Aims Tumour 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.
Methods Immunohistochemistry 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.
Results Detailed 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.
Conclusions The 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.
- COLORECTAL CANCER
- MOLECULAR ONCOLOGY
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Handling editor Cheok Soon Lee
Contributors TS collected the biopsy materials and the clinical data with the help of GV. TS performed the IHC stainings and examined the expression of mTOR-related proteins jointly with ÁM, NN and AM. The pathological evaluation was performed by TM, MH and LK. Statistical data analysis was performed by TS, ÁM and NN. AS designed, coordinated and supervised the study and prepared the manuscript, figures and tables with the help of LK, AM, MH and TS.
Funding OTKA (K84262), Hungarian Academy of Sciences (Bolyai and Medinprot support for AS).
Competing interests None declared.
Ethics approval All protocols were approved by the Institutional Ethical Review Board (TUKEB no. 7/2006).
Provenance and peer review Not commissioned; externally peer reviewed.
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