Activation of the Akt-mTOR pathway and receptor tyrosine kinase in patients with solitary fibrous tumors

Yuichi Yamada, Kenichi Kouhashi, Fumiyoshi Fushimi, Yusuke Takahashi, Nokitaka Setsu, Makoto Endo, Hidetaka Yamamoto, Shoji Tokunaga, Yukihide Iwamoto, Yoshinao Oda

Research output: Contribution to journalArticle

20 Citations (Scopus)

Abstract

BACKGROUND Solitary fibrous tumors (SFTs) are soft tissue tumors of intermediate malignancy that rarely metastasize. Although unresectable SFTs are reported to have a poor prognosis, to the authors' knowledge there is currently no effective therapy. Molecular target therapy is a promising approach for patients with unresectable tumors, but knowledge of the molecular biology of SFTs is currently insufficient to support such therapy. The current study investigated the activation of receptor tyrosine kinases (RTKs) and the Akt-mammalian target of rapamycin (Akt-mTOR) pathway in SFTs as therapeutic targets. METHODS The phosphorylation statuses of Akt-mTOR pathway proteins (p-Akt, p-mTOR, phosphorylated 4E-binding protein [p-4EBP1], and phosphorylated S6 ribosomal protein [p-S6RP]) and RTKs (phosphorylated platelet-derived growth factor receptor-α [p-PDGFRα], p-PDGFRβ, p-c-met, and phosphorylated insulin-like growth factor-1 receptor-β [p-IGF-1Rβ]) were assessed by immunohistochemistry in 66 samples of SFTs, and the data were compared with clinicopathological and histopathological findings. The expression of phosphorylated proteins was assessed by Western blot analysis in 6 frozen samples. RESULTS The immunohistochemical results were as follows: p-Akt, 56.0% (nuclear and cytoplasmic staining); p-mTOR, 69.6% (nuclear and cytoplasmic staining); p-4EBP1, 80.3% (nuclear and cytoplasmic staining); p-S6RP, 69.6% (cytoplasmic staining); p-PDGFRα, 39.0% (cytoplasmic staining); p-PDGFRβ, 52.0% (cytoplasmic staining); p-c-met, 37.8% (nuclear staining) and 19.6% (cytoplasmic staining); and p-IGF-1Rβ, 16.6% (nuclear staining). Phosphorylation of the Akt-mTOR pathway proteins was correlated with one another except for p-Akt with S6RP. p-PDGFRβ and p-IGF-1Rβ were correlated with p-Akt. Moreover, significant relationships were noted between disease-free survival or overall survival and the presence of hypoglycemia, necrosis, cystic and myxoid degeneration, and atypical findings. CONCLUSIONS The Akt/mTOR pathway was activated in approximately 50% of the cases of SFTs and was associated with RTKs, which were phosphorylated at different rates. Thus, the Akt-mTOR pathway may be involved in the tumorigenesis of SFTs. Cancer 2014;120:864-876.

Original languageEnglish
Pages (from-to)864-876
Number of pages13
JournalCancer
Volume120
Issue number6
DOIs
Publication statusPublished - Mar 15 2014

Fingerprint

Solitary Fibrous Tumors
Receptor Protein-Tyrosine Kinases
Sirolimus
Platelet-Derived Growth Factor Receptors
Staining and Labeling
Somatomedin Receptors
TOR Serine-Threonine Kinases
Neoplasms
Ribosomal Protein S6
Phosphorylation
S 6
Therapeutics
Hypoglycemia
Disease-Free Survival
Molecular Biology
Carrier Proteins
Carcinogenesis
Necrosis
Western Blotting
Immunohistochemistry

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

Cite this

Activation of the Akt-mTOR pathway and receptor tyrosine kinase in patients with solitary fibrous tumors. / Yamada, Yuichi; Kouhashi, Kenichi; Fushimi, Fumiyoshi; Takahashi, Yusuke; Setsu, Nokitaka; Endo, Makoto; Yamamoto, Hidetaka; Tokunaga, Shoji; Iwamoto, Yukihide; Oda, Yoshinao.

In: Cancer, Vol. 120, No. 6, 15.03.2014, p. 864-876.

