Review Article

The Clinical and Prognostic Significance of Activated AKT-mTOR Pathway in Human Astrocytomas

Table 1

Summary of reports investigating the role of AKT and p-AKT in astrocytomas.

Report (number of cases and grades)Antibody usedImmunostaining percentageCorrelations with clinicopathological featuresOther correlationsSurvival analysis

Yang et al. [12] (96 patients: 16 grade II, 35 III, and 45 IV)Rabbit monoclonal anti-p-AKT (Ser473) ab (CST), at a concentration of 1.5 Ig/mL (IHC)92.7% (89/96) showed nuclear and cytoplasmic stainingp-AKT with
(i) higher grade
(ii) lower KPS score
(i) p-AKT associated with a worse prognosis
(ii) Multivariate analysis: p-AKT as an independent prognostic factor
Saetta et al. [13] (82 patients: 20 grade II, 14 III, and 48 IV)Rabbit polyclonal anti-p-AKT1/2/3 ab (SCB), diluted 1 : 250 (IHC)p-AKT:
(i) nuclear 93.05% (67/72)
(ii) cytoplasmic 59.72% (43/72)
(i) Nuclear and cytoplasmic p-AKT with tumor grade
(ii) Cytoplasmic p-AKT with patients’ age
(i) Nuclear p-AKT with cytoplasmic p-AKT
(ii) Nuclear and cytoplasmic p-AKT with nuclear and cytoplasmic p-ERK
(iii) Nuclear p-AKT with VEGF and MVD
Multivariate analysis: cytoplasmic p-AKT as independent predictor of survival (higher survival probability)
Li et al. [14] (87 patients: 27 grade I-II, 24 III, and 36 IV)Rabbit monoclonal anti-p-AKT ab (EP), diluted 1 : 200 (IHC)(i) 72.4% (63/87) showed nuclear and/or cytoplasmic staining
(ii) 36.1% of grade IV showed strong expression
High p-AKT levels with tumor grade
El-Habr et al. [15] (71 patients: 7 grade II, 5 III, and 59 IV)Rabbit polyclonal anti-p-AKT1/2/3 ab (SCB), diluted 1 : 250 (IHC)p-AKT:
(i) nuclear 97% (22/24)
(i) cytoplasmic 100%
Cytoplasmic p-AKT with tumor gradeNuclear p-AKT with cytoplasmic p-AKT
Wang and Kang [16] (48 patients: 16 grade II, 23 III, and 9 IV)(i) Mouse monoclonal anti-AKT2 ab SCB, diluted 1 : 100 for IHC and 1 : 500 for WB
(ii) p-AKT (information not provided) diluted 1 : 500 for WB
64.6% (31/48) showed cytoplasmic AKT2 stainingAKT2 and p-AKT with tumor gradeAKT2 with Ki-67
Suzuki et al. [17] (64 patients grade IV)Rabbit polyclonal anti-p-AKT (Ser473) ab (CST), diluted 1 : 200 (IHC)(i) 68.8% (44/64)
(ii) 29.7% (19/64) had greater than 50% p-AKT positivity
(i) p-AKT positive, lower survival rate than p-AKT negative
(ii) Multivariate analysis: higher expression of p-AKT with poor prognosis
Annovazzi et al. [18] (54 patients: 10 grade II, 10 III, and 34 IV)(i) Mouse monoclonal anti-p-AKT (Ser473) ab (CST), diluted 1 : 100 (IHC)
(ii) Rabbit monoclonal anti-p-AKT (Ser473) ab (CST), diluted 1 : 1000 (WB)
(i) 0%, 50%, and 56.6% in grade II, III, and IV, respectively
(ii) Nuclear in grade II and III but mainly cytoplasmic in grade IV
p-AKT with tumor gradep-AKT with
(i) EGFR amplification
(ii) p-mTOR
No significant correlation
Matsutani et al. [19] (24 patients)Mouse monoclonal anti-AKT1 (B-1) ab (SCB) (IHC)58.3% (14/24), cytoplasmic staining(i)Positive AKT with tumor recurrences
(ii) Overexpressed AKT with invasive recurrence into surrounding brain
AKT overexpression with:
(i) shorter OS
(ii) PFS
Multivariate analysis: AKT overexpression as a significant prognostic factor for shorter PFS
Hlobilkova et al. [20] (89 patients: 42 grade I-II and 47 grade III-IV)Mouse monoclonal anti-p-AKT (Ser473) ab (IHC)86% of low grade and in 79% of high gradeNo correlation with gradep-AKT with EGFR activation
Mizoguchi et al. [21] (82 patients: 27 grade III and 55 IV)Rabbit polyclonal anti-p-AKT (Ser473) ab (CST), diluted 1 : 100 (IHC)(i) 78.2% of glioblastomas (43/55) positive nuclear and/or cytoplasmic
(ii) 18.5% of anaplastic astrocytomas (5/27) positive nuclear and/or cytoplasmic
p-AKT with tumor gradep-AKT with
(i) EGFRvIII
(ii) EGFRwt
(iii) p-STAT3
p-AKT marginally predictive of worse prognosis
Pelloski et al. [22] (268 grade IV)Rabbit polyclonal anti-p-AKT (Ser473) ab (CST), diluted 1 : 300 (IHC)Not providedp-AKT with
(i) p-ERK
(ii) p-p70S6K
(iii) p-mTOR
(iv) YKL-40
No significant correlation
Riemenschneider et al. [23] (29 grade IV)Rabbit monoclonal anti-p-AKT (Ser473) ab (CST), diluted 1 : 50 (IHC)Not providedp-AKT with
(i) p-TSC2
(ii) p-S6K
(iii) p-S6
Wang et al. [24] (128 patients: 9 grade II, 49 III, and 70 IV)Rabbit polyclonal anti-p-AKT (Ser473) ab (CST), diluted 1 : 50 (IHC)p-AKT in:
(i) 84% (59/70) grade IV
(ii) 44% (20/46) grade III
(iii) 22% (2/9) grade II
p-AKT with tumor gradep-AKT with activated NFκB
Chakravarti et al. [25] (11 grade II, 13 III, and 56 IV)p-AKT (Thr308) ab (CST) (WB)66% (50/92) of grade IVp-AKT with tumor gradep-AKT with
(i) p-PI3K
(ii) p-p70S6K
(iii) inversely with cCas3
p-AKT with
(i) adverse outcome
(ii) reduced time to death
Choe et al. [26] (45 grade IV)Rabbit polyclonal anti-p-AKT (Ser473) ab (CST), diluted 1 : 50 (IHC)Not providedp-AKT with
(i) PTEN protein loss
(ii) p-FKHR
(iii) p-S6
(iv) p-mTOR

ab: antibody, cCas3: cleaved caspase 3, CST: Cell Signaling Technology (Beverly, MA), EP: Epitomics (CA, USA), IHC: immunohistochemistry, KPS: Karnofsky Performance Status, MVD: microvessel density, OS: overall survival, p-ERK: phosphorylated extracellular-signal-regulated kinase, PFS: progression-free survival, SCB: Santa Cruz Biotechnology, VEGF: vascular endothelial growth factor, WB: Western blot.