EGFR-dependent and independent activation of Akt/mTOR cascade in bone and soft tissue tumors

Dobashi, Yoh; Suzuki, Shioto; Satô, Eiichi; Hamada, Y.; Yanagawa, Takashi; Ooi, Akishi

doi:10.1038/modpathol.2009.104

Cited by 75 publications

(78 citation statements)

References 45 publications

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“…3,5 However, the expression profiles of the molecules along the Akt/mTOR pathway have been analyzed in a relatively small number of clinical materials. 5,13,14 Some authors investigated Akt/mTOR pathway involvement in STS series and demonstrated a correlation between Akt activation and a worse prognosis 15 or a greater probability of metastasis 13 ; whereas, to our knowledge, no investigations have focused on SS as a single entity, and the prognostic impact of this pathway on SS has remained to be clarified.…”

Section: Discussionmentioning

confidence: 99%

Prognostic impact of the activation status of the Akt/mTOR pathway in synovial sarcoma

Setsu

Kohashi

Fushimi

et al. 2013

Cancer

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BACKGROUND:The Akt/mammalian target of rapamycin (mTOR) pathway, downstream from phosphatidylinositol 3-kinase (PI3K), mediates cell survival and proliferation. Although this pathway reportedly contributes to the progression of synovial sarcoma, its prognostic impact has not been clarified. METHODS: The authors analyzed clinicopathologic data and phosphorylation status of Akt (a serine/threonine kinase also known as protein kinase B), mTOR, the eukaryotic translation initiation factor 4E binding protein (4E-BP1), and the S6 ribosomal protein by immunohistochemical analysis of 120 formalin-fixed, paraffin-embedded samples and by Western blot analysis of 24 frozen samples from 112 patients with synovial sarcoma. RESULTS: Akt, mTOR, 4E-BP1, and S6 were activated in 76.5%, 67.6%, 59.6%, and 42.6% of samples, respectively. Immunohistochemically positive phosphorylated (p) mTOR (pmTOR) and p4E-BP1 results were correlated with higher mitotic activity, and positive p4E-BP1 results were correlated with greater necrosis. No mutations around the hot spots in the PI3K catalytic subunit a (PI3KCA) and Akt1 genes were observed. In multivariate analysis of clinicopathologic parameters, frequent mitosis was a risk factor for shorter overall survival; and male sex, visceral location, larger tumor size, and frequent mitosis were identified as risk factors for shorter event-free survival. Positive pmTOR and p4E-BP1 results were correlated significantly with shorter overall survival, and positive p4E-BP1 results were correlated with shorter event-free survival in univariate analysis. Positive pAkt results were associated significantly with shorter event-free survival in multivariate analysis. CONCLUSIONS: In this study, the Akt/mTOR pathway was activated and was associated with worse clinical and pathologic behavior in patients with synovial sarcoma. The authors propose that this pathway may have potential as a therapeutic target.

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Section: Discussionmentioning

confidence: 99%

Prognostic impact of the activation status of the Akt/mTOR pathway in synovial sarcoma

Setsu

Kohashi

Fushimi

et al. 2013

Cancer

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“…The AKT/mTOR and MAPK pathways are known to be activated in some kinds of sarcomas (19)(20)(21)(22)(23), and several articles support that the AKT/mTOR and/or MAPK pathways, as well as their upstream receptor tyrosine kinases, are activated in MPNSTs (1,24,25). At least in patients with NF1, it is conceivable that Ras activation caused by Nf1 gene deficiency may induce the subsequent activation of the AKT/mTOR and Raf/MEK/ERK pathways.…”

Section: Introductionmentioning

confidence: 99%

Prognostic Significance of AKT/mTOR and MAPK Pathways and Antitumor Effect of mTOR Inhibitor in NF1-Related and Sporadic Malignant Peripheral Nerve Sheath Tumors

Endo

Yamamoto

Setsu

et al. 2013

Clinical Cancer Research

Self Cite

118

100

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Purpose: Malignant peripheral nerve sheath tumor (MPNST) is a rare soft tissue sarcoma with poor prognosis. MPNSTs occur frequently in patients with neurofibromatosis type 1 (NF1), in which NF1 gene deficiency leads to Ras hyperactivation. Ras activation causes the subsequent activation of the AKT/mTOR and Raf/MEK/ERK pathways and regulates cellular functions. However, the activation profiles of the AKT/ mTOR and MAPK pathways in MPNSTs are poorly understood. The purposes of this study are to examine the correlation between the activation of these pathways and clinicopathologic or prognostic factors and to identify candidate target molecules in MPNST. Moreover, we assessed the antitumor effects of the inhibitor of candidate target.Experimental Design: Immunohistochemistry was conducted to evaluate the activation profiles of AKT/ mTOR and MAPK pathways using 135 tumor specimens. Immunohistochemical expressions were confirmed by Western blotting. Then, an in vitro study was conducted to examine the antitumor effect of the mTOR inhibitor on MPNST cell lines.

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“…In recent years, many studies showing EGFR expression have been conducted in relation with chordomas 5,6,[38][39][40][41][42][43] . Based on the findings and previous studies, it was concluded that immunohistochemistry alone was not a good marker in demonstrating mutation or copy number 44,45 . In our study, EGFR overexpression was found by immunohistochemistry and/or FISH method in three of four patients with chordoma.…”

Section: Fish Methodsmentioning

confidence: 96%

Yumuşak dokunun nadir görülen tümörlerinde ve odontojenik tümörlerde immünohistokimyasal yöntem ve floresan in situ hibridizasyonla epidermal growth faktör reseptör varlığının gösterilmesi

Erdoğan¹,

Deveci²,

Gönlüşen³

et al. 2016

Cukurova Med J

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EGFR-dependent and independent activation of Akt/mTOR cascade in bone and soft tissue tumors

Cited by 75 publications

References 45 publications

Prognostic impact of the activation status of the Akt/mTOR pathway in synovial sarcoma

Prognostic impact of the activation status of the Akt/mTOR pathway in synovial sarcoma

Prognostic Significance of AKT/mTOR and MAPK Pathways and Antitumor Effect of mTOR Inhibitor in NF1-Related and Sporadic Malignant Peripheral Nerve Sheath Tumors

Yumuşak dokunun nadir görülen tümörlerinde ve odontojenik tümörlerde immünohistokimyasal yöntem ve floresan in situ hibridizasyonla epidermal growth faktör reseptör varlığının gösterilmesi

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