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Intratumoral Heterogeneity Determines the Expression of mTOR-pathway Proteins in Prostate Cancer

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 clinicopa...

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Autores principales: Russo, Giorgio Ivan, Hennenlotter, Jörg, Vogel, Ulrich, Kühs, Ursula, Wurm, Thomas Manfred, Gerber, Valentina, Neumann, Tim, Cimino, Sebastiano, Stenzl, Arnulf, Todenhöfer, Tilman
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Hindawi 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6927025/
https://www.ncbi.nlm.nih.gov/pubmed/31885728
http://dx.doi.org/10.1155/2019/1296865
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author Russo, Giorgio Ivan
Hennenlotter, Jörg
Vogel, Ulrich
Kühs, Ursula
Wurm, Thomas Manfred
Gerber, Valentina
Neumann, Tim
Cimino, Sebastiano
Stenzl, Arnulf
Todenhöfer, Tilman
author_facet Russo, Giorgio Ivan
Hennenlotter, Jörg
Vogel, Ulrich
Kühs, Ursula
Wurm, Thomas Manfred
Gerber, Valentina
Neumann, Tim
Cimino, Sebastiano
Stenzl, Arnulf
Todenhöfer, Tilman
author_sort Russo, Giorgio Ivan
collection PubMed
description 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.
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spelling pubmed-69270252019-12-29 Intratumoral Heterogeneity Determines the Expression of mTOR-pathway Proteins in Prostate Cancer Russo, Giorgio Ivan Hennenlotter, Jörg Vogel, Ulrich Kühs, Ursula Wurm, Thomas Manfred Gerber, Valentina Neumann, Tim Cimino, Sebastiano Stenzl, Arnulf Todenhöfer, Tilman Dis Markers Research Article 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. Hindawi 2019-12-11 /pmc/articles/PMC6927025/ /pubmed/31885728 http://dx.doi.org/10.1155/2019/1296865 Text en Copyright © 2019 Giorgio Ivan Russo et al. http://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
spellingShingle Research Article
Russo, Giorgio Ivan
Hennenlotter, Jörg
Vogel, Ulrich
Kühs, Ursula
Wurm, Thomas Manfred
Gerber, Valentina
Neumann, Tim
Cimino, Sebastiano
Stenzl, Arnulf
Todenhöfer, Tilman
Intratumoral Heterogeneity Determines the Expression of mTOR-pathway Proteins in Prostate Cancer
title Intratumoral Heterogeneity Determines the Expression of mTOR-pathway Proteins in Prostate Cancer
title_full Intratumoral Heterogeneity Determines the Expression of mTOR-pathway Proteins in Prostate Cancer
title_fullStr Intratumoral Heterogeneity Determines the Expression of mTOR-pathway Proteins in Prostate Cancer
title_full_unstemmed Intratumoral Heterogeneity Determines the Expression of mTOR-pathway Proteins in Prostate Cancer
title_short Intratumoral Heterogeneity Determines the Expression of mTOR-pathway Proteins in Prostate Cancer
title_sort intratumoral heterogeneity determines the expression of mtor-pathway proteins in prostate cancer
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6927025/
https://www.ncbi.nlm.nih.gov/pubmed/31885728
http://dx.doi.org/10.1155/2019/1296865
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