Alteration of PDGFR beta-Akt-mTOR pathway signaling in fibrosarcomatous transformation of dermatofibrosarcoma protuberans

作者：Hiraki Hotokebuchi Yuka; Yamada Yuichi; Kohashi Kenichi; Yamamoto Hidetaka; Endo Makoto; Setsu Nokitaka; Yuki Kuma; Ito Takamichi; Iwamoto Yukihide; Furue Masutaka; Oda Yoshinao^*

来源：Human Pathology, 2017, 67: 60-68.

DOI：10.1016/j.humpath.2017.07.001

• Dermatofibrosarcoma protuberans
• Fibrosarcoirra
• Akt-mTOR
• PDGFR
• Imatinib

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 PDGFR alpha/beta 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-PDGFR alpha positive tumors were 41.9% (18/43 cases), p-PDGFR beta 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 < .05). Phospho-PDGFR beta 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.

• 出版日期2017-9