Institute of Pathology and Neuropathology, University Hospital of Essen, University of Duisburg-Essen, Hufelandstrasse 55, 45147 Essen, NW, Germany.
Hum Pathol. 2013 Oct;44(10):2266-74. doi: 10.1016/j.humpath.2013.04.018. Epub 2013 Jul 17.
Alveolar soft part sarcoma (ASPS) is a distinct type of soft tissue sarcoma holding a specific ASPL-TFE3 fusion transcript. Curative therapy is based on surgical removal, whereas lately, antiangiogenic targeted therapy regimens have proven effective. In ASPS, analysis of small series additionally display mTOR (mammalian target of rapamycin) pathway activity, thus making mTOR a possible additive target in ASPS, because it is in other tumor entities. Therefore, we systematically evaluated mTOR pathway activity in a large series of ASPS in comparison with soft tissue sarcomas of other differentiation (non-ASPS). Upstream and downstream factors of mTOR signaling and ancillary targets were analyzed in 103 cases (22 ASPS, 81 non-ASPS) by immunohistochemistry mostly using phospho-specific antibodies. TFE3 (transcription factor for immunoglobulin heavy-chain enhancer 3) translocation status was determined by FISH and RT-PCR. All ASPS were positive in TFE3 break-apart FISH and exhibited specific fusion products when RNA was available (type 1: 9x, type 2: 11x), whereas TFE3-immunoreactive non-ASPS did not. In ASPS, TFE3-, cMET-, pAKT T308- (all P < .0001), pp70S6K- (P = .002), and p4EBP1 (P = .087) expression levels were elevated, whereas pAKT S473 was decreased (P < .0001). In addition, ASPS exhibited higher TFE3-, cMET-, pAKT T308-, and pp70S6K- expression levels compared with TFE3-immunopositive non-ASPS sarcomas (all P < .001). We demonstrate elevated mTOR complex 1 (mTORC1) activity in ASPS independent of mTOR complex 2 (mTORC2) activation. mTORC1 activity seems to be related to the existence of ASPL-TFE3 fusion transcripts because TFE3-immunoreactive non-ASPS without ASPL-TFE3 fusion transcripts exhibit significantly lower mTORC1 activation status. Small molecule-based targeting of mTOR might therefore represent a potential mechanism in ASPS alone or in combination with contemporary upstream approaches.
腺泡状软组织肉瘤 (ASPS) 是一种独特的软组织肉瘤，具有特定的 ASPL-TFE3 融合转录本。治愈性治疗基于手术切除，而最近，抗血管生成靶向治疗方案已被证明有效。在 ASPS 中，对小系列的分析还显示 mTOR（哺乳动物雷帕霉素靶蛋白）途径活性，因此使 mTOR 成为 ASPS 中的一个可能的附加靶点，因为它在其他肿瘤实体中也是如此。因此，我们系统地评估了大量 ASPS 中的 mTOR 途径活性，并与其他分化的软组织肉瘤（非-ASPS）进行了比较。通过免疫组织化学（主要使用磷酸化特异性抗体）分析了 103 例病例（22 例 ASPS，81 例非-ASPS）中的 mTOR 信号的上游和下游因子以及辅助靶标。TFE3（免疫球蛋白重链增强子 3 的转录因子）易位状态通过 FISH 和 RT-PCR 确定。所有 ASPS 在 TFE3 断裂 FISH 中均为阳性，并在有 RNA 时显示出特异性融合产物（类型 1：9x，类型 2：11x），而 TFE3-免疫反应性非-ASPS 则没有。在 ASPS 中，TFE3、cMET、pAKT T308-（均 P<0.0001）、pp70S6K-（P=0.002）和 p4EBP1（P=0.087）的表达水平升高，而 pAKT S473 降低（P<0.0001）。此外，ASPS 表现出比 TFE3 免疫阳性的非-ASPS 肉瘤更高的 TFE3、cMET、pAKT T308-和 pp70S6K-表达水平（均 P<0.001）。我们证明了 ASPS 中 mTOR 复合物 1（mTORC1）活性的升高是独立于 mTOR 复合物 2（mTORC2）激活的。mTORC1 活性似乎与 ASPL-TFE3 融合转录本的存在有关，因为 TFE3 免疫反应性非-ASPS 没有 ASPL-TFE3 融合转录本，其 mTORC1 激活状态明显较低。基于小分子的 mTOR 靶向治疗因此可能是 ASPS 中的一种潜在机制，或与当前的上游方法联合使用。
