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Metastatic role of mammalian target of rapamycin signaling activation by chemoradiotherapy in advanced rectal cancer

Postoperative distant metastasis dramatically affects rectal cancer patients who have undergone neoadjuvant chemoradiotherapy (NACRT). Here, we clarified the association between NACRT‐mediated mammalian target of rapamycin (mTOR) signaling pathway activation and rectal cancer metastatic potential. W...

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Autores principales: Shiratori, Hiroshi, Kawai, Kazushige, Okada, Masamichi, Nozawa, Hiroaki, Hata, Keisuke, Tanaka, Toshiaki, Nishikawa, Takeshi, Shuno, Yasutaka, Sasaki, Kazuhito, Kaneko, Manabu, Murono, Koji, Emoto, Shigenobu, Ishii, Hiroaki, Sonoda, Hirofumi, Ushiku, Tetsuo, Ishihara, Soichiro
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7156826/
https://www.ncbi.nlm.nih.gov/pubmed/31997546
http://dx.doi.org/10.1111/cas.14332
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author Shiratori, Hiroshi
Kawai, Kazushige
Okada, Masamichi
Nozawa, Hiroaki
Hata, Keisuke
Tanaka, Toshiaki
Nishikawa, Takeshi
Shuno, Yasutaka
Sasaki, Kazuhito
Kaneko, Manabu
Murono, Koji
Emoto, Shigenobu
Ishii, Hiroaki
Sonoda, Hirofumi
Ushiku, Tetsuo
Ishihara, Soichiro
author_facet Shiratori, Hiroshi
Kawai, Kazushige
Okada, Masamichi
Nozawa, Hiroaki
Hata, Keisuke
Tanaka, Toshiaki
Nishikawa, Takeshi
Shuno, Yasutaka
Sasaki, Kazuhito
Kaneko, Manabu
Murono, Koji
Emoto, Shigenobu
Ishii, Hiroaki
Sonoda, Hirofumi
Ushiku, Tetsuo
Ishihara, Soichiro
author_sort Shiratori, Hiroshi
collection PubMed
description Postoperative distant metastasis dramatically affects rectal cancer patients who have undergone neoadjuvant chemoradiotherapy (NACRT). Here, we clarified the association between NACRT‐mediated mammalian target of rapamycin (mTOR) signaling pathway activation and rectal cancer metastatic potential. We performed immunohistochemistry for phosphorylated mTOR (p‐mTOR) and phosphorylated S6 (p‐S6) on surgical specimen blocks from 98 rectal cancer patients after NACRT (cohort 1) and 80 colorectal cancer patients without NACRT (cohort 2). In addition, we investigated the association between mTOR pathway activity, affected by irradiation, and the migration ability of colorectal cancer cells in vitro. Based on the results of the clinical study, p‐mTOR was significantly overexpressed in cohort 1 (with NACRT) as compared to levels in cohort 2 (without NACRT) (P < .001). High p‐mTOR and p‐S6 levels correlated with the development of distant metastasis only in cohort 1. Specifically, high p‐S6 expression (HR 4.51, P = .002) and high pathological T‐stage (HR 3.73, P = .020) after NACRT were independent predictors of the development of distant metastasis. In vitro, p‐S6 levels and migration ability increased after irradiation in SW480 cells (TP53 mutation‐type) but decreased in LoVo cells (TP53 wild‐type), suggesting that irradiation modulates mTOR signaling and migration through cell type‐dependent mechanisms. We next assessed the expression level of p53 by immunostaining in cohort 1 and demonstrated that p‐S6 was overexpressed in samples with high p53 expression as compared to levels in samples with low p53 expression (P = .008). In conclusion, p‐S6 levels after NACRT correlate with postoperative distant metastasis in rectal cancer patients, suggesting that chemoradiotherapy might modulate the mTOR signaling pathway, promoting metastasis.
