Abstract
Lymphangiogenesis, the growth of lymphatic vessels, contributes to lymphatic metastasis. However, the precise mechanism underlying lymphangiogenesis remains poorly understood. This study aimed to examine chemokine/chemokine receptors that directly contribute to chemoattraction of activated lymphatic endothelial cells (LEC) and tumor lymphangiogenesis. We used quantitative RT-PCR to analyze specifically expressed chemokine receptors in activated LECs upon stimulation of vascular endothelial growth factor-C (VEGF-C). Subsequently, we established in vitro and in vivo models to show lymphangiogenic functions of the chemokine axis. Effects of targeting the chemokine axis on tumor lymphangiogenesis and lymphatic metastasis were determined in an orthotopic breast cancer model. VEGF-C specifically upregulates CXCR4 expression on lymphangiogenic endothelial cells. Moreover, hypoxia-inducible factor-1α (HIF-1α) mediates the CXCR4 expression induced by VEGF-C. Subsequent analyses identify the ligand CXCL12 as a chemoattractant for LECs. CXCL12 induces migration, tubule formation of LECs in vitro, and lymphangiogenesis in vivo. CXCL12 also stimulates the phosphorylation of intracellular signaling Akt and Erk, and their specific antagonists impede CXCL12-induced chemotaxis. In addition, its level is correlated with lymphatic vessel density in multiple cancer tissues microarray. Furthermore, the CXCL12-CXCR4 axis is independent of the VEGFR-3 pathway in promoting lymphangiogenesis. Intriguingly, combined treatment with anti-CXCL12 and anti-VEGF-C antibodies results in additive inhibiting effects on tumor lymphangiogenesis and lymphatic metastasis. These results show the role of the CXCL12-CXCR4 axis as a novel chemoattractant for LECs in promoting lymphangiogenesis, and support the potential application of combined targeting of both chemokines and lymphangiogenic factors in inhibiting lymphatic metastasis.
Highlights
The major cause of cancer mortality is metastasis that occurs via multiple pathways including lymphatic vasculature
The CXCL12–CXCR4 axis is independent of the vascular endothelial growth factor receptor-3 (VEGFR-3) pathway in promoting lymphangiogenesis
Our study provides direct evidence that the chemokine system is involved in regulating lymphangiogenesis and shows that the CXCL12–CXCR4 chemotactic axis plays a critical role in promoting lymphangiogenesis in a VEGFR-3 independent pattern
Summary
The major cause of cancer mortality is metastasis that occurs via multiple pathways including lymphatic vasculature. A considerable number of studies has documented that lymphangiogenesis, the growth of lymphatic vessels, contributes to lymphatic metastasis in experimental tumor models and in clinic [1, 2], it remains controversial in several types of human cancer [3, 4]. Tumors can actively induce the growth of lymphatic vessels toward. Note: Supplementary data for this article are available at Clinical Cancer Research Online (http://clincancerres.aacrjournals.org/). Studies over the past decade have identified several growth factors and receptors, vascular endothelial growth factor-C (VEGF-C), VEGF-D, and their receptor vascular endothelial growth factor receptor-3 (VEGFR-3) on lymphatic endothelial cells (LEC), contributing to LEC growth, migration, and survival [5, 6]. The precise mechanism underlying lymphangiogenesis is still a focus of intensive investigation
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