Abstract
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.
Highlights
IntroductionMany cancers disseminate first through lymphatic system, and metastasis in sentinel lymph nodes indicates the spread of tumors from a primary site [1,2]
The lymphatic system is involved in diverse physiological and pathological processes like immune modulation, tissue fluid homeostasis, wound healing, chronic inflammation, and tumor metastasis.Cancers 2019, 11, 1120; doi:10.3390/cancers11081120 www.mdpi.com/journal/cancersMany cancers disseminate first through lymphatic system, and metastasis in sentinel lymph nodes indicates the spread of tumors from a primary site [1,2]
We demonstrated that cancer-derived vascular endothelial growth factor-C (VEGF-C) stimulated the production of chemokines from lymphatic endothelial cells (LECs), and that the released chemokines in turn promoted the recruitment of
Summary
Many cancers disseminate first through lymphatic system, and metastasis in sentinel lymph nodes indicates the spread of tumors from a primary site [1,2]. The presence of tumor cells in sentinel or draining lymph nodes is a major prognostic indicator in breast, melanoma, prostate, and head and neck cancers [3,4,5,6]. The concept of a passive role of lymphatic endothelial cells (LECs) in cancer metastasis has been challenged. To recruit CCR7- and CXCR4-expressing cancer cells into sentinel lymph nodes (LNs) [7]. In addition to CCL21 and CXCL12, CCL1 produced from LN lymphatic sinuses enhances lymph node entry of CCR8-expressing melanoma cells [8]. The role of tumor-associated LECs in the remodeling of the lymphovascular niche is still unclear
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