and was applied to block the expression of HIF-1α. When HIF-1α of BMSCs was blocked, the expression of VEGF and SDF-1α secreted by stromal cells was decreased. When HIF-1α was blocked, the co-cultured Jurkat cell's adhesion and migration functions were also decreased. Taken together, these results suggest that HIF-1α acts as an important transcription factor and can significantly affect the secretion and adhesion functions of leukemia BMSCs.

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Section: Discussionmentioning

confidence: 99%

Silencing HIF-1α reduces the adhesion and secretion functions of acute leukemia hBMSCs

Zeng¹,

Liu²,

Chen³

et al. 2012

Braz J Med Biol Res

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“…127 Hypoxia has been shown to upregulate c-Met expression, which enhances scatter factor/hepatocyte growth factor-induced cell migration. 128 In addition to MMPs, other studies have identified the protease cathepsin B as an important mediator of ECM degradation secreted by gliomas.…”

Section: Molecular Biology Of Glioma Invasionmentioning

confidence: 99%

Biology of Angiogenesis and Invasion in Glioma

2009

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Summary: Treatment of adult brain tumors, in particular glioblastoma, remains a significant clinical challenge, despite modest advances in surgical technique, radiation, and chemotherapeutics. The formation of abnormal, dysfunctional tumor vasculature and glioma cell invasion along white matter tracts are believed to be major components of the inability to treat these tumors effectively. Recent insight into the fundamental processes governing glioma angiogenesis and invasion provide a renewed hope for development of novel strategies aimed at reducing the morbidity of this uniformly fatal disease. In this review, we discuss background biology of the blood brain barrier and its pertinence to blood vessel formation and tumor invasion. We will then focus our attention on the biology of glioma angiogenesis and invasion, and the key mediators of these processes. Last, we will briefly discuss recent and ongoing clinical trials targeting mediators of angiogenesis or invasion in glioma patients. The findings provide a renewed hope for those endeavoring to improve treatment of patients with glioma by providing a novel set of rational targets for translational drug discovery.

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“…21 HIF-1 is a known activator of c-MET in many cell types, including gliomas, and is thought to play a role in their invasiveness. 8,13 This reduced c-MET activity may explain the lack of invasion that we observed in the HIF-1a knock-down mice (data not shown). Although the cell line that we used has been criticized for its reduced invasive properties in our intracranial model, it does express scatter factor/hepatocyte growth factor (SF/ HGF) and c-MET.…”

mentioning

confidence: 74%

RNA interference targeting hypoxia-inducible factor 1α via a novel multifunctional surfactant attenuates glioma growth in an intracranial mouse model

Gillespie

Aguirre

Ravichandran

et al. 2015

JNS

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P atients with the most malignant type of glioma, Grade IV glioblastoma, have a mean survival time of approximately 15 months and an estimated 5-year survival rate of less than 5%.11 High-grade gliomas (Grades III and IV) are the most common primary brain tumors in adults and the fourth leading cause of cancerrelated death. 40 Tumor hypoxia is thought to play an important role in glioblastoma tumor pathobiology by proabbreviatioNs CA-IX = carbonic anhydrase-IX; CED = convection-enhanced delivery; DAB = 3,3′-diaminobenzidine tetrahydrochloride; DCA = dichloroacetate; EHCO = 1-(aminoethyl)iminobis [N-(oleicylcysteinylhistinyl-1-aminoethyl)propionamide]; GFP = green fluorescent protein; GLUT-1 = glucose transporter 1; HIF-1a = hypoxia-inducible factor 1a; IHC = immunohistochemistry; MVD = microvascular density; PEG = polyethylene glycol; PI = proliferation index; RNAi = RNA interference; siRNA = small interfering RNA; VEGF = vascular endothelial growth factor. obJeCt High-grade gliomas are the most common form of adult brain cancer, and patients have a dismal survival rate despite aggressive therapeutic measures. Intratumoral hypoxia is thought to be a main contributor to tumorigenesis and angiogenesis of these tumors. Because hypoxia-inducible factor 1a (HIF-1a) is the major mediator of hypoxia-regulated cellular control, inhibition of this transcription factor may reduce glioblastoma growth. MetHoDs Using an orthotopic mouse model with U87-LucNeo cells, the authors used RNA interference to knock down HIF-1a in vivo. The small interfering RNA (siRNA) was packaged using a novel multifunctional surfactant, 1-(amino ethyl)iminobis[N-(oleicylcysteinylhistinyl-1-aminoethyl)propionamide] (EHCO), a nucleic acid carrier that facilitates cellular uptake and intracellular release of siRNA. Stereotactic injection was used to deliver siRNA locally through a guide-screw system, and delivery/uptake was verified by imaging of fluorescently labeled siRNA. Osmotic pumps were used for extended siRNA delivery to model a commonly used human intracranial drug-delivery technique, convectionenhanced delivery. resUlts Mice receiving daily siRNA injections targeting HIF-1a had a 79% lower tumor volume after 50 days of treatment than the controls. Levels of the HIF-1 transcriptional targets vascular endothelial growth factor (VEGF), glucose transporter 1 (GLUT-1), c-MET, and carbonic anhydrase-IX (CA-IX) and markers for cell growth (MIB-1 and microvascular density) were also significantly lower. Altering the carrier EHCO by adding polyethylene glycol significantly increased the efficacy of drug delivery and subsequent survival. CoNClUsioNs Treating glioblastoma with siRNA targeting HIF-1a in vivo can significantly reduce tumor growth and increase survival in an intracranial mouse model, a finding that has direct clinical implications.

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Hypoxia can induce c‐Met expression in glioma cells and enhance SF/HGF‐induced cell migration

Cited by 120 publications

References 47 publications

Silencing HIF-1α reduces the adhesion and secretion functions of acute leukemia hBMSCs

Silencing HIF-1α reduces the adhesion and secretion functions of acute leukemia hBMSCs

Biology of Angiogenesis and Invasion in Glioma

RNA interference targeting hypoxia-inducible factor 1α via a novel multifunctional surfactant attenuates glioma growth in an intracranial mouse model

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