Mammalian target of rapamycin signaling activation patterns in pancreatic neuroendocrine tumors

Yoko Komori, Kazuhiro Yada, Masayuki Ohta, Hiroki Uchida, Yukio Iwashita, Kengo Fukuzawa, Kenji Kashima, Shigeo Yokoyama, Masafumi Inomata, Seigo Kitano

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Abstract

Background Phosphatidylinositol 3-kinase/Akt/mammalian target of rapamycin (mTOR) pathway dysregulation has been implicated in the development of various human cancers. However, expression of mTOR cascade components in pancreatic neuroendocrine tumors (PNETs) has not been fully explored. The aim of this study was to assess the expression of mTOR pathway in PNETs using immunohistochemistry. Methods From December 1984 to April 2012, we surgically treated 42 patients with PNETs. We used immunohistochemistry to evaluate expression of mTOR, phosphorylated mTOR (p-mTOR), p70S6 kinase (S6K), phosphorylated S6 ribosomal protein (p-S6rp), eukaryotic initiation factor 4E-binding protein 1 (4E-BP1), and phosphorylated 4E-BP1 (p-4E-BP1) in the resected specimens. The relation between the expression of these molecules and clinicopathological characteristics was investigated. Results We identified the expression of mTOR (28.6%), p-mTOR (52.4%), S6K (52.4%), p-S6rp (40.5%), 4E-BP1 (81.0%), and p-4E-BP1 (26.2%) in PNETs. The expression of mTOR, p-mTOR, S6K, and p-S6rp was significantly associated with tumor invasion, proliferation, and an advanced-stage. Particularly, the expression of p-mTOR was related to clinically relevant factors such as tumor size, vascular invasion, extrapancreatic invasion, lymph node and/or distant metastasis, mitotic count, and European Neuroendocrine Tumor Society TNM staging as well as the 2004 and 2010 World Health Organization (WHO) classification. In addition, p-S6rp expression was related to vascular invasion, extrapancreatic invasion, lymph node and distant metastasis, mitotic count, and the 2010 WHO classification. In contrast, no significant relation between 4E-BP1 activation and clinicopathological factors was observed. The expression of p-mTOR was strongly correlated with that of p-S6rp (r = 0.474, P = 0.002). Conclusions Our results suggest that activation of the mTOR/S6K signaling pathway plays a significant role in tumorigenesis and progression of PNET.

Original languageEnglish
Pages (from-to)288-295
Number of pages8
JournalJournal of Hepato-Biliary-Pancreatic Sciences
Volume21
Issue number4
DOIs
Publication statusPublished - Jan 1 2014
Externally publishedYes

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Ribosomal Protein S6
Neuroendocrine Tumors
Sirolimus
Carrier Proteins
Blood Vessels
Lymph Nodes
Immunohistochemistry
Eukaryotic Initiation Factor-4E
Phosphatidylinositol 3-Kinase
Neoplasm Metastasis
Neoplasms
Neoplasm Staging
Human Development
Carcinogenesis
Phosphotransferases

All Science Journal Classification (ASJC) codes

  • Hepatology
  • Surgery
  • Medicine(all)

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Mammalian target of rapamycin signaling activation patterns in pancreatic neuroendocrine tumors. / Komori, Yoko; Yada, Kazuhiro; Ohta, Masayuki; Uchida, Hiroki; Iwashita, Yukio; Fukuzawa, Kengo; Kashima, Kenji; Yokoyama, Shigeo; Inomata, Masafumi; Kitano, Seigo.

In: Journal of Hepato-Biliary-Pancreatic Sciences, Vol. 21, No. 4, 01.01.2014, p. 288-295.

Research output: Contribution to journalArticle

Komori, Y, Yada, K, Ohta, M, Uchida, H, Iwashita, Y, Fukuzawa, K, Kashima, K, Yokoyama, S, Inomata, M & Kitano, S 2014, 'Mammalian target of rapamycin signaling activation patterns in pancreatic neuroendocrine tumors', Journal of Hepato-Biliary-Pancreatic Sciences, vol. 21, no. 4, pp. 288-295. https://doi.org/10.1002/jhbp.26
Komori, Yoko ; Yada, Kazuhiro ; Ohta, Masayuki ; Uchida, Hiroki ; Iwashita, Yukio ; Fukuzawa, Kengo ; Kashima, Kenji ; Yokoyama, Shigeo ; Inomata, Masafumi ; Kitano, Seigo. / Mammalian target of rapamycin signaling activation patterns in pancreatic neuroendocrine tumors. In: Journal of Hepato-Biliary-Pancreatic Sciences. 2014 ; Vol. 21, No. 4. pp. 288-295.
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abstract = "Background Phosphatidylinositol 3-kinase/Akt/mammalian target of rapamycin (mTOR) pathway dysregulation has been implicated in the development of various human cancers. However, expression of mTOR cascade components in pancreatic neuroendocrine tumors (PNETs) has not been fully explored. The aim of this study was to assess the expression of mTOR pathway in PNETs using immunohistochemistry. Methods From December 1984 to April 2012, we surgically treated 42 patients with PNETs. We used immunohistochemistry to evaluate expression of mTOR, phosphorylated mTOR (p-mTOR), p70S6 kinase (S6K), phosphorylated S6 ribosomal protein (p-S6rp), eukaryotic initiation factor 4E-binding protein 1 (4E-BP1), and phosphorylated 4E-BP1 (p-4E-BP1) in the resected specimens. The relation between the expression of these molecules and clinicopathological characteristics was investigated. Results We identified the expression of mTOR (28.6{\%}), p-mTOR (52.4{\%}), S6K (52.4{\%}), p-S6rp (40.5{\%}), 4E-BP1 (81.0{\%}), and p-4E-BP1 (26.2{\%}) in PNETs. The expression of mTOR, p-mTOR, S6K, and p-S6rp was significantly associated with tumor invasion, proliferation, and an advanced-stage. Particularly, the expression of p-mTOR was related to clinically relevant factors such as tumor size, vascular invasion, extrapancreatic invasion, lymph node and/or distant metastasis, mitotic count, and European Neuroendocrine Tumor Society TNM staging as well as the 2004 and 2010 World Health Organization (WHO) classification. In addition, p-S6rp expression was related to vascular invasion, extrapancreatic invasion, lymph node and distant metastasis, mitotic count, and the 2010 WHO classification. In contrast, no significant relation between 4E-BP1 activation and clinicopathological factors was observed. The expression of p-mTOR was strongly correlated with that of p-S6rp (r = 0.474, P = 0.002). Conclusions Our results suggest that activation of the mTOR/S6K signaling pathway plays a significant role in tumorigenesis and progression of PNET.",
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AU - Komori, Yoko

