Abstract
The aim of this study was to evaluate the expression of mammalian target of rapamycin (mTOR), phosphorylated-mTOR (p-mTOR), and eukaryotic translation initiation factor 4E-binding protein 1 (4E-BP1) in prostate cancer (PCa) in order to assess intratumoral heterogeneity and correlation with clinicopathological parameters. Tissue samples from 115 patients undergoing radical prostatectomy were included in a tissue microarray comprising (A) tissue from the tumor center, (B) malignant border of the tumor, (C) tumor-adjacent benign tissue, and (D) tumor-distant benign prostatic tissue. Immune reactive scores 0-12 were correlated with clinical data in reference to localization. A meta-analysis of studies investigating the association between biochemical recurrence (BCR) and parameters of the mTOR pathway was conducted. Regardless of the location within the tumor, cancer tissue showed higher expression of mTOR, p-mTOR, and 4EB-P1 compared to benign tissue (p < 0.01). Significant differences in expression between tissue samples from groups C and D were observed for mTOR and p-mTOR. When considering expression according to the pathological stage, we observed lower p-mTOR expression in pT3 vs. pT2 (7.9 and 6.3; p = 0.01). After a median follow-up of 74.5 months (IQR 65.0-84.0), 27 patients (23.47%) developed BCR. Weak staining of mTOR was associated with shorter time to BCR (HR: 2.0; p = 0.049) after correcting for PSA and T stage. However, a significant association of mTOR expression with BCR was found for specimens from the malignant border of the tumor (B) but not the tumor center (A) (p = 0.0034 log rank). In a meta-analysis, we found that the expressions of mTOR ((RR) = 0.70; 95% CI 0.43-1.12; p = 0.13) and 4E-BP1 ((RR) = 0.86; p = 0.53) were not statistically associated with BCR, while strong staining of p-mTOR was associated with a lower risk of BCR ((RR) = 0.57; p = 0.002). All 3 markers showed stronger expression in PCa and exhibited local gradients in relation to the border of tumor and healthy tissue. Our results suggest an important role of intratumor heterogeneity for the use of mTOR parameters as biomarkers in PCa.
Highlights
Prostate cancer (PCa) represents the most common cancer in men in developed countries in 2013 [1]
We found that the expressions of mammalian target of rapamycin (mTOR) and 4EBP1 were not statistically associated with biochemical recurrence (BCR), while strong staining of p-mTOR was associated with a lower risk of BCR (Figure 6)
The mammalian target of rapamycin plays a central role in regulating critical PCa cellular processes and tumorigenesis [21]. mTOR is a protein kinase that is present in two distinct complexes: mTOR complex 1 and mTOR complex 2 [21]. mTORC1 increases mRNA translation by the phosphorylation of eukaryotic initiation factor 4E- binding protein-1 (4E-BP1) [22], which is crucial for tumor growth [23, 24]
Summary
Prostate cancer (PCa) represents the most common cancer in men in developed countries in 2013 [1]. The goal of precision cancer medicine has been to pair clinical and biologic data to provide better and more efficient treatment options for cancer care [2]. Tissue microarrays have been established as an important tool for biomarker analysis. TMA is useful to discover molecular aberrations in different regions of a tumor, defined as intratumor heterogeneity (ITH), having critical implications in precise diagnosis and the treatment of cancers [3]. The phosphatidylinositol 3-kinase/proteinkinase B/ mammalian target of rapamycin pathway Disease Markers pathway) has long been known to play an important role in the development of PCa [4]. The mTORC1 complex signals primarily through effectors, including phosphorylation of the 4E-binding protein (4E-BP1), leading to an increase in cap-dependent translation and promoting proliferation [5]
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