Associations Between PSTAT3-VEGF Signal Pathway And Peritumoral Edema, Prognosis In Newly Diagnosed Supratentorial Glioblastoma

Part 1: STAT3 Tyr705 phosphorylation affects clinical outcome in patients with newly diagnosed supratentorial glioblastomaBackground and Purpose: STAT3 Tyrosine705 phosphorylation(p Tyr705-STAT3) plays a central role in glioblastoma(GBM) carcinogenesis and progression. However, it is still controversial whether p Tyr705-STAT3 expression is associated with the clinical outcome of glioblastoma patients. The aim of this study was to investigate p Tyr705-STAT3 expression in glioblastoma tissues, and explore the relationship between its expression and prognosis in patients with GBM. Such evidence would contribute to further illustrate whether STAT3 inhibition is suitable for clinical treatment. Methods: The expression of p Tyr705-STAT3 was examined in the tumor tissues from 90 patients with newly diagnosed supratentorial GBM via immunohistochemical technique. Its association with the clinicopathological characteristics was analyzed, and the Kaplan-Meier curve and COX proportional hazards regression model were used to evaluate the influences of its expression on progression-free survival(PFS) and overall survival(OS). Results: Immunohistochemical assay indicated increased expression of p Tyr705-STAT3 in GBM tissue compared to adjacent normal brain tissue without p Tyr705-STAT3 expression. There were no association between p Tyr705-STAT3 expression and patient gender(P = 0.660), age(P = 0.867) or preoperative Karnofsky performance status(KPS)(P = 0.121). Univariate survival analysis revealed significant correlation of high p Tyr705-STAT3 expression with shorter PFS(P = 0.012) and OS(P = 0.009). Multivariate survival analysis confirmed high p Tyr705-STAT3 expression as a significant prognostic indicator for shorter PFS(HR 2.158, P = 0.019) and OS(HR 2.120, P = 0.031), independent of age, KPS and chemoradiotherapy. Conclusion: The high percentage of p Tyr705-STAT3 positive tumor cells is a significant independent prognostic indicator for poor clinical outcome in patients with GBM, in addition toadvanced age, poor performance status and nonstandard chemoradiotherapy, and suggesting that STAT3 may be serve as a promising therapeutic target in GBM.Part 2: STAT3 serine 727 phosphorylation influences clinical outcome in glioblastomaBackground and Purpose: Besides STAT3 tyrosine 705 phosphorylation(p Tyr705-STAT3), phosphorylation of STAT3 at serine 727(p Ser727-STAT3) is shown to contribute to tumorigenesis and be closely related with resistance to chemoradiotherapy in glioma, but there is still limited knowledge regarding its relevance to prognosis in glioblastoma(GBM). The purpose of this study was to detect the expression of phosphorylated STAT3 in GBM and further investigate its prognosis value. Methods: Phosphorylated STAT3 was detected in tumor specimens from 88 patients with newly diagnosed GBM by immunohistochemistry. The Kaplan-Meier survival curve and COX proportional hazards regression model were applied to estimate its influences on progression-free survival(PFS) and overall survival(OS). Results: Immunohistochemical assay showed elevated expression of p Ser727-STAT3 in GBM compared with normal brain tissue. Univariate analysis indicated significant correlations of high percentage of p Ser727-STAT3 positive tumor cells with shorter PFS(P = 0.006) and OS(P = 0.002). In multivariate analysis, high p Ser727-STAT3 expression was demonstrated as an independent unfavorable prognostic indicator for PFS(HR 1.830, P = 0.022) and OS(HR 1.797, P = 0.040). And patients with high expression of both p Tyr705-STAT3 and p Ser727-STAT3 had a poorer prognosis compared with the remainder(P < 0.05). Conclusions: This is the first study to confirm that the high proportion of p Ser727-STAT3 positive neoplastic cells in GBM is an independent unfavorable prognostic factor, and increased expression of both p Tyr705-STAT3 and p Ser727-STAT3 is predictive of poorer clinical outcome, adding to the growing evidence that STAT3 inhibition may be a potential therapeutic strategy in glioblastoma.Part 3: Association of p Tyr705-STAT3-VEGF signaling pathway with peritumoral edema in newly diagnosed glioblastoma – an immunohistochemical studyBackground and Purpose: It is well recognized that peritumoral edema(PTE) is vasogenic cerebral edema in malignant glioma, and VEGF induced by p Tyr705-STAT3 strongly contributes to tumor angiogenesis in glioblastoma(GBM). However, there is no study with regard to correlation between them. This study aimed to detect the expression of p Tyr705-STAT3 and VEGF in glioblastoma specimens, and analyze the relationship of p Tyr705-STAT3-VEGF pathway with peritumoral edema in patients with GBM. Such evidence may contribute to provide new targets for the management of PTE. Methods: The newly diagnosed GBM tissues from 84 patients were collected to investigate p Tyr705-STAT3 and VEGF expression by immunohistochemistry. PTE shown by preoperative MRI was classified as grade 1( ≤ 2 cm) and grade 2( > 2 cm). Utilising the appropriate statistical methods, the association of p Tyr705-STAT3 with VEGF expression and the correlations between PTE and the expression level of p Tyr705-STAT3, VEGF were analyzed. Results: A significant positive correlation emerged between VEGF and p Tyr705-STAT3 expression(P = 0.000), but they were not related to patient gender and age(P > 0.05). The expression of p Tyr705-STAT3 and VEGF were associated with PTE extent(P = 0.005), but not with edema shape(P > 0.05). Conclusions: The p Tyr705-STAT3-VEGF signaling pathway, which is correlated with PTE extent, might be a regulatory mechanism in the course of peritumoral edema formation during GBM tumorigenesis and progression, thereby suggesting that STAT3 inhibition might be helpful for alleviation of peritumoral edema.