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

• Published in: Human pathology 2017-09, Vol.67, p.60-68
• Main Authors: Hiraki-Hotokebuchi, Yuka, Yamada, Yuichi, Kohashi, Kenichi, Yamamoto, Hidetaka, Endo, Makoto, Setsu, Nokitaka, Yuki, Kuma, Ito, Takamichi, Iwamoto, Yukihide, Furue, Masutaka, Oda, Yoshinao
• Format: Article
• Language: English
• Subjects: Adaptor Proteins, Signal Transducing - analysis; Adolescent; Adult; Aged; Akt-mTOR; Biopsy; Blotting, Western; Cancer; Cell Transformation, Neoplastic - chemistry; Cell Transformation, Neoplastic - metabolism; Child; Child, Preschool; Dermatofibrosarcoma - enzymology; Dermatofibrosarcoma - pathology; Dermatofibrosarcoma protuberans; Disease Progression; Female; Fibrosarcoma; Growth factors; Humans; Imatinib; Immunohistochemistry; Infant; Kinases; Male; Medical prognosis; Metastasis; Middle Aged; PDGFR; Phosphoproteins - analysis; Phosphorylation; Polyclonal antibodies; Proteins; Proto-Oncogene Proteins c-akt - analysis; Receptor, Platelet-Derived Growth Factor alpha - analysis; Receptor, Platelet-Derived Growth Factor beta - analysis; Ribosomal Protein S6 Kinases - analysis; Signal Transduction; Skin Neoplasms - enzymology; Skin Neoplasms - pathology; Targeted cancer therapy; TOR Serine-Threonine Kinases - analysis; Tumors; Young Adult
• ISSN: 0046-8177; 1532-8392
• DOI: 10.1016/j.humpath.2017.07.001

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 < .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. •Activation of Akt-mTOR pathway proteins was shown in DFSP.•The correlation of p-PDGFRβ with p-Akt/p-mTOR was weaker in FS than DFSP.•Alteration of PDGFR-Akt-mTOR may associate with progression of DFSP to FS.•Akt-mTOR pathway is a potential therapeutic target in imatinib-resistant DFSP/FS.