title: The CXCL12-CXCR4 chemokine pathway: a novel axis regulates lymphangiogenesis.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: National Engineering Laboratory for Anti-tumor Protein Therapeutics, Beijing, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Zhuo
authors.forename: Lin
authors.initials: L
authors.lastname: Jia
authors.forename: Nan
authors.initials: N
authors.lastname: Song
authors.forename: Xin-An
authors.initials: XA
authors.lastname: Lu
authors.forename: Yanping
authors.initials: Y
authors.lastname: Ding
authors.forename: Xiaofeng
authors.initials: X
authors.lastname: Wang
authors.forename: Xiaomin
authors.initials: X
authors.lastname: Song
authors.forename: Yan
authors.initials: Y
authors.lastname: Fu
authors.forename: Yongzhang
authors.initials: Y
authors.lastname: Luo
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D002465:Cell Movement / Q000235:genetics; D054377:Chemokine CXCL12 / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D042783:Endothelial Cells / Q000166:cytology / Q000378:metabolism / Q000473:pathology; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D042583:Lymphangiogenesis / Q000235:genetics* / Q000276:immunology; D008207:Lymphatic Metastasis / Q000235:genetics / Q000473:pathology; D015674:Mammary Neoplasms, Animal / Q000188:drug therapy / Q000276:immunology / Q000378:metabolism; D051379:Mice; D019718:Receptors, CXCR4 / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D015398:Signal Transduction; D042582:Vascular Endothelial Growth Factor C / Q000378:metabolism
chemical_list: C515255:CXCL12 protein, human; C527276:CXCR4 protein, human; D054377:Chemokine CXCL12; D019718:Receptors, CXCR4; D042582:Vascular Endothelial Growth Factor C