Int J Biol Sci 2022; 18(7):2867-2881. doi:10.7150/ijbs.66854 This issue

Research Paper

SNAIL Induces EMT and Lung Metastasis of Tumours Secreting CXCL2 to Promote the Invasion of M2-Type Immunosuppressed Macrophages in Colorectal Cancer

Zhen Bao1,2,3*, Wei Zeng1,2,4*, Di Zhang3*, Liyong Wang3, Xin Deng3, Jianqin Lai3, Jian Li5, Jin Gong3✉, Guoan Xiang1,2✉

1. The Second School of Clinical Medicine, Southern Medical University, Guangzhou, Guangdong 510515, P.R. China.
2. Department of General Surgery, Guangdong Second Provincial General Hospital, Guangzhou, Guangdong 510317, P.R. China.
3. Department of General Surgery, The First Affiliated Hospital of Jinan University, Guangzhou, Guangdong 510632, P.R. China.
4. Department of General Surgery, Yiyang Central Hospital, Yiyang, Hunan 413000, P.R. China.
5. Department of General Surgery, Henan Cancer Hospital, Zhengzhou Henan, 450003, P.R. China.
* Joint first authors

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Citation:
Bao Z, Zeng W, Zhang D, Wang L, Deng X, Lai J, Li J, Gong J, Xiang G. SNAIL Induces EMT and Lung Metastasis of Tumours Secreting CXCL2 to Promote the Invasion of M2-Type Immunosuppressed Macrophages in Colorectal Cancer. Int J Biol Sci 2022; 18(7):2867-2881. doi:10.7150/ijbs.66854. Available from https://www.ijbs.com/v18p2867.htm

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Abstract

Graphic abstract

Background: There is increasing evidence that tumour-associated macrophages (TAMs) are critical in the formation of lung metastases. However, the molecular mechanisms of tumour interactions with TAMs via EMT are largely unknown.

Methods: The mechanism of lung metastasis was studied in patient tissues. The mechanism of SNAIL regulation of the interaction between mesenchymal cells and M2 macrophages was elucidated using coculture of M2 macrophages and Transwell assays in vitro and in vivo in nude mice and NOD-SCID mice.

Results: We demonstrated for the first time that SNAIL and CXCL2 were abnormally overexpressed in colorectal cancer, especially lung metastasis, and were associated with poor prognosis in colorectal cancer patients. We demonstrated that SNAIL promoted the secretion of CXCL2 by mesenchymal cells and induced the activation of M2 macrophages. We found that CXCL2 attracted M2-type macrophages to infiltrate and promote tumour metastasis.

Conclusion: These findings suggest that SNAIL promotes epithelial tumour transformation, and that transformed mesenchymal cells secrete CXCL2, which promotes M2 macrophage infiltration and tumour cell metastasis. These findings elucidate the tumour-TAM interaction in the metastatic microenvironment, which is mediated by tumour-derived CXCL2 and affects lung metastasis. This study also provides a theoretical basis for the occurrence of secondary lung cancer.

Keywords: SNAIL, EMT, Lung Metastasis, CXCL2, Macrophages, Colorectal Cancer