Activation of the Akt/mammalian target of rapamycin pathway in myxofibrosarcomas.

The Akt/mammalian target of rapamycin (mTOR) pathway plays important roles in modulating cellular function in response to extracellular signals such as growth factors and cytokines. The Akt/mTOR signaling pathway is activated in certain kinds of sarcomas. Myxofibrosarcoma is a soft tissue sarcoma, characterized by abundant myxoid stroma and frequent local recurrence. Here, we conducted a large-scale examination of the clinicopathological and activation statuses of the Akt/mTOR pathways in myxofibrosarcoma. The phosphorylation status of Akt, mTOR, S6 ribosomal protein, and the eukaryotic translation initiation factor 4E-binding protein, and mitogen-activated protein kinase were assessed by immunohistochemistry in 101 formalin-fixed, paraffin-embedded samples, including 68 primary tumors in myxofibrosarcoma. Immunohistochemical expressions were confirmed by Western blotting with 20 frozen samples, which were paired with normal tissue samples. PIK3CA and AKT1 gene mutations were also analyzed using 12 primary tumor frozen samples. Immunohistochemically, phosphorylations of Akt, mTOR, S6 ribosomal protein, 4E-binding protein, and mitogen-activated protein kinase 1/2 were observed in 64.7%, 45.6%, 42.6%, 63.2%, and 64.7% of samples. Phosphorylated Akt/mTOR pathway proteins were correlated with one another and were also correlated with the phosphorylation of these proteins in the concordant recurrent tumors. Immunoblotting showed a high degree of phosphorylation in tumor samples, compared with that in normal tissue samples. Activation of the Akt/mTOR pathway was correlated with histologic grade and tumor progression. Mutational analysis failed to reveal any PIK3CA or AKT1 mutations around the hot spots. Activation of the Akt/mTOR pathway was associated with histologic malignancy and tumor progression in primary and recurrent myxofibrosarcoma.