title: C-X-C receptor type 4 promotes metastasis by activating p38 mitogen-activated protein kinase in myeloid differentiation antigen (Gr-1)-positive cells.
abstract: Increasing evidence suggests that myeloid bone marrow-derived cells (BMDCs) play a critical role in lung metastasis. Blockade of VEGF receptor 1 (VEGFR1) has been proposed as a potential strategy to limit myeloid BMDC recruitment to tumors. However, preclinical evidence indicates that this strategy may not be effective in all tumors. Thus, establishing which molecular mechanisms are responsible for the "escape" of these BMDCs from VEGFR1 inhibition would facilitate development of strategies to control metastasis. Here, we report the complementary role of the chemokine (C-X-C motif) ligand 12/C-X-C chemokine receptor 4 (CXCR4) and VEGF/VEGFR1 pathways in promoting lung metastasis in mice via BMDC recruitment using chimeric mice with deficiency in CXCR4 and VEGFR1-tyrosine kinase in the BMDCs. We first demonstrate that CXCR4 activity is essential for recruitment of myeloid differentiation antigen (Gr-1)-positive BMDCs, whereas VEGFR1 activity is responsible for macrophage recruitment in established tumors. Inhibition of both VEGFR1 and CXCR4 signaling in myeloid BMDCs exerted greater effects on tumor vascular density, growth, and lung metastasis than inhibition of VEGFR1 alone. These effects were reproduced after pharmacologic inhibition of CXCR4 with AMD3100. VEGFR1 and CXCR4 independently exerted a promigratory effect in myeloid BMDCs by activating p38 mitogen-activating protein kinase. Thus, combining CXCR4 blockade with inhibition of VEGFR1 may induce greater tumor growth delay and prevent or inhibit metastasis.
authors.affiliation: Steele Laboratory for Tumor Biology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA.
authors.forename: Sachie
authors.initials: S
authors.lastname: Hiratsuka
authors.forename: Dan G
authors.initials: DG
authors.lastname: Duda
authors.forename: Yuhui
authors.initials: Y
authors.lastname: Huang
authors.forename: Shom
authors.initials: S
authors.lastname: Goel
authors.forename: Tatsuki
authors.initials: T
authors.lastname: Sugiyama
authors.forename: Takashi
authors.initials: T
authors.lastname: Nagasawa
authors.forename: Dai
authors.initials: D
authors.lastname: Fukumura
authors.forename: Rakesh K
authors.initials: RK
authors.lastname: Jain
mesh_terms: D000818:Animals; D015153:Blotting, Western; D016026:Bone Marrow Transplantation; D007150:Immunohistochemistry; D008175:Lung Neoplasms / Q000378:metabolism / Q000503:physiopathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D022423:Myeloid Cells / Q000378:metabolism*; D009362:Neoplasm Metastasis / Q000503:physiopathology*; D019718:Receptors, CXCR4 / Q000378:metabolism*; D019707:Receptors, Chemokine / Q000378:metabolism*; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000235:genetics; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
chemical_list: C503133:Gr-1 protein, mouse; D019718:Receptors, CXCR4; D019707:Receptors, Chemokine; D040281:Vascular Endothelial Growth Factor Receptor-1; D048051:p38 Mitogen-Activated Protein Kinases