Immunohistochemical characterization of the mTOR pathway in stage-I non-small-cell lung carcinoma.
BACKGROUND
Dysregulation of mammalian target of rapamycin (mTOR) pathway has been linked with malignant tumorigenesis. This study explored the expression profiles of proteins involved in the mTOR pathway and their relationships with clinicopathologic characteristics in stage-I non-small-cell lung carcinoma (NSCLC).


METHODS
The protein expression profiles of PTEN, p-Akt, p-mTOR, p-S6, and eIF4E were examined using immunohistochemical staining and tissue microarray method in 408 patients with stage-I NSCLC (250 adenocarcinomas [ADC] and 158 squamous cell carcinomas).


RESULTS
Retained PTEN expression (P<0.001), p-mTOR expression (P<0.001), and p-S6 expression (P=0.007) were associated with ADC histology. Expression of PTEN (P=0.001), p-Akt (P=0.005), p-mTOR (P=0.007), p-S6 (P<0.001) were correlated with lower pathologic T stage. PTEN loss was correlated with male gender and smoking history and p-mTOR expression was inversely correlated with these factors (P<0.001). Subgroup analysis of ADCs indicated that male gender, high pT stage, lymphovascular invasion, and PTEN loss were poor prognostic factors. Multivariate analysis revealed that the PTEN(-)/p-Akt(+)/p-mTOR(+) combination more effectively determined the prognosis of ADC (hazard ratio=2.2, P=0.004) than PTEN alone.


CONCLUSIONS
Activation of the mTOR pathway in early-stage ADCs suggests a significant role for the mTOR axis in early carcinogenesis. The combination of PTEN(-)/p-Akt(+)/p-mTOR(+) expression was correlated with poor overall survival in patients with stage-I lung ADC.
Department of Pathology, Seoul National University Bundang Hospital, 173-82 Gumiro, Bundang-gu, Seongnam 463-707, Gyeonggi-do, Republic of Korea.
Eun
E
Shin
Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, 88 Olympic-Ro 43-Gil, Songpa-Gu, 138-736 Seoul, Republic of Korea.
Chang Min
CM
Choi
Department of Thoracic Surgery, Asan Medical Center, University of Ulsan College of Medicine, 88 Olympic-Ro 43-Gil, Songpa-Gu, 138-736 Seoul, Republic of Korea.
Hyeong Ryul
HR
Kim
Department of Pathology, Asan Medical Center, University of Ulsan College of Medicine, 88 Olympic-Ro 43-Gil, Songpa-Gu, 138-736 Seoul, Republic of Korea.
Se Jin
SJ
Jang
Department of Pathology, Asan Medical Center, University of Ulsan College of Medicine, 88 Olympic-Ro 43-Gil, Songpa-Gu, 138-736 Seoul, Republic of Korea. Electronic address: youngspark@amc.seoul.kr.
Young Soo
YS
Park
D000230:Adenocarcinoma / Q000737:chemistry* / Q000473:pathology; D000368:Aged; D002289:Carcinoma, Non-Small-Cell Lung / Q000737:chemistry* / Q000473:pathology; D039561:Eukaryotic Initiation Factor-4E / Q000032:analysis; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D008175:Lung Neoplasms / Q000737:chemistry* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009361:Neoplasm Invasiveness; D009367:Neoplasm Staging; D051059:PTEN Phosphohydrolase / Q000032:analysis; D010766:Phosphorylation; D011379:Prognosis; D051057:Proto-Oncogene Proteins c-akt / Q000032:analysis / Q000378:metabolism; D019893:Ribosomal Protein S6 Kinases / Q000032:analysis / Q000378:metabolism; D012737:Sex Factors; D015398:Signal Transduction; D012907:Smoking; D015996:Survival Rate; D058570:TOR Serine-Threonine Kinases / Q000032:analysis* / Q000378:metabolism; D046888:Tissue Array Analysis
D039561:Eukaryotic Initiation Factor-4E; C546842:MTOR protein, human; D051057:Proto-Oncogene Proteins c-akt; D019893:Ribosomal Protein S6 Kinases; D058570:TOR Serine-Threonine Kinases; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human
Immunohistochemistry; Non-small-cell lung cancer; PTEN; Prognosis; mTOR; p-Akt