Research On Roles Of HIF-1, Angiopoietin-2 And Its Receptor Tie-2 In Angiogenesis Of Glioma

Background and PurposeMalignant gliomas, the most common primary brain tumors occurring in humans are highly dependent on angiogenesis, obviously microvascular proliferation and formation of vascular entities. The molecular mechanisms driving the abnormal vascular architecture in malignant gliomas are not understood. Hypoxia-induciblefactor-1 (HIF-1), one of the master regulators for the cellular responses to hypoxia. is present at high levels in human tumors and plays a crucial role in tumor promotion by up-regulating several target genes. Vascular endothelial growth factor (VEGF) and angiopoietins(Ang), a family of growth factor ligands binding to tyrosine kinase receptors Tie-2 have been shown to be critically involved in the angiogenesis during both developmental and pathological angiogenesis.We detecte the expression of HIF-1, angiopoietin-2 and Tie-2mRNA, try to find some new reaction mechanism on tumor angiogenesis and clinicalpathological sense during the growth and progression of malignant human gliomas.MethodsForty-six cases of human gliomas and 8 cases of Intracal decompression were analyzed by immunohistochemistry for HIF-1 alpha,Ang-2, and in situ hybridization for Tie-2 mRNA using formalin-fixed paraffin-embedded material. SPSS 12.0 software was employed to analyze all data and P＜0.05 was considered statistically significant. ResultsHIF-1αwas detected only in glioma cells, both in the nucleus and in the cytoplasm, the expression in gradesⅢandⅣwas higher than in lower gradesⅠandⅡP＜0.05.The Ang-2 was expressed in the cytoplasm of tumor cells, and the expression was increased in gradesⅢ,Ⅳthan gradeⅠ,Ⅱ(P＜0.01).the expression of Ang-2 in gradesⅠ,Ⅱwas statistically significantly than normal brain tissue (P＜0.05).Tie-2 mRNA was localized in the vascular endothelial cytoplasm. the expression in gradesⅢandⅣ(22.95±6.88) was higher than in lower gradesⅠandⅡ(15.32±4.69) P＜0.01.In the normal brain the expression of Tie-2 mRNA was lower than in tumor (P＜0.01). HIF-1α, Ang-2 and Tie-2 mRNA are not correlated with the age of patient,sex and the size of tumor, the expression of Tie-2 mRNA in positive group of HIF-lalpha was higher than in negative group, (P＜0.05).positive links with expression of HIF-1αand Ang-2 were noted (r=0.631, P＜0.05).but the expression of Tie-2 mRNA and Ang-2 was not statistically correlationship P＞0.05.DiscussionHIF-1αwas expressed in the hypoxic zone of tumor and up-regulated with the malignant degree of tumor. It was obviously found on the necrosis edge. Ang-2 was negative correlation with the degree of blood vessel maturity, its expression was up-regulated with the tumor malignant degree. Through depressing the stability of the blood vessel, Ang-2 maybe start the primary signal of angiogenesis, and cooperate with VEGF to promote the tumor angiogenesis. Tie-2 mRNA was expressed in the vascular endothelial cell and was strengthened with the tumor malignant degree. participate in the tumor angiogenesis.Under the tumor hypoxia microenvironment, HIF-1αwill activate Ang-2 reacting with Tie-2 and cooperate with VEGF to promote the tumor angiogenesis. ConclusionWe believe that the gliomas with high expressions of HIF-la and Ang-2 have shown high vicious and poor prognosis,they maybe a new index to assess the malignant degree and prognosis of gliomas. HIF-1alpha expression affects glioma tumor growth, suggesting clinical applications for malignant glioma treatment. Under the tumor hypoxia microenvironment, HIF-1alpha will activate Ang-2 reacting with Tie-2 and cooperate with VEGF to promote the angiogenesis and remodeling of tumor.