title: Activation of the Akt-mTOR and MAPK pathways in dedifferentiated liposarcomas.
abstract: 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.
authors.affiliation: Department of Anatomic Pathology, Graduate School of Medical Sciences, Kyushu University, Maidashi 3-1-1, Higashi-ku, Fukuoka, 812-8582, Japan.
authors.forename: Takeaki
authors.initials: T
authors.lastname: Ishii
authors.affiliation: Department of Anatomic Pathology, Graduate School of Medical Sciences, Kyushu University, Maidashi 3-1-1, Higashi-ku, Fukuoka, 812-8582, Japan.
authors.forename: Kenichi
authors.initials: K
authors.lastname: Kohashi
authors.affiliation: Department of Anatomic Pathology, Graduate School of Medical Sciences, Kyushu University, Maidashi 3-1-1, Higashi-ku, Fukuoka, 812-8582, Japan.
authors.forename: Kunio
authors.initials: K
authors.lastname: Iura
authors.affiliation: Department of Anatomic Pathology, Graduate School of Medical Sciences, Kyushu University, Maidashi 3-1-1, Higashi-ku, Fukuoka, 812-8582, Japan.
authors.forename: Akira
authors.initials: A
authors.lastname: Maekawa
authors.affiliation: Department of Anatomic Pathology, Graduate School of Medical Sciences, Kyushu University, Maidashi 3-1-1, Higashi-ku, Fukuoka, 812-8582, Japan.
authors.forename: Hirofumi
authors.initials: H
authors.lastname: Bekki
authors.affiliation: Department of Anatomic Pathology, Graduate School of Medical Sciences, Kyushu University, Maidashi 3-1-1, Higashi-ku, Fukuoka, 812-8582, Japan.
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Yamada
authors.affiliation: Department of Anatomic Pathology, Graduate School of Medical Sciences, Kyushu University, Maidashi 3-1-1, Higashi-ku, Fukuoka, 812-8582, Japan.
authors.forename: Hidetaka
authors.initials: H
authors.lastname: Yamamoto
authors.affiliation: Department of Pathology, Fukuoka University School of Medicine and Hospital, Fukuoka, Japan.
authors.forename: Kazuki
authors.initials: K
authors.lastname: Nabeshima
authors.affiliation: Division of Orthopedic Surgery, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Kawashima
authors.affiliation: Department of Orthopaedic Surgery, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
authors.forename: Yukihide
authors.initials: Y
authors.lastname: Iwamoto
authors.affiliation: Department of Anatomic Pathology, Graduate School of Medical Sciences, Kyushu University, Maidashi 3-1-1, Higashi-ku, Fukuoka, 812-8582, Japan. oda@surgpath.med.kyushu-u.ac.jp.
authors.forename: Yoshinao
authors.initials: Y
authors.lastname: Oda
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000494:pharmacology; D001549:Benzamides / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D004159:Diphenylamine / Q000031:analogs & derivatives / Q000494:pharmacology; D004357:Drug Synergism; D000068338:Everolimus / Q000494:pharmacology; D005260:Female; D006801:Humans; D020128:Inhibitory Concentration 50; D008080:Liposarcoma / Q000188:drug therapy / Q000378:metabolism*; D020935:MAP Kinase Signaling System; D008297:Male; D008875:Middle Aged; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D001549:Benzamides; C506614:mirdametinib; D000068338:Everolimus; D004159:Diphenylamine; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases
keywords: Dedifferentiated liposarcoma; Immunohistochemistry; Mammalian target of rapamycin; Mitogen-activated protein kinase; Prognosis