ABSTRACT
BACKGROUND: Glioma, the most frequent primary tumor of the central nervous system, has poor prognosis. The epidermal growth factor receptor (EGFR) pathway and angiogenesis play important roles in glioma growth, invasion, and recurrence. The present study aimed to use proteomic methods to probe into the role of the EGF-EGFR-angiogenesis axis in the tumorigenesis of glioma and access the therapeutic efficacy of selumetinib on glioma. METHODS: Proteomic profiling was used to characterize 200 paired EGFR-positive and EGFR-negative glioma tissues of all pathological types. The quantitative mass spectrometry data were used for systematic analysis of the proteomic profiles of 10 EGFR-positive and 10 EGFR-negative glioma cases. Consensus-clustering analysis was used to screen target proteins. Immunofluorescence analysis, cell growth assay, and intracranial xenograft experiments were used to verify and test the therapeutic effect of selumetinib on glioma. RESULTS: Advanced proteomic screening demonstrated that the expression of EGF-like domain multiple 7 (EGFL7) was higher in EGFR-positive tumor tissues than in EGFR-negative tumor tissues. In addition, EGFL7 could act as an activator in vitro and in vivo to promote glioma cell proliferation. EGFL7 was associated strongly with EGFR and prognosis. EGFL7 knockdown effectively suppressed glioma cell proliferation. Selumetinib treatment showed tumor reduction effect in EGFR-positive glioblastoma xenograft mouse model. CONCLUSIONS: EGFL7 is a potential diagnostic biomarker and therapeutic target of glioma. Selumetinib could target the EGFR pathway and possibly improve the prognosis of EGFR-positive glioma.
Subject(s)
Calcium-Binding Proteins , EGF Family of Proteins , Epidermal Growth Factor , Glioma , Adult , Animals , Benzimidazoles/pharmacology , Cell Movement , Endothelial Growth Factors/metabolism , ErbB Receptors/metabolism , Female , Humans , Male , Mice , Neoplasm Recurrence, Local , Proteomics , Xenograft Model Antitumor AssaysABSTRACT
Epidermal Growth Factor like domain 7 (EGFL7), also known as Vascular Endothelial-statin (VE-statin), is a secreted angiogenic factor. Recent data have demonstrated the potential oncogenic role and prognostic significance of EGFL7 in several human cancers. However, the clinical signature and further mechanisms of EGFL7's function in gliomagenesis are poorly understood. In the present study, we found that increased EGFL7 expression was associated with tumor grade. High expression of EGFL7 in EGFRvIII-positive glioblastoma multiforme (GBM) was determined to be a strong and independent risk factor for reduced life expectancy. EGFRvIII cells can secrete the EGFL7 protein to improve the activity of the ß-catenin/TCF4 Transcription complex in EGFRwt cells, thus promoting their own EGFL7 expression. Our research demonstrates that oncogenic activation of EGFRwt in GBM is likely maintained by a continuous EGFL7 autocrine flow line, and may be an attractive target for therapeutic intervention.
