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Cancers (Basel). 2019 Aug 6;11(8). pii: E1120. doi: 10.3390/cancers11081120.

Cancer-Derived VEGF-C Increases Chemokine Production in Lymphatic Endothelial Cells to Promote CXCR2-Dependent Cancer Invasion and MDSC Recruitment.

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National Institute of Cancer Research, National Health Research Institutes, Tainan 704, Taiwan.
Department of Pathology, Show Chwan Memorial Hospital, Changhua City 500, Taiwan.
Chinese Medicine Research Center and Graduate Institute of Integrated Medicine, China Medical University, Taichung 404, Taiwan.
Institute of Molecular and Genomic Medicine, National Health Research Institutes, Miaoli 350, Taiwan.
National Institute of Cancer Research, National Health Research Institutes, Tainan 704, Taiwan.
Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan.
Drug Development and Value Creation Research Center, Kaohsiung Medical University, Kaohsiung 807, Taiwan.


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.


CXC chemokine receptor 2; lymphovascular niche; myeloid-derived suppressor cells; vascular endothelial growth factor-C

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