Shi Junlin, Wang Lihui, Zou Chunlin, Xia Yudui, Qin Siyuan, Keller Evan, Mizokami Atsushi, Zhang Jian, Lu Yi
Key Laboratory of Longevity and Aging-Related Diseases (Guangxi Medical University), Ministry of Education, Nanning, China.
Southern University of Science and Technology School of Medicine, Shenzhen, China.
Oncotarget. 2018 Jan 9;9(10):9206-9218. doi: 10.18632/oncotarget.24104. eCollection 2018 Feb 6.
Metastasis causes high mortality in various malignancies, including prostate cancer (PCa). Accumulating data has suggested that cancer cells spread from the primary tumor to distant sites at early stage, which is characterized by disseminated tumor cells (DTCs). However, lack of direct evidence of partial localized PCa cells occurring epithelial-to-mesenchymal transition (EMT) and disseminating to distant sites (e.g bone marrow). In this study, we used luciferase labeled PCa cells to establish an EMT mouse model and to detect whether DTCs spread into the bone marrow. We observed tumor cells existing in mouse bone marrow when tumor grew subcutaneously at palpable stage. Studies also showed that tumor cells exhibited increased proliferative, migratory, invasive and angiogenesis abilities. When compared tumor cells with parental cells, hallmarks of EMT including E-cadherin, Vimentin, Snail, and ZO-1 were altered significantly. Specifically, the tumor cells showed more mesenchymal properties. Angiogenesis markers, including VEGFR2, VEGFR3, MCP-3, I-TAC, I309, uPAR and GROα, were also increased in the tumor cells. Intriguingly, MCP-1 expression was dramatically increased in those cells. Mechanistic analyses indicated that AP1 mediates PCa EMT and the appearance of DTCs via the Akt/mTOR pathway. This study may provide potential therapeutic targets and diagnostic biomarkers of PCa progression and metastasis.
转移导致包括前列腺癌（PCa）在内的各种恶性肿瘤的高死亡率。越来越多的数据表明，癌细胞在早期就从原发性肿瘤扩散到远处部位，其特征是播散性肿瘤细胞（DTCs）。然而，缺乏部分局限性PCa细胞发生上皮-间质转化（EMT）并扩散到远处部位（如骨髓）的直接证据。在本研究中，我们使用荧光素酶标记的PCa细胞建立了一个EMT小鼠模型，并检测DTCs是否扩散到骨髓中。当肿瘤在可触及阶段皮下生长时，我们观察到小鼠骨髓中存在肿瘤细胞。研究还表明，肿瘤细胞表现出增殖、迁移、侵袭和血管生成能力增强。将肿瘤细胞与亲本细胞比较时，包括E-钙黏蛋白、波形蛋白、Snail和ZO-1在内的EMT标志物发生了显著改变。具体而言，肿瘤细胞表现出更多的间质特性。肿瘤细胞中血管生成标志物，包括VEGFR2、VEGFR3、MCP-3、I-TAC、I309、uPAR和GROα也增加。有趣的是，这些细胞中MCP-1表达显著增加。机制分析表明，AP1通过Akt/mTOR途径介导PCa EMT和DTCs的出现。本研究可能为PCa进展和转移提供潜在的治疗靶点和诊断生物标志物。
