| Glioma is the most common primary tumor of the central nervous system.Glioblastoma(GBM),the most malignant type of glioma,is highly lethal that the survival time of most GBM patients after diagnosis is between 15~18 months.Currently,the treatments of GBM include maximal surgical resection of tumor plus radiotherapy,chemotherapy and molecular targeted therapy.Although these treatments have been proved to be effective,the survival of most patients is still limited.Therefore,to find new predictors of patient response to therapies and to propose new therapeutic strategies are urgent for improving the effectiveness of glioma treatment.Neovascularization has been raised as a hallmark of cancer.Our group has found that significant heterogeneities of microvessels(including morphology,density,wall integrity and molecular phenotype,etc.)exist in the different types,individuals and stages of tumor,which is defined as ‘Tumor Microvascular Architecture Phenotype Heterogeneity(T-MAPH)'.Glioma has prosperous newly-formed microvessels,the morphology of which in high-grade glioma is always quite different from that of normal microvessels.Therefore,the characterization of T-MAPH in glioma is promosing to provide new predictive markers for assisting patient diagnosis and treatment as well as to deepen our understandings on the mechanisms of tumor neovascularization.In this study,by using methods in quantitative pathology,we firstly raised two parameters,microvessel fractal dimension(mv FD)and pericyte coverage ratio,to quantify glioma microvessel morphology and pericyte coverage status,separately.Next,we analyzed the clinicopathological significances of mv FD and pericyte coverage ratio in the prediction of prognosis and the response to treatment in GBM patients.To elucidate the possible mechanisms,we correlated mv FD with tumor glycolytic metabolism status as well as identified the key molecule which contributes to the formation of pericytes in GBM.The main results are as follows:1.To study the morphological heterogeneity of microvessels in glioma,we established the calculation method of mvFD,and found that mv FD characterizes the morphological complexity of microvessels.Notably,mvFD was shown to favor the prognosis as well as the response to chemotherapy in GBM patients.2.The metabolic heterogeneity featured by glycolysis exists in GBM and is closely associated with the morphological heterogeneity of microvasculature as we showed that the level of glycolysis was inversely correlated with mv FD in GBM.Furthermore,the bioinformatic analyses revealed that a glycolytic gene expression signature score(GGESS)predicted poor prognosis in GBM patients.In addition,the glycolytic status is closely associated with IDH1 mutation in GBM,which is evidenced by the downregulated gene expressions of key glycolytic genes in IDH1-mutant GBM.3.Microvascular pericyte coverage status predicts prognosis and the response to chemotherapy of GBM patients.Higher pericyte coverage ratio predicted worse prognosis and worse response to chemotherapy of GBM patients.4.Leptin-Leptin receptor(Lep R)pathway promotes the differentiation of glioma stem cells(GSCs)into pericytes.Blocking this pathway decreases microvascular pericyte coverage in orthotopically transplanted xenografts from GSCs.In summary,mv FD and pericyte coverage ratio are effective markers of T-MAPH in glioma,which could serve for guiding the clinical prognosis and the response to chemotherapy of GBM patients.For the mechanisms,we revealed a close relation between tumor glycolytic metabolism and microvascular morphological heterogeneity,and identified the roles of GSC "plasticity" in regulating the T-MAPH in glioma.These findings suggest that T-MAPH in glioma plays key roles as predictors for the clinical prognosis and response to treatment of GBM patients.Reversing the tumor glycolysis and targeting GSC-derived pericytes may change the specific microvascular phenotype related with poor clinical outcome of glioma patients,thus promote the treatment efficacy of glioma. |
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