Zeng Weixing, Yang Yawen, Xiong Jia, Li Cui, He Yang, Liang Zhihao, He Yongwen
Kunming Medical University Kunming 650106, Yunnan, China.
Department of Oral and Maxillofacial Surgery, Kunming Medical University School and Hospital of Stomatology Kunming 650106, Yunnan, China.
Am J Cancer Res. 2025 Jun 15;15(6):2657-2681. doi: 10.62347/EHVJ7118. eCollection 2025.
Fibroblasts can transform into cancer-associated fibroblasts (CAFs) when continuously stimulated by cancer cells, thereby playing a crucial role in cancer progression. Growing evidence indicates that targeted therapy for CAF can influence tumor progression. Dihydroartemisinin (DHA) and artemether (ARM), semisynthetic derivatives of the natural compound artemisinin, have exhibited anticancer effects in various tumors. In this study, we found that tumor cells secreted platelet-derived growth factor-BB (PDGF-BB), which stimulated fibroblasts to transition into the CAF phenotype (cell phenotype and secretory phenotype). CAFs promote Cal-27 cell proliferation by secreting lactate. We focused on the mechanisms by which DHA and ARM affect the tumor-stroma interactions. These findings demonstrated that DHA and ARM effectively suppressed the secretion of PDGF-BB from Cal-27 cells, maintaining the normal state of hOMF and preventing the proliferative effect on Cal-27 cells. These findings were confirmed in xenograft models. Our study showed that artemisinin derivatives prevent the progression of oral tongue squamous cell carcinoma (OTSCC) by inhibiting the production of PDGF-BB in cancer cells to maintain the normal state of fibroblasts, thus providing a potential avenue for targeted OTSCC treatment.
当受到癌细胞持续刺激时，成纤维细胞可转变为癌症相关成纤维细胞（CAFs），从而在癌症进展中发挥关键作用。越来越多的证据表明，针对CAF的靶向治疗可影响肿瘤进展。双氢青蒿素（DHA）和蒿甲醚（ARM）是天然化合物青蒿素的半合成衍生物，已在多种肿瘤中表现出抗癌作用。在本研究中，我们发现肿瘤细胞分泌血小板衍生生长因子-BB（PDGF-BB），其刺激成纤维细胞转变为CAF表型（细胞表型和分泌表型）。CAFs通过分泌乳酸促进Cal-27细胞增殖。我们聚焦于DHA和ARM影响肿瘤-基质相互作用的机制。这些发现表明，DHA和ARM有效抑制了Cal-27细胞中PDGF-BB的分泌，维持了人正常口腔黏膜成纤维细胞（hOMF）的正常状态，并阻止了对Cal-27细胞的增殖作用。这些发现在异种移植模型中得到了证实。我们的研究表明，青蒿素衍生物通过抑制癌细胞中PDGF-BB的产生来维持成纤维细胞的正常状态，从而阻止口腔舌鳞状细胞癌（OTSCC）的进展，为OTSCC的靶向治疗提供了一条潜在途径。
