國家衛生研究院 NHRI:Item 3990099045/12142
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    題名: Cancer-derived VEGF-C increases chemokine production in lymphatic endothelial cells to promote CXCR2-dependent cancer invasion and MDSC recruitment
    作者: Chen, JY;Lai, YS;Chu, PY;Chan, SH;Wang, LH;Hung, WC
    貢獻者: National Institute of Cancer Research;Institute of Molecular and Genomic Medicine
    摘要: Breast cancer-derived vascular endothelial growth factor-C (VEGF-C) has been shown to enhance lymphangiogenesis in lymph nodes to accelerate cancer metastasis. However, the remodeling of lymph node microenvironments by VEGF-C remains elusive. By in vivo selection, we established a subline (named as "LC") with strong lymphatic tropism and high VEGF-C expression from the human MDA-MB-231 breast cancer cell line. Co-culture with LC cells or treatment with LC-conditioned medium upregulated the expression of CXC chemokines in lymphatic endothelial cells (LECs), which could be inhibited by pre-incubation with VEGF-C-neutralizing antibodies and VEGFR3 inhibitors. The chemokines produced by LECs enhanced recruitment of myeloid-derived suppressor cells (MDSCs) to tumor-draining and distant lymph nodes in tumor-bearing mice. Treatment with a CXCR2 inhibitor after tumor cell inoculation dramatically decreased the number of MDSCs in lymph nodes, suggesting the importance of the chemokine/CXCR2 signaling axis in MDSC recruitment. In addition, LEC-released chemokines also stimulated the expression of serum amyloid A1 (SAA1) in cancer cells, enhancing their lymphatic invasion by increasing VE-cadherin phosphorylation, junction disruption, and vascular permeability of LECs. Clinical sample validation confirmed that SAA1 expression was associated with increased lymph node metastasis. Collectively, we reveal a novel mechanism by which cancer cell-derived VEGF-C remodels lymphovascular microenvironments by regulating chemokine production in LECs to promote cancer invasion and MDSC recruitment. Our results also suggest that inhibition of CXCR2 is effective in treating lymphatic metastasis.
    日期: 2019-08-06
    關聯: Cancers. 2019 Aug 6;11(8):Article number 1120.
    Link to: http://dx.doi.org/10.3390/cancers11081120
    JIF/Ranking 2023: http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcAuth=NHRI&SrcApp=NHRI_IR&KeyISSN=2072-6694&DestApp=IC2JCR
    Cited Times(WOS): https://www.webofscience.com/wos/woscc/full-record/WOS:000484438000080
    Cited Times(Scopus): https://www.scopus.com/inward/record.url?partnerID=HzOxMe3b&scp=85071090701
    顯示於類別:[洪文俊] 期刊論文
    [王陸海] 期刊論文

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