Alteration of PDGFRβ-Akt–mTOR Pathway Signaling in Fibrosarcomatous Transformation of Dermatofibrosarcoma Protuberans

Publication date: Available online 13 July 2017
Source:Human Pathology
Author(s): Yuka Hiraki-Hotokebuchi, Yuichi Yamada, Kenichi Kohashi, Hidetaka Yamamoto, Makoto Endo, Nokitaka Setsu, Kuma Yuki, Takamichi Ito, Yukihide Iwamoto, Masutaka Furue, Yoshinao Oda
Dermatofibrosarcoma protuberans (DFSP) is a cutaneous mesenchymal tumor of intermediate malignancy and fibroblastic/myofibroblastic differentiation. Fibrosarcomatous (FS) component is a high-grade component of DFSP. The detailed oncogenic difference between DFSP and FS components is not clear. We thus investigated the Akt–mTOR pathway in both components. We used 65 tumor samples obtained from 65 patients. The phosphorylation of Akt–mTOR pathway proteins (Akt, mTOR, 4EBP1, and S6RP) and PDGFRα/β was assessed by immunohistochemical staining, the results of which were confirmed by western blotting. The immunohistochemical results were as follows: in ordinary DFSP components, p-PDGFRα-positive tumors were 41.9% (18/43 cases), p-PDGFRβ 55.8% (24/43 cases), p-Akt 51.2% (22/43 cases), p-mTOR 39.5% (17/43 cases), p-4EBP1 46.5% (20/43 cases), and p-S6RP 41.8% (18/43 cases); in DFSP components of FS-DFSP, 52.6% (10/19 cases), 47.4% (9/19 cases), 52.6% (10/19 cases), 36.8% (7/19 cases), 52.6% (10/19 cases), and 52.6% (10/19 cases); and in FS components, 45.5% (10/22 cases), 36.4% (8/22 cases), 72.7% (16/22 cases), 54.5% (12/22 cases), 72.7% (16/22 cases), and 68.2% (15/22 cases), respectively. There were significant positive correlations of the phosphorylation of most of the Akt–mTOR pathway proteins (p-Akt, p-mTOR, p-4EBP1, and p-S6RP) with each other (p values <.05). Phospho-PDGFRβ was well correlated with the phosphorylation of Akt–mTOR pathway proteins in DFSP components of ordinary and FS-DFSPs, but these correlations were weaker in FS components. This study suggested the association of activation of Akt–mTOR pathway proteins and PDGFR with the progression of DFSP to FS. The Akt–mTOR pathway is thus a potential therapeutic target in imatinib-resistant DFSP/FS.



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