Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan.
Department of Pathology & Experimental Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan.
Int J Cancer. 2019 Feb 15;144(4):828-840. doi: 10.1002/ijc.31953. Epub 2018 Dec 3.
Lymph node metastasis is a pathognomonic feature of spreading tumors, and overcoming metastasis is a challenge in attaining more favorable clinical outcomes. Esophageal cancer is an aggressive tumor for which lymph node metastasis is a strong poor prognostic factor, and the tumor microenvironment (TME), and cancer-associated fibroblasts (CAFs) in particular, has been implicated in esophageal cancer progression. CAFs play a central role in the TME and have been reported to provide suitable conditions for the progression of esophageal cancer, similar to their role in other malignancies. However, little is known concerning the relevance of CAFs to the lymph node metastasis of esophageal cancer. Here, we used clinical samples of esophageal cancer to reveal that CAFs promote lymph node metastasis and subsequently verified the intercellular relationships in vitro and in vivo using an orthotopic metastatic mouse model. In the analysis of clinical samples, FAP CAFs were strongly associated with lymph node metastasis rather than with other prognostic factors. Furthermore, CAFs affected the ability of esophageal cancer cells to acquire metastatic phenotypes in vitro; this finding was confirmed by data from an in vivo orthotopic metastatic mouse model showing that the number of lymph node metastases increased upon injection of cocultured cancer cells and CAFs. In summary, we verified in vitro and in vivo that the accumulation of CAFs enhances the lymph node metastasis of ESCC. Our data suggest that CAF targeted therapy can reduce lymph node metastasis and improve the prognosis of patients with esophageal cancer in the future.
淋巴结转移是肿瘤扩散的一个特征，克服转移是获得更有利临床结果的一个挑战。食管癌是一种侵袭性肿瘤，淋巴结转移是一个强烈的预后不良因素，肿瘤微环境（TME），特别是癌相关成纤维细胞（CAFs），被认为与食管癌的进展有关。CAFs 在 TME 中发挥核心作用，并被报道为食管癌进展提供合适的条件，这与它们在其他恶性肿瘤中的作用相似。然而，CAFs 与食管癌淋巴结转移的相关性知之甚少。在这里，我们使用食管癌的临床样本揭示了 CAFs 促进淋巴结转移，随后使用原位转移小鼠模型在体外和体内验证了细胞间关系。在临床样本分析中，FAP-CAFs 与淋巴结转移密切相关，而与其他预后因素无关。此外，CAFs 影响食管癌细胞在体外获得转移表型的能力；这一发现通过体内原位转移小鼠模型的数据得到了证实，表明注射共培养的癌细胞和 CAFs 后，淋巴结转移的数量增加。总之，我们在体外和体内验证了 CAFs 的积累增强了 ESCC 的淋巴结转移。我们的数据表明，CAF 靶向治疗可以减少淋巴结转移，并改善食管癌患者的预后。
