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) cel...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.展开更多
基金supported by the National Natural Science Foundation of China(82273941,81973340,82204427,81803566,82003796,81773758)Local Innovative and Research Teams Project of Guangdong Pearl River Talents Program(2017BT01Y036,China)+9 种基金Natural Science Foundation of Guangdong Province(2022A1515011813,2021A1515110242,2020A1515010071,2019A1515010144,2019A1515110543,2019A1515011934,China)Ministry of Science and Technology of China(2018ZX09711001-008-008)National high-level personnel of special support program(Zhang Dongmei),National Key R&D Program of China(2017YFC 1703800)Technology Key Project of Guangdong Province(2020B1111110004,China)Guangdong Province Key Laboratory of Pharmacodynamic Constituents of Traditional Chinese Medicine and New Drugs Research,College of Pharmacy(2020B1212060076,China)Special Funds for the Cultivation of Guangdong College Students’Scientifc and Technological Innovation(“Climbing Program”Special Funds)(pdjh2021a0052,China)Science and Technology Projects in Guangzhou(2023A03J0602,202201010173,202102070001,202002030010,China)Young S&T Talent Training Program of Guangdong Provincial Association for S&T,China(SKXRC202216)Clinical Frontier Technology Program of the First Affiliated Hospital of Jinan University(JNU1AF-CFTP-2022-a01227,China)China Postdoctoral Science Foundation(2022M 711345,China).
文摘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.
