Li Xia, Xu Qing, Wu Yuhui, Li Jinyun, Tang Dongsheng, Han Lu, Fan Qinqiao
Department of Stomatology, Medical College of FoShan University, Foshan 528000, People's Republic of China,
Department of Pathology, Anatomy and Cell Biology, Thomas Jefferson University, Philadelphia, PA 19107, USA.
Carcinogenesis. 2014 Jun;35(6):1362-70. doi: 10.1093/carcin/bgu046. Epub 2014 Feb 15.
Cancer-associated fibroblasts (CAFs) have been described to play critical roles in initiation, progression and metastasis of various cancers. However, the involvement of CAFs in oral cancer (OC) has not been well addressed. In this study, we demonstrate that CAFs, when cocultured with OC cells (OCCs), produce high levels of chemokine (C-C motif) ligand 2 (CCL2) and, subsequently, enhance endogenous reactive oxygen species production in cells. Oxidative stress stimulates expression of cell cycle progression proteins in OCCs, leading to promotion of OCC proliferation, migration, invasion and, OC tumor growth. On the other hand, oxidative stress triggered the activation of nuclear factor-kappaB (NF-κB) and STAT3 in CAFs, resulting in accelerating CCL2 expression. In this way, CAFs-OCCs coculture creates a favorable cytokine-rich microenvironment, beneficial for both CAFs and OCCs. In addition, upregulation of CCL2 expression has been observed in oral squamous cell carcinoma tumors and patient plasma. We also showed that inhibition of CCL2 reduced OC tumor burden in mice. Therefore, our data suggested that CCL2 represents a potential therapeutic target for treatment of OC.
癌症相关成纤维细胞（CAFs）已被描述在多种癌症的起始、进展和转移中发挥关键作用。然而，CAFs在口腔癌（OC）中的作用尚未得到充分研究。在本研究中，我们证明，当CAFs与口腔癌细胞（OCCs）共培养时，会产生高水平的趋化因子（C-C基序）配体2（CCL2），随后增强细胞内源性活性氧的产生。氧化应激刺激OCCs中细胞周期进展蛋白的表达，导致OCCs增殖、迁移、侵袭增加以及口腔癌肿瘤生长。另一方面，氧化应激触发CAFs中核因子-κB（NF-κB）和信号转导与转录激活因子3（STAT3）的激活，导致CCL2表达加速。通过这种方式，CAFs与OCCs的共培养创造了一个有利于两者的富含细胞因子的微环境。此外，在口腔鳞状细胞癌肿瘤和患者血浆中观察到CCL2表达上调。我们还表明，抑制CCL2可减轻小鼠口腔癌肿瘤负担。因此，我们的数据表明CCL2是治疗口腔癌的一个潜在治疗靶点。
