Int J Biol Sci 2023; 19(5):1352-1368. doi:10.7150/ijbs.79022 This issue Cite

Research Paper

Neutrophils promote tumor invasion via FAM3C-mediated epithelial-to-mesenchymal transition in gastric cancer

Yaohui Wang1,2*, Xiang Li1*, Tiancheng Zhang1,3*, Fangyuan Li1,3*, Yuke Shen1, Yani He1, Qiang You4, Yifen Zhang2, Jing Zhai1, Xuequan Yao1, Lizong Shen1,5✉

1. Department of Surgical Oncology, Jiangsu Province Hospital of Chinese Medicine, Affiliated Hospital of Nanjing University of Chinese Medicine; Nanjing 210029, China.
2. Department of Pathology, Jiangsu Province Hospital of Chinese Medicine, Affiliated Hospital of Nanjing University of Chinese Medicine; Nanjing 210029, China.
3. Digestive Endoscopy Center, Jiangsu Province Hospital of Chinese Medicine, Affiliated Hospital of Nanjing University of Chinese Medicine; Nanjing 210029, China.
4. Department of Geriatrics, the Second Affiliated Hospital, Nanjing Medical University; Nanjing 210003, China.
5. Department of General Surgery, the First Affiliated Hospital, Nanjing Medical University; Nanjing 210029, China.
* These authors have contributed equally to this work.

Citation:
Wang Y, Li X, Zhang T, Li F, Shen Y, He Y, You Q, Zhang Y, Zhai J, Yao X, Shen L. Neutrophils promote tumor invasion via FAM3C-mediated epithelial-to-mesenchymal transition in gastric cancer. Int J Biol Sci 2023; 19(5):1352-1368. doi:10.7150/ijbs.79022. https://www.ijbs.com/v19p1352.htm
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Abstract

Graphic abstract

In gastric cancer, lymph node metastasis (LNM) is the major metastasis route, and lymphatic invasion is the precursor of LNM. Tumor-associated neutrophils (TANs) promote LNM. However, the molecular mechanisms underlying TANs-mediated lymphatic invasion and/or LNM remain unclear. Herein, we revealed that high level of TANs was the independent risk factor for lymphatic invasion and LNM respectively, and lymphatic tumor cell-neutrophil clusters were positively correlated with LNM. Crosstalk between neutrophils and tumor cells was required for enhanced tumor cell invasiveness, endowing neutrophils to boost epithelial-to-mesenchymal transition (EMT) of tumor cells and in turn promoting LNM. Mechanically, tumor cells educated neutrophils via TGFβ1 to produce more FAM3C through Smad2/3 signaling activation, and FAM3C promoted tumor cell EMT through JNK-ZEB1/Snail signaling pathway. The crosstalk enhanced the affinity of neutrophils with tumor cells through interaction of integrins α6β1 and α6β4 with CD151. Furthermore, studies using tumor-bearing mice demonstrated that neutrophils were the important driver for gastric cancer tumorigenesis and invasiveness. The study clearly identifies the functional roles of TANs in promoting tumor invasion, and facilitates a better understanding of novel mechanisms responsible for LNM of gastric cancer, which provides potential targets for developing new strategies to prevent or treat LNM in gastric cancer.

Keywords: Gastric cancer, Tumor-associated neutrophils, Lymph node metastasis, Epithelial-to-mesenchymal transformation, FAM3C.


Citation styles

APA
Wang, Y., Li, X., Zhang, T., Li, F., Shen, Y., He, Y., You, Q., Zhang, Y., Zhai, J., Yao, X., Shen, L. (2023). Neutrophils promote tumor invasion via FAM3C-mediated epithelial-to-mesenchymal transition in gastric cancer. International Journal of Biological Sciences, 19(5), 1352-1368. https://doi.org/10.7150/ijbs.79022.

ACS
Wang, Y.; Li, X.; Zhang, T.; Li, F.; Shen, Y.; He, Y.; You, Q.; Zhang, Y.; Zhai, J.; Yao, X.; Shen, L. Neutrophils promote tumor invasion via FAM3C-mediated epithelial-to-mesenchymal transition in gastric cancer. Int. J. Biol. Sci. 2023, 19 (5), 1352-1368. DOI: 10.7150/ijbs.79022.

NLM
Wang Y, Li X, Zhang T, Li F, Shen Y, He Y, You Q, Zhang Y, Zhai J, Yao X, Shen L. Neutrophils promote tumor invasion via FAM3C-mediated epithelial-to-mesenchymal transition in gastric cancer. Int J Biol Sci 2023; 19(5):1352-1368. doi:10.7150/ijbs.79022. https://www.ijbs.com/v19p1352.htm

CSE
Wang Y, Li X, Zhang T, Li F, Shen Y, He Y, You Q, Zhang Y, Zhai J, Yao X, Shen L. 2023. Neutrophils promote tumor invasion via FAM3C-mediated epithelial-to-mesenchymal transition in gastric cancer. Int J Biol Sci. 19(5):1352-1368.

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