Subject(s)
Brain Neoplasms/metabolism , Endothelial Growth Factors/metabolism , ErbB Receptors/metabolism , Glioma/metabolism , Oncogenes , Signal Transduction , Adult , Antineoplastic Agents/pharmacology , Autocrine Communication , Basic Helix-Loop-Helix Leucine Zipper Transcription Factors/metabolism , Brain Neoplasms/drug therapy , Brain Neoplasms/genetics , Brain Neoplasms/pathology , Calcium-Binding Proteins , Carrier Proteins/metabolism , Cell Line, Tumor , Cell Movement , Cell Proliferation , EGF Family of Proteins , Endothelial Growth Factors/genetics , ErbB Receptors/genetics , Female , Gene Expression Regulation, Neoplastic , Glioma/drug therapy , Glioma/genetics , Glioma/pathology , Humans , Kaplan-Meier Estimate , Ligands , Male , Membrane Proteins/metabolism , Middle Aged , Neoplasm Grading , Neoplasm Invasiveness , Protein Binding , Protein Interaction Maps , RNA Interference , Signal Transduction/drug effects , Sulfonamides/pharmacology , Thyroid Hormones/metabolism , Time Factors , Transcription Factor 4 , Transcription Factors/metabolism , Transcription, Genetic , Transfection , beta Catenin/metabolism , Thyroid Hormone-Binding ProteinsABSTRACT
PURPOSE: Tumor angiogenesis is an important factor for the continuous growth of human malignancies and can be used to predict the prognosis for patients. In the current study, we examined the expression of EGF-like domain 7 (EGFL7), an endothelial cell-derived secreted factor, in malignant gliomas and explored its clinical significance. METHODS: We determined the steady-state mRNA levels of EGFL7 from 36 fresh glioma samples by semi-quantitative RT-PCR and the protein levels from 45 paraffin-embedded glioma samples by immunohistochemistry, respectively. Normal brain tissues from 10 patients with brain trauma were used as control. We also analyzed the correlations between the expression levels of EGFL7 and various clinical parameters, including patient gender, age, tumor grade, tumor proliferation marker Ki-67, and microvessel density (MVD). RESULTS: We found that EGFL7 was not detectable in normal brain tissues, but was up-regulated in both tumor cells and vascular endothelial cells within malignant glioma. The expression level of EGFL7 in malignant glioma significantly correlated with the tumor grade, Ki-67 expression and MVD (P < 0.01). CONCLUSIONS: Our data suggest that EGFL7 expression is a novel predictive factor for the clinical progression of malignant glioma, and may constitute a therapeutic target for anti-angiogenesis therapy in patients with the disease.
Subject(s)
Endothelial Growth Factors/genetics , Glioma/genetics , Adult , Age Factors , Angiogenesis Inhibitors/therapeutic use , Antineoplastic Agents/therapeutic use , Calcium-Binding Proteins , Cell Division , DNA Primers , EGF Family of Proteins , Endothelial Growth Factors/metabolism , Female , Gene Expression Regulation, Neoplastic , Glioma/blood supply , Glioma/drug therapy , Glioma/metabolism , Glioma/pathology , Humans , Immunohistochemistry , Male , Microcirculation/genetics , Middle Aged , RNA, Messenger/genetics , RNA, Neoplasm/genetics , Reverse Transcriptase Polymerase Chain ReactionABSTRACT
OBJECTIVE: To provide pertinent anatomic data and details for the clinical application of the extended transsphenoidal approach; to probe the anatomic characteristic and method under endoscope; METHODS: 25 adult cadaver heads fixed in formalin were used to dissect, observe, measure and photograph the relationship between the neural and vascular structure and the important anatomic landmarks related to the extended transsphenoidal approach under endoscope. RESULTS: The posterior and lateral wall of sphenoidal sinus could be well exposed by bilateral approach under endoscope. The clinical application of endoscope could improve the illumination of the operative field, magnify the objects and provide two-dimensional images. The distortion of the images under endoscope depended upon the distance between the lens and the object as well as the angle of the lens. To establish the anatomic vertical compartment under the endoscope might be helpful to the operation. The midline vertical compartment consisted of the planum sphenoidale, tuberculum sella, sella and clival indentation. The paramedian vertical compartment was composed of the medial third of the optic canal and the carotid artery protuberance. The lateral vertical compartment contained four bony protuberances (optic, cavernous sinus apex, maxillary, and mandibular). Endoscopic surgical maneuvering was under non-midline direction. Precise surgical landmarks are essential for a successful operation. These landmarks allowed the surgeon to recognize and approach the surgical target without confusion. The nasopharynx, middle turbinate, and inferior turbinate were some of the landmarks in the nasal cavity. Once the sphenoidal sinus was entered, the anatomic structures of the sphenoidal sinus posterior wall, which were described above, were the unique landmarks that will guide the surgeon to the surgical target. CONCLUSION: The anatomic characteristics under endoscope were different from those under microscope. The application of the extended transsphenoidal approach under endoscope could provide more extensive vision and satisfied exposure to reach the area of the central skull base.
