The Effect Of IDH1 Mutation On The Vascular Morphology Of Glioma And Its Mechanism

Glioma is one of the most common primary malignant tumors in central nervous system which is rich in blood vessels,resulting in easy recurrence and poor prognosis.Based on the density and morphology of microvessels and the three-dimensional distribution in glioma tissue,the concept of tumor microvascular architecture phenotype(T-MAP)was proposed.The diverse vessel architecture phenotype was termed T-MAP heterogeneity(T-MAPH).Glioma is one of the best human tumor models for studies of angiogenic heterogeneity.We classified the vascular morphology in glioma into eight types based on the T-MAP,but its mechanism and clinical pathological significance in glioma is still unclear.IDH is one of the rate limiting enzymes of three carboxylic acid cycle and is one of the three types of IDH isomerase.The incidence of IDH1 mutation was higher in gliomas,which occurred in patients with grade II-III gliomas and recurrent glioblastoma.Previous studies have shown that the prognosis of glioma patients with IDH1 mutation is better.However,the effect of IDH1 mutation on the morphology of glioma is still unknown.Type IV collagen(COL4)as an important component of the vascular basement membrane has been reported that is immature in mice with IDH1 mutations in mice and can lead to vascular discontinuity to affect the stability and vascular morphology,but the mechanism in human glioma samples are still unknown.In this study,we investigated the clinical and pathological characteristics of T-MAP vascular morphology,identified the effect of IDH1 mutation on the vascular morphology,and explored the mechanism of the effect of IDH1 mutation on the morphology of glioma by COL4.Methods and results are as follows:1.the clinical and pathological features of IDH1 mutation in 314 patients with glioma in the Southwest Hospital were analyzed by gene detection and immunohistochemical staining.(1).Prognosis analysis showed that IDH1 mutation had a better prognosis in patients with grade II-III gliomas,and the recurrence time of patients with recurrent glioma was prolonged.Through the analysis of clinical features,the patients with IDH1 mutation occurred mainly in patients over 20 years old,not found in patients under 20 years of age,Most of the patients with IDH1 mutation in the frontal lobe.(2).Immunohistochemical staining revealed that IDH1 was expressed in glioma cells but not in normal glial cells,vascular endothelial cells and perivascular cells.2.Immunohistochemical staining was used to analyze the eight kinds of vessels in T-MAP(1).Immunohistochemical analysis showed that pseudosarcoma-like microvessle(PLM)was mainly composed of perivascular cells;snake-like microvessel(SLM)was mainly composed of vascular endothelial cells and perivascular cells;thick-wall microvessel(TWM)mainly with COL4 proliferation;glomeruloid microvessel(GM)consists of several thin-walled capillaries;pseudorossette microvessel(PM)was similar to thin-wall microvessel,but the tumor cells can be seen in the periphery of chrysanthemum like arrangement.(2).In the eight types of blood vessels,the incidence rate of PLM SLM GM TWM and PM increased with the increase of the tumor grade.(3).Different vascular morphology in different parts of the tumor.PLM and GM were more common in the tumor region;SLM is more common in the tumor region,tumor necrosis area and peritumoral region;TWM and PM were more common in tumor necrosis area.(4).Through the analysis of prognosis,the results showed that the expression of Ki-67 was higher and the prognosis was poor in the patients with glioma in the presence of PLM SLM GM TWM and PM.According to the prognosis,the morphology of T-MAP vessels in glioma was divided into two types: T-MAP-A type(PLM SLM GM TWM and PM)and T-MAP-B type(Spindle shaped without cavity microvessel Thin-wall microvessel Dendritic-like microvessel).(5).By analyzing the ratio of T-MAP two vessels in IDH1 mutant and IDH1 wild type,we found that the IDH1 mutation group was mainly T-MAP-B type,suggestting that IDH1 may influence the occurrence of vascular morphology.3.By using immunohistochemistry,immunofluorescence,cell co-culture and Q-PCR,we found that there was a phenomenon of COL4 discontinuity in the case of IDH1 mutation,and the expression of COL4 was enhanced.(1).Immunohistochemistry and immunofluorescence showed that COL4 was not continuous in the case of IDH1 mutation in II-III gliomas.(2).Immunohistochemical analysis showed that the expression of COL4 protein was higher in the glioma cells with IDH1 mutation.(3).In vitro experiments showed that IDH1 mutation promotes the expression of COL4 gene in vascular endothelial cells.(4).In vitro experiments showed that IDH1 mutation did not promote angiogenesis by activating m TOR signaling pathway.In conclusion,there were significant differences in the classification of T-MAP in the tumor grade and tumor location,and the vascular morphology of T-MAP was closely related to the prognosis of glioma.IDH1 mutation is closely related to T-MAP vascular morphology,and it can lead to vascular discontinuity and increased expression of col4.The results of this study provides an important basis for the diagnosis and prognosis of glioma based on T-MAP,and it also provides a potential mechanism for the prognosis of IDH1.which may be a potential mechanism for better prognosis of IDH1 mutations.