The Akt/mammalian target of rapamycin pathway is activated and associated with adverse prognosis in soft tissue leiomyosarcomas.

Abstract

BACKGROUND:

The Akt/mammalian target of rapamycin (mTOR) pathway mediates cell survival and proliferation and contributes to tumor progression. Soft tissue leiomyosarcoma continues to show poor prognosis, and little is known about its mechanisms of tumor progression. Here the authors investigated the significance of activation of the Akt/mTOR pathway in soft tissue leiomyosarcomas.

METHODS:

The phosphorylation status of Akt, mTOR, S6, and the eukaryotic translation initiation factor 4E-binding protein (4E-BP1) and the protein expression of phosphatase and tensin homologue (PTEN) were assessed by immunohistochemistry in 145 formalin-fixed paraffin-embedded samples of soft tissue leiomyosarcoma including 129 primary tumors. The expression of phosphorylated Akt and mTOR in comparison with their total forms was assessed by Western blot analysis in 13 frozen samples, which were paired with normal tissue samples. Moreover, 39 frozen tumor samples were analyzed for PIK3CA and AKT1 gene mutation.

RESULTS:

Immunohistochemically, phosphorylated forms of Akt, mTOR, S6, and 4E-BP1 were positive in 78.3%, 72.6%, 74.5%, and 70.5% of the samples, respectively. These results were correlated with each other, and associated with higher mitotic activity and adverse prognosis. Decreased expression of PTEN was recognized in only 19.7% and had no statistically significant correlation with Akt or other molecules. Immunoblotting showed a high degree of Akt and mTOR phosphorylation in tumor samples compared with that in non-neoplastic tissue. Mutational analysis failed to reveal any PIK3CA or AKT1 mutations around the hot spots.

CONCLUSIONS:

The Akt/mTOR pathway was activated in most cases of soft tissue leiomyosarcoma and associated with worse clinical behavior and aggressive pathological findings.

• Authors: Nokitaka Setsu, Hidetaka Yamamoto, Kenichi Kohashi, Makoto Endo, Shuichi Matsuda, Ryohei Yokoyama, Kenichi Nishiyama, Yukihide Iwamoto, Yoh Dobashi, Yoshinao Oda
• Journal: Cancer (Cancer) Vol. 118 Issue 6 Pg. 1637-48 (Mar 15 2012) ISSN: 1097-0142 [Electronic] United States
• PMID: 21837670 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2011 American Cancer Society.

Chemical References

• Adaptor Proteins, Signal Transducing
• Cell Cycle Proteins
• EIF4EBP1 protein, human
• Phosphoproteins
• MTOR protein, human
• Proto-Oncogene Proteins c-akt
• TOR Serine-Threonine Kinases
• PTEN Phosphohydrolase
• PTEN protein, human

Topics

• Adaptor Proteins, Signal Transducing (analysis)
• Adult
• Aged
• Aged, 80 and over
• Cell Cycle Proteins
• Female
• Humans
• Immunohistochemistry
• Leiomyosarcoma (chemistry, mortality, pathology)
• Male
• Middle Aged
• Multivariate Analysis
• PTEN Phosphohydrolase (analysis)
• Phosphoproteins (analysis)
• Phosphorylation
• Prognosis
• Proto-Oncogene Proteins c-akt (physiology)
• Sarcoma (chemistry, mortality, pathology)
• TOR Serine-Threonine Kinases (analysis, physiology)