Abstract
Purpose
Impaired regulation of the Akt/mammalian target of rapamycin (mTOR) pathway has been implicated in mechanisms related to neoplastic transformation in renal cell cancer (RCC) through enhancement of cell proliferation and survival and mTOR activation has been reported to occur due to phosphorylation of mTOR. To further determine the relevance of mTOR expression and activation and to analyze their putative role as a biomarker for systemic treatment in metastatic RCC, we investigated the expression of mTOR and phospho(p)-mTOR in primary RCC and metastases and correlated levels with pathological variables and clinical outcome.
Methods
Tissue microarrays (TMA) from paraffin-embedded tissue from 342 patients with primary clear cell renal cell carcinoma and 90 patients undergoing surgical resection for metastases were immunohistochemically stained for mTOR and p-mTOR and expression was quantified with immunoreactivity scores. Clinical patient characteristics and follow-up were recorded. Comparative evaluation of protein expression levels and association of expression with clinical variables and survival was performed.
Results
mTOR staining revealed differential expression in benign, primary and RCC metastasis (average staining score: 1.64, 0.78, and 1.44, respectively). Average staining of p-mTOR was 0.99 in benign kidney tissue, 0.73 in primary RCC and 1.14 in RCC metastasis tissue. Elevated mTOR expression in primary RCC tissue was associated with the presence of tumor necrosis, while a high level of p-mTOR was significantly correlated with advanced T-stage, high Fuhrman grade, the presence of tumor necrosis and sarcomatoid features. An elevated ratio of p-mTOR/mTOR was significantly correlated with advanced stage and sarcomatoid histology. mTOR expression was not predictive of overall survival (OS), while high p-mTOR levels were associated with impaired OS (p = 0.0046) and cancer-specific survival (p = 0.0067). In univariate analysis, advanced stage (HR 3.78), high Fuhrman grade (HR 4.0), the presence of tumor necrosis (HR 1.99), and sarcomatoid features (HR 5.12) were significant predictors of OS. Moreover, elevated levels of p-mTOR (HR 1.67) and an elevated ratio of p-mTOR/mTOR ratio (HR 1.73) were significantly predictive of OS. In the multivariate regression model only the presence of locally advanced tumors (HR 2.44) was of independent prognostic value for OS, while there was a trend for impaired OS for patients with a high p-mTOR (HR 1.27, p = 0.21).
Conclusions
Phosphorylated mTOR is differentially expressed in localized RCC and metastasis. Elevated phosphorylation of mTOR is associated with aggressive pathologic features and unfavorable outcome. Whether these findings portend to relevance for mTOR inhibition treatment for metastatic RCC should be objective of further investigations.
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Acknowledgements
We thank Ms. Ursula Kühs for her excellent technical assistance during tissue-microarray performance. The study was supported by a grant from Novartis AG, Basel, Switzerland.
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Protocol development: SK, SR, JB. Data collection and experiments: SR, DS, JH, VS. Data analysis and interpretation: SR, DS, JB, VS. Study supervision: AS, JB. Manuscript writing/ editing: SR, JB, SK, AS.
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JB: consultancies, honoraria or study participation from Bayer, BMS, Eisai, Eusa, Immatics, Ipsen, Novartis, Pfizer and Roche. AS: consultancies, honoraria or study participation from Bayer, BMS, Eisai, Immatics, Ipsen, Novartis, Pfizer and Roche.
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The study was approved by the institutional review board and conducted in accordance with the Helsinki and START protocol. We take responsibility to the integrity of the data and accuracy of the reported study. All authors have made a substantial contribution to the information or material submitted for publication and approved the final version.
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Rausch, S., Schollenberger, D., Hennenlotter, J. et al. mTOR and mTOR phosphorylation status in primary and metastatic renal cell carcinoma tissue: differential expression and clinical relevance. J Cancer Res Clin Oncol 145, 153–163 (2019). https://doi.org/10.1007/s00432-018-2775-5
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DOI: https://doi.org/10.1007/s00432-018-2775-5