Clinicopathological and Prognostic Significance of Akt-mTOR and MAPK Pathways and Antitumor Effect of mTOR Inhibitor in Malignant Peripheral Nerve Sheath Tumor
Makoto Endo, Nokitaka Setsu, Yusuke Takahashi, Takeaki Ishii, Kenichi Kohashi, Hidetaka Yamamoto, Sadafumi Tamiya, Shuichi Matsuda, Yukihide Iwamoto, Michiyuki Hakozaki, Hiroshi Iwasaki, Yoshinao Oda. Kyushu University, Fukuoka, Japan; Fukushima Medical University School of Medicine, Fukushima, Japan; Fukuoka University, Fukuoka, Japan
Background: Malignant peripheral nerve sheath tumor (MPNST) is a chemotherapy-resistant sarcoma showing a poor prognosis. A novel effective antitumor drug for MPNST is desired, but it has not been found yet. Akt-mTOR and MAPK signaling pathways are known to be activated in various types of cancer, and some kinds of mTOR inhibitors are available in clinical practice. However, the clinicopathological and prognostic significance of activation of Akt-mTOR and MAPK pathways in MPNSTs have yet not been revealed. Additionally, antitumor efficacy of mTOR inhibitor in MPNST has not been investigated well.
Design: We investigated the activation status of Akt-mTOR (Akt, mTOR, p70S6K, S6RP, 4E-BP1, HIF-1α) and MAPK (Erk1/2) pathways in 129 MPNST formalin-fixed paraffin-embedded (FFPE) samples from 99 patients by immunohistochemistry (IHC). Five samples, for which frozen material was available, were also investigated by Western blotting (WB). The antitumor effect of mTOR inhibitor (Everolimus) was examined using 6 MPNST cell lines (FU-SFT8611, FU-SFT9817, HS-sch-2, HS-PSS, YST-1, FMS-1) by CCK-8 cell viability assay, Matrigel invasion assay and wound healing assay.
Results: Immunohistochemically positive expressions of phosphorylated-Akt (p-Akt), p-mTOR, p-p70S6K, p-S6RP, p-4E-BP1, HIF-1α and p-Erk1/2 were observed in 59.7%, 48.8%, 62.8%, 54.3%, 62.8%, 74.4% and 72.9% of MPNST samples, respectively. The expression levels of p-Akt and p-mTOR by WB corresponded closely to the levels observed by IHC. Clinicopathological examination showed that activation of Akt-mTOR and MAPK pathways was frequently observed in the subgroups of deep location, frequent mitoses, high MIB-1 labeling index and high histological grade. Prognostic analysis revealed that activation of Akt-mTOR pathway was significantly associated with poor prognosis, but activation of MAPK pathway did not influence the prognosis. Experiments with MPNST cell lines showed that Everolimus caused concentration-dependent inhibition of MPNST cell proliferation. Everolimus also inhibited cell invasion and cell migration at a lower drug concentration achieved clinically.
Conclusions: Activation of Akt-mTOR pathway is associated with malignant progression and poor prognosis in MPNST. mTOR inhibition by Everolimus shows antitumor effect in MPNST cell lines and can be a candidate therapeutic target in MPNST.
Category: Bone & Soft Tissue
Monday, March 19, 2012 9:30 AM
Poster Session I Stowell-Orbison/Surgical Pathology/Autopsy Awards Poster Session # 10, Monday Morning