Activation of the Akt-mTOR and MAPK pathways in dedifferentiated liposarcomas

作者：Ishii Takeaki; Kohashi Kenichi; Iura Kunio; Maekawa Akira; Bekki Hirofumi; Yamada Yuichi; Yamamoto Hidetaka; Nabeshima Kazuki; Kawashima Hiroyuki; Iwamoto Yukihide; Oda Yoshinao^*

来源：Tumor Biology, 2016, 37(4): 4767-4776.

DOI：10.1007/s13277-015-4232-2

• Dedifferentiated liposarcoma
• Prognosis
• Mammalian target of rapamycin
• Mitogen-activated protein kinase
• Immunohistochemistry

The Akt/mTOR and MAPK pathways play important roles in modulating cellular function in response to extracellular signals, and they are known to be activated in certain kinds of sarcomas. Few investigations have examined these pathways in dedifferentiated liposarcoma (DDLS), in relation to clinicopathological features. Clinicopathological and immunohistochemical analyses were conducted using 99 DDLS specimens. An in vitro study was also conducted to examine the antitumor effects of an mTOR inhibitor and a MEK inhibitor on two DDLS cell lines. The clinicopathological analyses revealed that the AJCC staging was a significant prognostic factor for overall survival and that the tumor size, depth, and location were significant prognostic factors for event-free survival. Phosphorylated Akt (pAkt), pmTOR, pS6RP, p4E-BP1, pMEK, and pERK expressions were positive in 57.4, 52.4, 71.4, 57.1, 84.1, and 50.8 % of the dedifferentiated component of the 63 primary DDLSs. Positive staining for pmTOR was significantly more frequent in the dedifferentiated component than the well-differentiated component. A univariate prognostic analysis revealed that pmTOR expression was associated with poor prognosis in the tumors in the retroperitoneum/ventral body cavity. The mTOR and MEK inhibitors dose-dependently inhibited the cell proliferation of both DDLS cell lines and decreased the expression of downstream pS6RP and pERK, respectively. The combined use of the two inhibitors enhanced antiproliferative activity. In conclusion, the Akt/mTOR and MAPK pathways were activated in DDLS specimens, and the inhibition of these pathways decreased cell proliferation in DDLS cell lines. Our findings suggest that these pathways could be a therapeutic target for patients with DDLS.

• 出版日期2016-4