Onagi Hiroko, Son Raku, Oguchi Akiko, Sano Kei, Sasa Keita, Hasegawa Nobuhiko, Akaike Keisuke, Kubota Daisuke, Takagi Tatsuya, Hayashi Takuo, Ishijima Muneaki, Yao Takashi, Suehara Yoshiyuki, Murakawa Yasuhiro, Saito Tsuyoshi
Department of Human Pathology, Juntendo University School of Medicine, Tokyo 113-8421, Japan.
RIKEN Center for Integrative Medical Sciences, Yokohama 230-0045, Japan.
Int J Mol Sci. 2025 Aug 8;26(16):7676. doi: 10.3390/ijms26167676.
High-grade sarcomas often lack typical morphological features and exhibit no clear differentiation, often leading to a diagnosis of undifferentiated sarcoma (US). Pleomorphic leiomyosarcoma (PLMS) is a high-grade sarcoma consisting of a typical leiomyosarcoma (LMS) component alongside dedifferentiated high-grade areas. A few decades ago, PLMS was regarded as a subtype of high-grade sarcoma previously referred to as malignant fibrous histiocytoma; it is now classified as a variant of LMS. The mechanisms underlying myogenic differentiation and their relevance to the pathological diagnosis of high-grade sarcomas remain poorly understood. To investigate the gene expression networks associated with myogenic differentiation, we employed Cap Analysis of Gene Expression (CAGE) to distinguish PLMS from other high-grade sarcoma subtypes. We analyzed 27 frozen high-grade sarcoma samples, comprising 10 PLMSs, 11 high-grade myxofibrosarcomas, 3 dedifferentiated liposarcomas, 2 USs, and 1 high-grade sarcoma not otherwise specified, using CAGE profiling. Hierarchical clustering based on differentially expressed genes identified by CAGE separated 7 of the 10 PLMSs from other high-grade sarcomas, while the remaining 3 PLMSs clustered with a single US case. CAGE analysis also revealed that the myostatin () promoter (false discovery rate [FDR] < 0.05) was more strongly activated in the high-grade sarcoma group lacking morphological and immunohistochemical smooth muscle differentiation than in the PLMS group, whereas the alpha smooth muscle actin () promoter (FDR < 0.05) was more prominently activated in the PLMS group. Immunohistochemical analysis showed reduced or absent myostatin expression in PLMSs, in contrast to diffuse myostatin expression in other high-grade sarcomas. Smooth muscle actin, encoded by , was expressed in all 10 PLMS cases but only in 11 of 17 other high-grade sarcomas. Furthermore, both conventional immunohistochemistry and double immunostaining revealed that myostatin and myogenic markers exhibited largely mutually exclusive expression patterns within these tumors. A validation study was performed using 59 soft tissue sarcoma cases, including 27 PLMSs and 16 LMSs. Loss or reduction in myostatin expression was confirmed in both LMS and PLMS, and the ratio of myostatin loss was comparable (62.5% in LMS vs. 63% in PLMS). Collectively, these findings suggest that myostatin contributes to smooth muscle differentiation in high-grade sarcomas and has potential utility as a diagnostic marker.
高级别肉瘤通常缺乏典型的形态学特征，且无明显分化，常导致诊断为未分化肉瘤（US）。多形性平滑肌肉瘤（PLMS）是一种高级别肉瘤，由典型的平滑肌肉瘤（LMS）成分以及去分化的高级别区域组成。几十年前，PLMS被视为高级别肉瘤的一种亚型，此前称为恶性纤维组织细胞瘤；现在它被归类为LMS的一种变体。肌源性分化的潜在机制及其与高级别肉瘤病理诊断的相关性仍知之甚少。为了研究与肌源性分化相关的基因表达网络，我们采用基因表达帽分析（CAGE）来区分PLMS与其他高级别肉瘤亚型。我们使用CAGE分析对27个冷冻的高级别肉瘤样本进行了分析，这些样本包括10个PLMS、11个高级别黏液纤维肉瘤、3个去分化脂肪肉瘤、2个US以及1个未另行指定的高级别肉瘤。基于CAGE鉴定出的差异表达基因进行的层次聚类，将10个PLMS中的7个与其他高级别肉瘤区分开来，而其余3个PLMS与1个US病例聚类在一起。CAGE分析还显示，在缺乏形态学和免疫组化平滑肌分化的高级别肉瘤组中，肌生成抑制素（）启动子（错误发现率[FDR]<0.05）的激活比PLMS组更强，而α平滑肌肌动蛋白（）启动子（FDR<0.05）在PLMS组中激活更为显著。免疫组化分析显示，PLMS中肌生成抑制素表达减少或缺失，而其他高级别肉瘤中肌生成抑制素呈弥漫性表达。由编码的平滑肌肌动蛋白在所有10个PLMS病例中均有表达，但在17个其他高级别肉瘤中只有11个表达。此外，传统免疫组化和双重免疫染色均显示，在这些肿瘤中，肌生成抑制素和肌源性标志物在很大程度上呈现相互排斥的表达模式。使用59例软组织肉瘤病例进行了验证研究，包括27个PLMS和16个LMS。在LMS和PLMS中均证实了肌生成抑制素表达缺失或减少，且肌生成抑制素缺失的比例相当（LMS中为62.5%，PLMS中为63%）。总体而言，这些发现表明肌生成抑制素有助于高级别肉瘤中的平滑肌分化，并具有作为诊断标志物的潜在用途。
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