Targeting FAP<i>α</i>-positive lymph node metastatic tumor cells suppresses colorectal cancer metastasis.

Shuran Fan; Ming QI; Qi QI; Qun Miao; Lijuan Deng; Jinghua Pan; Shenghui Qiu; Jiashuai HE; Maohua Huang; Xiaobo LI; Jie Huang; Jiapeng Lin; Wenyu Lyu; Weiqing Deng; Yingyin HE; Xuesong Liu; Lvfen Gao; Dongmei Zhang; Wencai YE; Minfeng Chen

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Targeting FAPα-positive lymph node metastatic tumor cells suppresses colorectal cancer metastasis.

Author: Shuran FAN ¹ ; Ming QI ¹ ; Qi QI ² ; Qun MIAO ¹ ; Lijuan DENG ³ ; Jinghua PAN ⁴ ; Shenghui QIU ⁴ ; Jiashuai HE ⁴ ; Maohua HUANG ¹ ; Xiaobo LI ¹ ; Jie HUANG ¹ ; Jiapeng LIN ⁵ ; Wenyu LYU ⁵ ; Weiqing DENG ⁵ ; Yingyin HE ⁵ ; Xuesong LIU ⁴ ; Lvfen GAO ⁴ ; Dongmei ZHANG ¹ ; Wencai YE ¹ ; Minfeng CHEN ¹
Author Information

1. State Key Laboratory of Bioactive Molecules and Druggability Assessment, Jinan University, Guangzhou 510632, China.
2. School of Medicine, Jinan University, Guangzhou 510632, China.
3. School of Traditional Chinese Medicine, Jinan University, Guangzhou 510630, China.
4. The First Affiliated Hospital of Jinan University, Guangzhou 510632, China.
5. Guangdong Province Key Laboratory of Pharmacodynamic Constituents of Traditional Chinese Medicine and New Drugs Research, College of Pharmacy, Jinan University, Guangzhou 510632, China.
Publication Type:Journal Article
Keywords: Colorectal cancer; Epithelial–mesenchymal transition; Extracellular matrix remodeling; FAPα-activated prodrug; Fibroblast activation protein α; Immunosuppressive; Lymphatic metastasis; STAT3
From: Acta Pharmaceutica Sinica B 2024;14(2):682-697
CountryChina
Language:English
Abstract: Lymphatic metastasis is the main metastatic route for colorectal cancer, which increases the risk of cancer recurrence and distant metastasis. The properties of the lymph node metastatic colorectal cancer (LNM-CRC) cells are poorly understood, and effective therapies are still lacking. Here, we found that hypoxia-induced fibroblast activation protein alpha (FAPα) expression in LNM-CRC cells. Gain- or loss-function experiments demonstrated that FAPα enhanced tumor cell migration, invasion, epithelial-mesenchymal transition, stemness, and lymphangiogenesis via activation of the STAT3 pathway. In addition, FAPα in tumor cells induced extracellular matrix remodeling and established an immunosuppressive environment via recruiting regulatory T cells, to promote colorectal cancer lymph node metastasis (CRCLNM). Z-GP-DAVLBH, a FAPα-activated prodrug, inhibited CRCLNM by targeting FAPα-positive LNM-CRC cells. Our study highlights the role of FAPα in tumor cells in CRCLNM and provides a potential therapeutic target and promising strategy for CRCLNM.