Affiliation:
1. Department of Urology Sun Yat‐sen Memorial Hospital Sun Yat‐sen University Guangzhou Guangdong 510000 P. R. China
2. Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation Sun Yat‐sen Memorial Hospital Sun Yat‐sen University Guangzhou Guangdong 510000 P. R. China
3. Guangdong Provincial Clinical Research Center for Urological Diseases Guangzhou Guangdong 510000 P. R. China
Abstract
AbstractAs a key step of tumor lymphatic metastasis, lymphangiogenesis is regulated by VEGFC‐VEGFR3 signaling pathway mediated by immune cells, mainly macrophages, in the tumor microenvironment. However, little is known whether tumor associated neutrophils are involved in lymphangiogenesis. Here, it is found that TANs infiltration is increased in LN‐metastatic BCa and is associated with poor prognosis. Neutrophil depletion results in significant reduction in popliteal LN metastasis and lymphangiogenesis. Mechanistically, transcription factor ETV4 enhances BCa cells‐derived CXCL1/8 to recruit TANs, leading to the increase of VEGFA and MMP9 from TANs, and then facilitating lymphangiogenesis and LN metastasis of BCa. Moreover, phosphorylation of ETV4 at tyrosine 392 by tyrosine kinase PTK6 increases nuclear translocation of ETV4 and is essential for its function in BCa. Overall, the findings reveal a novel mechanism of how tumor cells regulate TANs‐induced lymphangiogenesis and LN metastasis and identify ETV4 as a therapeutic target of LN metastasis in BCa.
Funder
National Key Research and Development Program of China
National Natural Science Foundation of China
China Postdoctoral Science Foundation
Guangdong Science and Technology Department
Subject
General Physics and Astronomy,General Engineering,Biochemistry, Genetics and Molecular Biology (miscellaneous),General Materials Science,General Chemical Engineering,Medicine (miscellaneous)
Cited by
23 articles.
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