Mammalian target of rapamycin signaling pathway contributes to glioma progression and patients' prognosis

Abstract

Background: The mammalian target of rapamycin (mTOR) pathway plays an important role in the regulation of cell growth and increasing evidence suggests its dysregulation in tumors. It also implements many other critical cellular functions, including protein degradation and angiogenesis. To date, a correlation between the mTOR pathway in human glioma and patients' prognosis has not been reported.

Methods: To address this question, we carried out an immunohistochemical study of the mTOR upstream and downstream targets phosphorylated Akt (pAkt), phosphorylated S6 ribosomal protein (pS6), and p27, as well as phosphatase and tensin homologue (PTEN) using biopsies from 96 patients with primary glioma. Kaplan-Meier survival and Cox regression analyses were performed to evaluate the prognosis of patients.

Results: Immunostaining revealed that the mTOR pathway was significantly associated with the Karnofsky performance scale (KPS) score and World Health Organization (WHO) grade of patients with glioma. Especially, the positive expression rates of pAkt, cytoplasmic p27, and pS6 were significantly higher in patients with higher grade (P = 0.002, 0.001 and 0.002) and lower KPS score (P = 0.007, 0.005, and 0.008), which were opposite to the nuclear p27 and PENT expression. Statistical analysis showed that patients with glioma expressing pAkt, PTEN, cytoplasmic p27, nuclear p27, and pS6 have different overall survival rates relative to those not expressing these proteins. Cox multi-factor analysis showed that KPS (P = 0.02), WHO grade (P = 0.005), pAkt (P = 0.009), PTEN (P = 0.006), cytoplasm p27 (P = 0.008), nuclear p27 (P = 0.01), and pS6 (P = 0.003) were independent prognosis factors for human glioma.

Conclusion: These results provide convincing evidence for the first time that the mTOR pathway correlated closely with overall survival of patients with glioma and might be a novel prognostic marker.