The prognostic role of Beclin 1 protein expression in high-grade gliomas

Abstract

High-grade gliomas (HGG) have a poor outcome, however, prognostic subgroups of patients may be individuated by some clinico-biological parameters. It was recently demonstrated that the main response of HGG to therapy is autophagic death. Autophagy is involved in tumor suppression, and is defective in HGG, in which we previously found an underexpression of beclin 1 autophagic gene protein product. Underexpression of Beclin 1 protein has been correlated to poor patient outcome in other tumor types. In this paper, the prognostic role of Beclin 1 expression in HGG patients was investigated. We first evaluated the tumor cell cytoplasmic expression of Beclin 1 protein (BPCE), in a sample of 76 HGG by immunohistochemistry, and compared it with cell proliferation and apoptosis. We found high BPCE score positively correlated with apoptosis, and negatively with cell proliferation (p < 0.05). We then correlated BPCE score with survival and other prognostic parameters (histological grading, MGMT gene methylation status, age, patient performance status according to the Karnofski classification (KPS), extent of surgery, radiation therapy (RT) modality, temozolomide chemotherapy (TMZ CHT), and optimal/suboptimal post-surgical treatment). Forty-seven (61.8%) and twenty-nine (38.2%) patients showed high and low BPCE scores, respectively. BPCE showed statistically significant correlations with survival both at the univariate (p = 0.03) and multivariate analysis (p = 0.037). High BPCE was also positively correlated with high KPS values (p = 0.023), and with the accomplishment of an optimal postoperative therapy (p = 0.037). Furthermore, among patients showing a MGMT methylated gene, survival was significantly higher in cases with a higher BPCE score. BPCE score might be added to pathological evaluation of HGG for prognostic purposes.

Autophagy patterns and prognosis in uveal melanomas

“…Such decreased cytoplasmic expression of BECN1 has been correlated with tumor progression in breast, ovarian, and cerebral neoplasms 39,46,47 and with a reduced survival rate in neoplasms of esophageal, colorectal, hepatocellular, and cerebral origin. [48][49][50][51] Liang et al 46 explained this immunohistochemical decline in cytoplasmic expression of the protein in terms of BECN1 inactivation and loss of its tumor suppressor functions. There have been, however, other tumors, including colorectal and gastric adenocarcinomas, in which progression appeared to be dependent upon an increased BECN1 expression.…”

The autophagic paradox in cancer therapy

“…Importantly, some of these abnormalities have been shown to correlate with clinicopathological parameters and disease outcomes including overall survival in cancer patients. These findings not only underscore a pivotal role of autophagy in tumorigenesis, but also highlight the possibility of using autophagy-associated molecules as novel prognostic markers in clinical settings (Russell et al, 1990;Eccles et al, 1992;Futreal et al, 1992;Cliby et al, 1993;Saito et al, 1993;Gao et al, 1995;Ahn et al, 2007;Miracco et al, 2007Miracco et al, , 2010Ding et al, 2008;Fujii et al, 2008;Yoshioka et al, 2008;Kim et al, 2008a;Kang et al, 2009;Lazova and Pawelek, 2009;Nomura et al, 2009;Othman et al, 2009;Pirtoli et al, 2009;Li et al, 2009Zhang et al, 2009a;Koukourakis et al, 2010;Lazova et al, 2010;Miao et al, 2010;Negri et al, 2010;Sivridis et al, 2010;Wan et al, 2010;Karpathiou et al, 2010;Chang et al, 2011;Ma et al, 2011).…”

The role of the PI3K/AKT/mTOR pathway in brain tumor metastasis

“…[51][52][53] High-grade gliomas have been reported to have lower expression of autophagy-related proteins than low-grade gliomas. [54] The amplification of EGFR, which is often found in these tumors, is known to suppress autophagy. [55] The progression of astrocytic tumors is associated with a decrease in autophagic capacity.…”