Cancer‐associated fibroblasts (CAFs) promote the lymph node metastasis of esophageal squamous cell carcinoma

• Published in: International journal of cancer Vol. 144; no. 4; pp. 828 - 840
• Main Authors: Kashima, Hajime, Noma, Kazuhiro, Ohara, Toshiaki, Kato, Takuya, Katsura, Yuki, Komoto, Satoshi, Sato, Hiroaki, Katsube, Ryoichi, Ninomiya, Takayuki, Tazawa, Hiroshi, Shirakawa, Yasuhiro, Fujiwara, Toshiyoshi
• Format: Journal Article
• Language: English
• Published: Hoboken, USA John Wiley & Sons, Inc 15-02-2019; Wiley Subscription Services, Inc
• Subjects: Aged; Animals; Biopsy; Cancer; Cancer-Associated Fibroblasts - pathology; cancer‐associated fibroblasts; Carcinoma, Squamous Cell - pathology; Cell Line, Tumor; Cell Movement; Esophageal cancer; Esophageal Neoplasms - pathology; Esophagus; Female; fibroblast activation protein (FAP); Fibroblasts; Humans; Invasiveness; lymph node metastasis; Lymph nodes; Lymphatic Metastasis; Lymphatic system; Male; Medical prognosis; Medical research; Metastases; Metastasis; Mice, Inbred BALB C; Mice, Nude; Middle Aged; orthotopic mouse model; Phenotypes; Squamous cell carcinoma; Survival Analysis; Transplantation, Heterologous; Tumor Microenvironment; Tumors; cancer-associated fibroblasts; orthotopic mouse model; fibroblast activation protein (FAP); lymph node metastasis
• ISSN: 0020-7136; 1097-0215
• DOI: 10.1002/ijc.31953

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.
What's new?
When fighting a tumor, targeting the tumor microenvironment can be more effective than hitting the tumor itself. To study lymph node metastasis in esophageal cancer, these authors tested clinical samples to evaluate expression of fibroblast‐activation protein (FAP) by cancer‐associated fibroblasts in the tumor stroma. The more FAP‐positive CAFs, the greater the likelihood of lymph node metastasis, they found. Next, they tested the effect in vivo. Mice injected with FAP‐positive CAFs developed far more metastases than their control counterparts. Targeting CAFs may improve prognosis and reduce lymph node metastasis in esophageal cancer.