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spelling pubmed-71568262020-04-20 Metastatic role of mammalian target of rapamycin signaling activation by chemoradiotherapy in advanced rectal cancer Shiratori, Hiroshi Kawai, Kazushige Okada, Masamichi Nozawa, Hiroaki Hata, Keisuke Tanaka, Toshiaki Nishikawa, Takeshi Shuno, Yasutaka Sasaki, Kazuhito Kaneko, Manabu Murono, Koji Emoto, Shigenobu Ishii, Hiroaki Sonoda, Hirofumi Ushiku, Tetsuo Ishihara, Soichiro Cancer Sci Original Articles Postoperative distant metastasis dramatically affects rectal cancer patients who have undergone neoadjuvant chemoradiotherapy (NACRT). Here, we clarified the association between NACRT‐mediated mammalian target of rapamycin (mTOR) signaling pathway activation and rectal cancer metastatic potential. We performed immunohistochemistry for phosphorylated mTOR (p‐mTOR) and phosphorylated S6 (p‐S6) on surgical specimen blocks from 98 rectal cancer patients after NACRT (cohort 1) and 80 colorectal cancer patients without NACRT (cohort 2). In addition, we investigated the association between mTOR pathway activity, affected by irradiation, and the migration ability of colorectal cancer cells in vitro. Based on the results of the clinical study, p‐mTOR was significantly overexpressed in cohort 1 (with NACRT) as compared to levels in cohort 2 (without NACRT) (P < .001). High p‐mTOR and p‐S6 levels correlated with the development of distant metastasis only in cohort 1. Specifically, high p‐S6 expression (HR 4.51, P = .002) and high pathological T‐stage (HR 3.73, P = .020) after NACRT were independent predictors of the development of distant metastasis. In vitro, p‐S6 levels and migration ability increased after irradiation in SW480 cells (TP53 mutation‐type) but decreased in LoVo cells (TP53 wild‐type), suggesting that irradiation modulates mTOR signaling and migration through cell type‐dependent mechanisms. We next assessed the expression level of p53 by immunostaining in cohort 1 and demonstrated that p‐S6 was overexpressed in samples with high p53 expression as compared to levels in samples with low p53 expression (P = .008). In conclusion, p‐S6 levels after NACRT correlate with postoperative distant metastasis in rectal cancer patients, suggesting that chemoradiotherapy might modulate the mTOR signaling pathway, promoting metastasis. John Wiley and Sons Inc. 2020-02-22 2020-04 /pmc/articles/PMC7156826/ /pubmed/31997546 http://dx.doi.org/10.1111/cas.14332 Text en © 2020 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association. This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.
spellingShingle Original Articles
Shiratori, Hiroshi
Kawai, Kazushige
Okada, Masamichi
Nozawa, Hiroaki
Hata, Keisuke
Tanaka, Toshiaki
Nishikawa, Takeshi
Shuno, Yasutaka
Sasaki, Kazuhito
Kaneko, Manabu
Murono, Koji
Emoto, Shigenobu
Ishii, Hiroaki
Sonoda, Hirofumi
Ushiku, Tetsuo
Ishihara, Soichiro
Metastatic role of mammalian target of rapamycin signaling activation by chemoradiotherapy in advanced rectal cancer
title Metastatic role of mammalian target of rapamycin signaling activation by chemoradiotherapy in advanced rectal cancer
title_full Metastatic role of mammalian target of rapamycin signaling activation by chemoradiotherapy in advanced rectal cancer
title_fullStr Metastatic role of mammalian target of rapamycin signaling activation by chemoradiotherapy in advanced rectal cancer
title_full_unstemmed Metastatic role of mammalian target of rapamycin signaling activation by chemoradiotherapy in advanced rectal cancer
title_short Metastatic role of mammalian target of rapamycin signaling activation by chemoradiotherapy in advanced rectal cancer
title_sort metastatic role of mammalian target of rapamycin signaling activation by chemoradiotherapy in advanced rectal cancer
topic Original Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7156826/
https://www.ncbi.nlm.nih.gov/pubmed/31997546
http://dx.doi.org/10.1111/cas.14332
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