Research output: Contribution to journalArticle

@article{0a6d539b11b34a109cce9080c3365b42,
title = "Activation of the Akt-mTOR pathway and receptor tyrosine kinase in patients with solitary fibrous tumors",
abstract = "BACKGROUND Solitary fibrous tumors (SFTs) are soft tissue tumors of intermediate malignancy that rarely metastasize. Although unresectable SFTs are reported to have a poor prognosis, to the authors' knowledge there is currently no effective therapy. Molecular target therapy is a promising approach for patients with unresectable tumors, but knowledge of the molecular biology of SFTs is currently insufficient to support such therapy. The current study investigated the activation of receptor tyrosine kinases (RTKs) and the Akt-mammalian target of rapamycin (Akt-mTOR) pathway in SFTs as therapeutic targets. METHODS The phosphorylation statuses of Akt-mTOR pathway proteins (p-Akt, p-mTOR, phosphorylated 4E-binding protein [p-4EBP1], and phosphorylated S6 ribosomal protein [p-S6RP]) and RTKs (phosphorylated platelet-derived growth factor receptor-α [p-PDGFRα], p-PDGFRβ, p-c-met, and phosphorylated insulin-like growth factor-1 receptor-β [p-IGF-1Rβ]) were assessed by immunohistochemistry in 66 samples of SFTs, and the data were compared with clinicopathological and histopathological findings. The expression of phosphorylated proteins was assessed by Western blot analysis in 6 frozen samples. RESULTS The immunohistochemical results were as follows: p-Akt, 56.0{\%} (nuclear and cytoplasmic staining); p-mTOR, 69.6{\%} (nuclear and cytoplasmic staining); p-4EBP1, 80.3{\%} (nuclear and cytoplasmic staining); p-S6RP, 69.6{\%} (cytoplasmic staining); p-PDGFRα, 39.0{\%} (cytoplasmic staining); p-PDGFRβ, 52.0{\%} (cytoplasmic staining); p-c-met, 37.8{\%} (nuclear staining) and 19.6{\%} (cytoplasmic staining); and p-IGF-1Rβ, 16.6{\%} (nuclear staining). Phosphorylation of the Akt-mTOR pathway proteins was correlated with one another except for p-Akt with S6RP. p-PDGFRβ and p-IGF-1Rβ were correlated with p-Akt. Moreover, significant relationships were noted between disease-free survival or overall survival and the presence of hypoglycemia, necrosis, cystic and myxoid degeneration, and atypical findings. CONCLUSIONS The Akt/mTOR pathway was activated in approximately 50{\%} of the cases of SFTs and was associated with RTKs, which were phosphorylated at different rates. Thus, the Akt-mTOR pathway may be involved in the tumorigenesis of SFTs. Cancer 2014;120:864-876.",
author = "Yuichi Yamada and Kenichi Kouhashi and Fumiyoshi Fushimi and Yusuke Takahashi and Nokitaka Setsu and Makoto Endo and Hidetaka Yamamoto and Shoji Tokunaga and Yukihide Iwamoto and Yoshinao Oda",
year = "2014",
month = "3",
day = "15",
doi = "10.1002/cncr.28506",
language = "English",
volume = "120",
pages = "864--876",
journal = "Cancer",
issn = "0008-543X",
publisher = "John Wiley and Sons Inc.",
number = "6",

}

TY - JOUR

T1 - Activation of the Akt-mTOR pathway and receptor tyrosine kinase in patients with solitary fibrous tumors

