mTOR activity and its prognostic significance in human colorectal carcinoma depending on C1 and C2 complex-related protein expression

• Published in: Journal of clinical pathology Vol. 70; no. 5; pp. 410 - 416
• Main Authors: Sticz, Tamás, Molnár, Anna, Márk, Ágnes, Hajdu, Melinda, Nagy, Noémi, Végső, Gyula, Micsik, Tamás, Kopper, László, Sebestyén, Anna
• Format: Journal Article
• Language: English
• Published: England BMJ Publishing Group LTD 01.05.2017
• Subjects: Adenocarcinoma - diagnosis; Adenocarcinoma - metabolism; Adenocarcinoma - mortality; Adenocarcinoma - pathology; Adult; Aged; Cell Line, Tumor; Colorectal Neoplasms - diagnosis; Colorectal Neoplasms - metabolism; Colorectal Neoplasms - mortality; Colorectal Neoplasms - pathology; Female; Humans; Immunohistochemistry; Male; Mechanistic Target of Rapamycin Complex 1; Mechanistic Target of Rapamycin Complex 2; Middle Aged; Multiprotein Complexes - genetics; Multiprotein Complexes - metabolism; Phosphatidylinositol 3-Kinases - metabolism; Phosphoproteins - metabolism; Phosphorylation; Prognosis; Signal Transduction; Tissue Array Analysis; TOR Serine-Threonine Kinases - genetics; TOR Serine-Threonine Kinases - metabolism; MOLECULAR ONCOLOGY; COLORECTAL CANCER; IMMUNOHISTOCHEMISTRY
• ISSN: 0021-9746; 1472-4146
• DOI: 10.1136/jclinpath-2016-203913

AimsTumour heterogeneity and altered activation of signalling pathways play important roles in therapy resistance. The PI3K/Akt/mTOR signalling network is a well-known regulator of several functions that contribute to tumour growth. mTOR exists in two functionally different multiprotein complexes. We aimed to determine mTOR activity-related proteins in clinically followed, conventionally treated colon carcinomas and to analyse the correlation between clinical data and mTORC1 and mTORC2 activity.MethodsImmunohistochemistry was performed with different antibodies on tissue microarray blocks from 103 patients with human colorectal adenocarcinoma. mTORC1- and mTORC2-related activity were scored on different stainings including analysis of the expression of Raptor and Rictor—specific elements of mTORC1 and C2 complexes. The staining scores and clinical/survival data were compared and analysed.ResultsDetailed characterisation showed stage and grade independent high mTOR activity in 74% of cases. High mTOR activity was present in mTORC1 and/or mTORC2 complexes; >60% of cases had mTORC2-related high mTOR activity. Based on our analysis, high mTOR activity and Rictor overexpression could be markers of a bad prognosis. Combined phosphoprotein and Rictor/Raptor expression evaluation revealed even stronger statistical correlation with prognosis.ConclusionsThe presented staining panel could be appropriate and highly recommended for the accurate specification of mTORC1 and C2 activity of tumour tissues. This could help in the selection of mTOR inhibitors and can provide information about prognosis, which may guide decisions about the intensity of therapy.