Tashireva Liubov A, Zavyalova Marina V, Savelieva Olga E, Gerashchenko Tatyana S, Kaigorodova Evgeniya V, Denisov Evgeny V, Perelmuter Vladimir M
Department of General and Molecular Pathology, Cancer Research Institute, Tomsk National Research Medical Center, Tomsk, Russia.
Department of Pathological Anatomy, Siberian State Medical University, Tomsk, Russia.
Front Oncol. 2020 Feb 19;10:50. doi: 10.3389/fonc.2020.00050. eCollection 2020.
The identification of tumor cells that can be potential metastatic seeds would reach two key aims-prognosis of metastasis risk and appointment of the optimal adjuvant therapy to prevent metastatic disease. Single tumor cells (STCs) located out of multicellular structures can most likely demonstrate features that are needed to initiate metastasis. One-hundred-and-thirty-five patients with invasive breast carcinoma of no special type have been enrolled. Molecular subtypes of breast cancer were categorized according to St. Gallen recommendations. Hematoxylin and eosin staining was used to identify STCs with epithelial-like morphology (eSTCs) in breast tumors. Immunofluorescence staining was applied to evaluate stemness and epithelial-mesenchymal transition (EMT) in STCs. The correlation between STCs and recurrence and metastasis-free survival (MFS) was performed using the Kaplan-Meier method and the log-rank test. Distant metastasis was more frequent in eSTC-positive than eSTC-negative patients (28.0% vs. 9.4%, = 0.007). When tumor types were analyzed separately, distant metastasis tended to be more frequent in eSTC-positive than eSTC-negative patients for HER2-positive cancer [75.0% (3/4) vs. 12.5% (1/8), = 0.066]. In luminal A [22.7% (5/22) vs. 10.0% (3/30), = 0.259], luminal B [21.1% (4/19) vs. 6.7% (2/30), = 0.189], and triple-negative [40.0% (2/5) vs. 11.8% (2/17), = 0.209] cancers, distance metastasis was not associated with eSTCs. Median MFS was not reached in eSTC-positive and eSTC-negative patients. eSTC-positive patients had a higher risk of breast cancer metastasis [hazard ratio (HR) 3.57, 95% confidence interval (CI): 1.46-8.71; = 0.001]. When tumor types were analyzed separately, a higher risk of breast cancer metastasis occurred only in HER2-positive patients (HR 8.49, 95% CI: 1.29-55.59; = 0.016). Immunofluorescence analysis revealed mesenchymal-like STCs (mSTCs) and inter- and intra-tumor heterogeneity in STCs. There were breast tumors with either eSTCs or mSTCs and tumors with both types of STCs. Both eSTCs and mSTCs were represented by cells with different stem and/or EMT phenotypes. STCs with epithelial-like morphology contribute to breast cancer metastasis and represent an attractive model for studying mechanisms of metastatic seeding. The assessment of STCs in histological sections of breast tumors can be a simple and effective method for the prediction of metastasis risk.
识别可能成为潜在转移种子的肿瘤细胞将实现两个关键目标——预测转移风险以及确定预防转移性疾病的最佳辅助治疗方案。位于多细胞结构之外的单个肿瘤细胞（STC）最有可能展现出启动转移所需的特征。招募了135例非特殊类型的浸润性乳腺癌患者。根据圣加仑共识对乳腺癌的分子亚型进行分类。采用苏木精-伊红染色法在乳腺肿瘤中识别具有上皮样形态的STC（eSTC）。应用免疫荧光染色评估STC中的干性和上皮-间质转化（EMT）。采用Kaplan-Meier法和对数秩检验分析STC与无复发生存率和无转移生存率（MFS）之间的相关性。eSTC阳性患者的远处转移比eSTC阴性患者更常见（28.0%对9.4%，P = 0.007）。当分别分析肿瘤类型时，对于HER2阳性癌症，eSTC阳性患者的远处转移往往比eSTC阴性患者更常见[75.0%（3/4）对12.5%（1/8），P = 0.066]。在luminal A型[22.7%（5/22）对10.0%（3/30），P = 0.259]、luminal B型[21.1%（4/19）对6.7%（2/30），P = 0.189]和三阴性[40.0%（2/5）对11.8%（2/17），P = 0.209]癌症中，远处转移与eSTC无关。eSTC阳性和eSTC阴性患者均未达到中位MFS。eSTC阳性患者发生乳腺癌转移的风险更高[风险比（HR）3.57，95%置信区间（CI）：1.46 - 8.71；P = 0.001]。当分别分析肿瘤类型时，仅HER2阳性患者发生乳腺癌转移的风险更高（HR 8.49，95% CI：1.29 - 55.59；P = 0.016）。免疫荧光分析揭示了间质样STC（mSTC）以及STC之间和肿瘤内部的异质性。存在仅有eSTC或mSTC的乳腺肿瘤以及同时具有两种类型STC的肿瘤。eSTC和mSTC均由具有不同干性和/或EMT表型的细胞代表。具有上皮样形态的STC促进乳腺癌转移，是研究转移播种机制的一个有吸引力的模型。在乳腺肿瘤组织切片中评估STC可以是一种预测转移风险的简单有效的方法。