AU - Yamada, Yuichi

AU - Kouhashi, Kenichi

AU - Fushimi, Fumiyoshi

AU - Takahashi, Yusuke

AU - Setsu, Nokitaka

AU - Endo, Makoto

AU - Yamamoto, Hidetaka

AU - Tokunaga, Shoji

AU - Iwamoto, Yukihide

AU - Oda, Yoshinao

PY - 2014/3/15

Y1 - 2014/3/15

N2 - BACKGROUND Solitary fibrous tumors (SFTs) are soft tissue tumors of intermediate malignancy that rarely metastasize. Although unresectable SFTs are reported to have a poor prognosis, to the authors' knowledge there is currently no effective therapy. Molecular target therapy is a promising approach for patients with unresectable tumors, but knowledge of the molecular biology of SFTs is currently insufficient to support such therapy. The current study investigated the activation of receptor tyrosine kinases (RTKs) and the Akt-mammalian target of rapamycin (Akt-mTOR) pathway in SFTs as therapeutic targets. METHODS The phosphorylation statuses of Akt-mTOR pathway proteins (p-Akt, p-mTOR, phosphorylated 4E-binding protein [p-4EBP1], and phosphorylated S6 ribosomal protein [p-S6RP]) and RTKs (phosphorylated platelet-derived growth factor receptor-α [p-PDGFRα], p-PDGFRβ, p-c-met, and phosphorylated insulin-like growth factor-1 receptor-β [p-IGF-1Rβ]) were assessed by immunohistochemistry in 66 samples of SFTs, and the data were compared with clinicopathological and histopathological findings. The expression of phosphorylated proteins was assessed by Western blot analysis in 6 frozen samples. RESULTS The immunohistochemical results were as follows: p-Akt, 56.0% (nuclear and cytoplasmic staining); p-mTOR, 69.6% (nuclear and cytoplasmic staining); p-4EBP1, 80.3% (nuclear and cytoplasmic staining); p-S6RP, 69.6% (cytoplasmic staining); p-PDGFRα, 39.0% (cytoplasmic staining); p-PDGFRβ, 52.0% (cytoplasmic staining); p-c-met, 37.8% (nuclear staining) and 19.6% (cytoplasmic staining); and p-IGF-1Rβ, 16.6% (nuclear staining). Phosphorylation of the Akt-mTOR pathway proteins was correlated with one another except for p-Akt with S6RP. p-PDGFRβ and p-IGF-1Rβ were correlated with p-Akt. Moreover, significant relationships were noted between disease-free survival or overall survival and the presence of hypoglycemia, necrosis, cystic and myxoid degeneration, and atypical findings. CONCLUSIONS The Akt/mTOR pathway was activated in approximately 50% of the cases of SFTs and was associated with RTKs, which were phosphorylated at different rates. Thus, the Akt-mTOR pathway may be involved in the tumorigenesis of SFTs. Cancer 2014;120:864-876.

AB - BACKGROUND Solitary fibrous tumors (SFTs) are soft tissue tumors of intermediate malignancy that rarely metastasize. Although unresectable SFTs are reported to have a poor prognosis, to the authors' knowledge there is currently no effective therapy. Molecular target therapy is a promising approach for patients with unresectable tumors, but knowledge of the molecular biology of SFTs is currently insufficient to support such therapy. The current study investigated the activation of receptor tyrosine kinases (RTKs) and the Akt-mammalian target of rapamycin (Akt-mTOR) pathway in SFTs as therapeutic targets. METHODS The phosphorylation statuses of Akt-mTOR pathway proteins (p-Akt, p-mTOR, phosphorylated 4E-binding protein [p-4EBP1], and phosphorylated S6 ribosomal protein [p-S6RP]) and RTKs (phosphorylated platelet-derived growth factor receptor-α [p-PDGFRα], p-PDGFRβ, p-c-met, and phosphorylated insulin-like growth factor-1 receptor-β [p-IGF-1Rβ]) were assessed by immunohistochemistry in 66 samples of SFTs, and the data were compared with clinicopathological and histopathological findings. The expression of phosphorylated proteins was assessed by Western blot analysis in 6 frozen samples. RESULTS The immunohistochemical results were as follows: p-Akt, 56.0% (nuclear and cytoplasmic staining); p-mTOR, 69.6% (nuclear and cytoplasmic staining); p-4EBP1, 80.3% (nuclear and cytoplasmic staining); p-S6RP, 69.6% (cytoplasmic staining); p-PDGFRα, 39.0% (cytoplasmic staining); p-PDGFRβ, 52.0% (cytoplasmic staining); p-c-met, 37.8% (nuclear staining) and 19.6% (cytoplasmic staining); and p-IGF-1Rβ, 16.6% (nuclear staining). Phosphorylation of the Akt-mTOR pathway proteins was correlated with one another except for p-Akt with S6RP. p-PDGFRβ and p-IGF-1Rβ were correlated with p-Akt. Moreover, significant relationships were noted between disease-free survival or overall survival and the presence of hypoglycemia, necrosis, cystic and myxoid degeneration, and atypical findings. CONCLUSIONS The Akt/mTOR pathway was activated in approximately 50% of the cases of SFTs and was associated with RTKs, which were phosphorylated at different rates. Thus, the Akt-mTOR pathway may be involved in the tumorigenesis of SFTs. Cancer 2014;120:864-876.

UR - http://www.scopus.com/inward/record.url?scp=84896703916&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84896703916&partnerID=8YFLogxK

U2 - 10.1002/cncr.28506

DO - 10.1002/cncr.28506

M3 - Article

VL - 120

SP - 864

EP - 876

JO - Cancer

JF - Cancer

SN - 0008-543X

IS - 6

ER -