Periostin and Epithelial-Mesenchymal Transition Score as Novel Prognostic Markers for Leiomyosarcoma, Myxofibrosarcoma, and Undifferentiated Pleomorphic Sarcoma
Periostin and Epithelial-Mesenchymal Transition Score as Novel Prognostic Markers for Leiomyosarcoma, Myxofibrosarcoma, and Undifferentiated Pleomorphic Sarcoma
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DOI：
10.1158/1078-0432.ccr-19-2297
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发表时间：
2020-06-01
影响因子：
11.5
通讯作者：
Calabro, Maria Luisa
中科院分区：
文献类型：
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作者：
Piano, Maria Assunta;Brunello, Antonella;Calabro, Maria Luisa
目的：软组织肉瘤(STS)的患者间临床变异性凸显了支持患者风险分层的新的预后标记物的必要性。由于肉瘤可能表现出更多的间质或更上皮化的状态，我们关注上皮间充质和间充质-上皮转化(EMT/MET)以寻找预后线索，并选择了三种具有不同侵袭性的组织类型。实验设计：采用qRT-PCR方法检测55例来自平滑肌肉瘤、粘液纤维肉瘤或未分化多形性肉瘤的肿瘤标本中EMT/MET相关因子的表达。IHC对31例平滑肌肉瘤和67例患者的循环水平进行了进一步的评估。分析了针对肉瘤的EMT评分的预后价值。在原代STS培养中表阿霉素对化疗药物的敏感性和迁移进行了研究。结果：间充质基质蛋白Periostin在肉瘤组织中的高表达(P=0.0024)，其在平滑肌肉瘤中的高间质堆积(P=0.0075)，以及循环的增加(P=0.0008)与OS的降低有关。在多变量模型中，高Periostin表达[HR2.9；95%可信区间(CI1.3-6.9；P=0.0134)]和循环(HR2.6；95%可信区间，1.3-5.1；P=0.0086)和间质内膜移植评分(间充质与过渡；HR，5.2；95%CI，2.1-13.0，P=0.0005)与风险增加相关。结论：尽管这些发现仅限于初步研究，但这些发现提示骨膜蛋白在三种研究的STS组织类型中可能有助于预测预后信息。此外，在肿瘤中测量的过渡性EMT评分可能预示着一种不太活跃和更具化疗敏感性的疾病。
Purpose: Interpatient clinical variability in soft-tissue sarcomas (STS) highlights the need for novel prognostic markers supporting patient risk stratification. As sarcomas might exhibit a more mesenchymal or a more epithelial state, we focused on epithelialmesenchymal and mesenchymal-epithelial transitions (EMT/MET) for prognostic clues, and selected three histotypes with variable aggressiveness.Experimental Design: The expression of EMT/MET-related factors was measured by qRT-PCR in 55 tumor samples from patients with leiomyosarcoma, myxofibrosarcoma, or undifferentiated pleomorphic sarcoma. The identified marker was further evaluated by IHC in 31 leiomyosarcomas and by measuring its circulating levels in 67 patients. The prognostic value of a sarcoma-tailored EMT score was analyzed. Epirubicin chemosensitivity and migration were studied in primary STS cultures. Associations with overall survival (OS) were assessed using Kaplan-Meier and Cox regression methods.Results: High expression of periostin, a mesenchymal matricellular protein, in sarcoma tissues (P = 0.0024), its high stromal accumulation in leiomyosarcomas (P = 0.0075), and increased circulation (>20 ng/mL, P = 0.0008) were associated with reduced OS. High periostin expression [HR 2.9; 95% confidence interval (CI), 1.3-6.9; P = 0.0134] and circulation ( HR 2.6; 95% CI, 1.3-5.1; P = 0.0086), and a mesenchymal EMT score (mesenchymal vs. transitioning; HR, 5.2; 95% CI, 2.1-13.0, P = 0.0005) were associated with increased risk in multivariable models. An intrinsic or induced mesenchymal state enhanced chemoresistance and migration in sarcoma cell lines.Conclusions: Although limited to a pilot study, these findings suggest that periostinmight contribute prognostic information in the three studied STS histotypes. Moreover, a transitioning EMT scoremeasured in the tumormight predict a less active and a more chemosensitive disease.