Department of Stomatology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China.
Curr Med Sci. 2019 Jun;39(3):403-409. doi: 10.1007/s11596-019-2050-2. Epub 2019 Jun 17.
Accumulation of lactate in tumor has been linked to poor prognosis of oral squamous cell carcinoma (OSCC), but the underlying mechanism remained largely uncertain. Previous studies have suggested that presence of cancer stem cells (CSCs) closely correlated with cellular malignancy of OSCC. Here, using 3D organoid culture model, we investigated whether lactate promoted CSCs phenotype in primary OSCC cells. We generated organoids using fresh OSCC specimens and verified that organoids recapitulated histopathology and cellular heterogeneity of parental tumor. Organoids were then transfected with a Wnt reporter to visualize Wnt activity. The sphere forming assay demonstrated that high Wnt activity functionally designated CSCs population in OSCC cells. Further investigations indicated that lactate treatment promoted Wnt activity and increased the expression of CSCs (i.e. CD133 cells) in organoids. Moreover, silencing monocarboxylate transporter 1 (MCT1), the prominent path for lactate uptake in human tumor with siRNA significantly impaired organoid forming capacity of OSCC cells. Together, our study demonstrated that lactate can promote CSCs phenotype of OSCC, and MCT1 may be a therapeutic target against OSCC growth.
乳酸在肿瘤中的积累与口腔鳞状细胞癌（OSCC）的预后不良有关，但潜在的机制在很大程度上仍不清楚。先前的研究表明，癌症干细胞（CSCs）的存在与 OSCC 的细胞恶性程度密切相关。在这里，我们使用 3D 类器官培养模型，研究了乳酸是否能促进原发性 OSCC 细胞中的 CSCs 表型。我们使用新鲜的 OSCC 标本生成类器官，并验证了类器官重现了亲本肿瘤的组织病理学和细胞异质性。然后，将类器官转染 Wnt 报告基因以可视化 Wnt 活性。球体形成实验表明，高 Wnt 活性在 OSCC 细胞中功能性地指定了 CSCs 群体。进一步的研究表明，乳酸处理促进了 Wnt 活性，并增加了类器官中 CSCs（即 CD133 细胞）的表达。此外，用 siRNA 沉默单羧酸转运蛋白 1（MCT1），这是人类肿瘤中乳酸摄取的主要途径，显著削弱了 OSCC 细胞形成类器官的能力。总之，我们的研究表明，乳酸可以促进 OSCC 的 CSCs 表型，而 MCT1 可能是对抗 OSCC 生长的治疗靶点。
