The CXCL12―CXCR4 Chemokine Pathway: A Novel Axis Regulates Lymphangiogenesis

• Published in: Clinical cancer research Vol. 18; no. 19; pp. 5387 - 5398
• Main Authors: WEI ZHUO, LIN JIA, NAN SONG, LU, Xin-An, YANPING DING, XIAOFENG WANG, XIAOMIN SONG, YAN FU, YONGZHANG LUO
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Association for Cancer Research 01.10.2012
• Subjects: Animals; Antineoplastic agents; Biological and medical sciences; Breast Neoplasms - drug therapy; Breast Neoplasms - genetics; Breast Neoplasms - metabolism; Cell Movement - genetics; Chemokine CXCL12 - genetics; Chemokine CXCL12 - immunology; Chemokine CXCL12 - metabolism; Endothelial Cells - cytology; Endothelial Cells - metabolism; Endothelial Cells - pathology; Female; Gene Expression Regulation, Neoplastic; Humans; Lymphangiogenesis - genetics; Lymphangiogenesis - immunology; Lymphatic Metastasis - genetics; Lymphatic Metastasis - pathology; Mammary Neoplasms, Animal - drug therapy; Mammary Neoplasms, Animal - immunology; Mammary Neoplasms, Animal - metabolism; Medical sciences; Mice; Pharmacology. Drug treatments; Receptors, CXCR4 - genetics; Receptors, CXCR4 - immunology; Receptors, CXCR4 - metabolism; Signal Transduction; Vascular Endothelial Growth Factor C - metabolism; Stromal cell derived factor 1; Chemokine CXCL12; Chemokine receptor; CXC chemokine; Lymphangiogenesis; CXCR4 chemokine receptor; Biological receptor
• ISSN: 1078-0432; 1557-3265
• DOI: 10.1158/1078-0432.ccr-12-0708

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.