AU - Yada, Kazuhiro

AU - Ohta, Masayuki

AU - Uchida, Hiroki

AU - Iwashita, Yukio

AU - Fukuzawa, Kengo

AU - Kashima, Kenji

AU - Yokoyama, Shigeo

AU - Inomata, Masafumi

AU - Kitano, Seigo

PY - 2014/1/1

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N2 - Background Phosphatidylinositol 3-kinase/Akt/mammalian target of rapamycin (mTOR) pathway dysregulation has been implicated in the development of various human cancers. However, expression of mTOR cascade components in pancreatic neuroendocrine tumors (PNETs) has not been fully explored. The aim of this study was to assess the expression of mTOR pathway in PNETs using immunohistochemistry. Methods From December 1984 to April 2012, we surgically treated 42 patients with PNETs. We used immunohistochemistry to evaluate expression of mTOR, phosphorylated mTOR (p-mTOR), p70S6 kinase (S6K), phosphorylated S6 ribosomal protein (p-S6rp), eukaryotic initiation factor 4E-binding protein 1 (4E-BP1), and phosphorylated 4E-BP1 (p-4E-BP1) in the resected specimens. The relation between the expression of these molecules and clinicopathological characteristics was investigated. Results We identified the expression of mTOR (28.6%), p-mTOR (52.4%), S6K (52.4%), p-S6rp (40.5%), 4E-BP1 (81.0%), and p-4E-BP1 (26.2%) in PNETs. The expression of mTOR, p-mTOR, S6K, and p-S6rp was significantly associated with tumor invasion, proliferation, and an advanced-stage. Particularly, the expression of p-mTOR was related to clinically relevant factors such as tumor size, vascular invasion, extrapancreatic invasion, lymph node and/or distant metastasis, mitotic count, and European Neuroendocrine Tumor Society TNM staging as well as the 2004 and 2010 World Health Organization (WHO) classification. In addition, p-S6rp expression was related to vascular invasion, extrapancreatic invasion, lymph node and distant metastasis, mitotic count, and the 2010 WHO classification. In contrast, no significant relation between 4E-BP1 activation and clinicopathological factors was observed. The expression of p-mTOR was strongly correlated with that of p-S6rp (r = 0.474, P = 0.002). Conclusions Our results suggest that activation of the mTOR/S6K signaling pathway plays a significant role in tumorigenesis and progression of PNET.

AB - Background Phosphatidylinositol 3-kinase/Akt/mammalian target of rapamycin (mTOR) pathway dysregulation has been implicated in the development of various human cancers. However, expression of mTOR cascade components in pancreatic neuroendocrine tumors (PNETs) has not been fully explored. The aim of this study was to assess the expression of mTOR pathway in PNETs using immunohistochemistry. Methods From December 1984 to April 2012, we surgically treated 42 patients with PNETs. We used immunohistochemistry to evaluate expression of mTOR, phosphorylated mTOR (p-mTOR), p70S6 kinase (S6K), phosphorylated S6 ribosomal protein (p-S6rp), eukaryotic initiation factor 4E-binding protein 1 (4E-BP1), and phosphorylated 4E-BP1 (p-4E-BP1) in the resected specimens. The relation between the expression of these molecules and clinicopathological characteristics was investigated. Results We identified the expression of mTOR (28.6%), p-mTOR (52.4%), S6K (52.4%), p-S6rp (40.5%), 4E-BP1 (81.0%), and p-4E-BP1 (26.2%) in PNETs. The expression of mTOR, p-mTOR, S6K, and p-S6rp was significantly associated with tumor invasion, proliferation, and an advanced-stage. Particularly, the expression of p-mTOR was related to clinically relevant factors such as tumor size, vascular invasion, extrapancreatic invasion, lymph node and/or distant metastasis, mitotic count, and European Neuroendocrine Tumor Society TNM staging as well as the 2004 and 2010 World Health Organization (WHO) classification. In addition, p-S6rp expression was related to vascular invasion, extrapancreatic invasion, lymph node and distant metastasis, mitotic count, and the 2010 WHO classification. In contrast, no significant relation between 4E-BP1 activation and clinicopathological factors was observed. The expression of p-mTOR was strongly correlated with that of p-S6rp (r = 0.474, P = 0.002). Conclusions Our results suggest that activation of the mTOR/S6K signaling pathway plays a significant role in tumorigenesis and progression of PNET.

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