Diverse prognostic roles of Akt isoforms, PTEN and PI3K in tumor epithelial cells and stromal compartment in non-small cell lung cancer.
OBJECTIVE
By tissue microarray methodology, the expression of altered Akt isoforms, PTEN and PI3K and their prognostic significance in 335 non-small cell lung cancer (NSCLC) tumors were investigated.


METHODS
Tumor tissue was sampled and immunohistochemically quantified in 335 tumors from stage I to IIIA NSCLC patients both from tumor epithelial cells and surrounding stromal tissue in resected specimens. Correlations were made with clinicopathological variables. In addition, the expression of these markers was compared to 20 lung tissue cores from patients without any history of malignancy.


RESULTS
A significantly higher PTEN expression was observed in control tissue when compared with tumor (p=0.001). There was a significantly negative correlation between PI3K expression in control versus tumor tissue (p=0.001, r=-0.2). In univariate analyses, high tumor epithelial cell expression of non-phosphorylated Akt2 (p=0.014) was a positive prognostic indicator for disease-specific survival (DSS), while high tumor epithelial cell expression of p-Akt Thr(308) (p=0.045) was a negative prognosticator. High stromal expression of total Akt3 (p=0.0008) and total PI3K (p=0.0003) correlated with a good prognosis. In the multivariate analysis, tumor epithelial cell expression of p-Akt Thr(308) (p=0.0009) and Akt2 (p=0.004) and the stromal cell expression of Akt3 (p=0.0008) and PI3K (p=0.012) were independent prognostic factors for DSS.


CONCLUSIONS
High expression of non-phosphorylated Akt2 and low expression of p-Akt Thr(308) in tumor epithelial cells are independent predictors of improved survival in patients with primary NSCLC. In stromal cells, high expression of total Akt3 and total PI3K are both favourable independent prognostic indicators.
Institute of Medical Biology, University of Tromso, Norway. samer.al-saad@unn.no
Samer
S
Al-Saad
Tom
T
Donnem
Khalid
K
Al-Shibli
Magnus
M
Persson
Roy M
RM
Bremnes
Lill-Tove
LT
Busund
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002289:Carcinoma, Non-Small-Cell Lung / Q000201:enzymology* / Q000473:pathology; D004847:Epithelial Cells / Q000201:enzymology / Q000473:pathology; D006801:Humans; D007150:Immunohistochemistry; D007527:Isoenzymes; D008175:Lung Neoplasms / Q000201:enzymology* / Q000473:pathology; D008875:Middle Aged; D009367:Neoplasm Staging; D051059:PTEN Phosphohydrolase / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D010766:Phosphorylation; D011379:Prognosis; D016016:Proportional Hazards Models; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D015398:Signal Transduction; D017154:Stromal Cells / Q000201:enzymology / Q000473:pathology
D007527:Isoenzymes; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human