title: Tumor angiogenesis mediated by myeloid cells is negatively regulated by CEACAM1.
abstract: Bv8 (prokineticin 2) expressed by Gr1(+)CD11b(+) myeloid cells is critical for VEGF-independent tumor angiogenesis. Although granulocyte colony-stimulating factor (G-CSF) has been shown to be a key inducer of Bv8 expression, the basis for Bv8 production in driving tumor angiogenesis is undefined. Because the cell adhesion molecule CEACAM1, which is highly expressed on Gr1(+)CD11b(+) myeloid cells, is known to regulate G-CSF receptor (G-CSFR) signaling, we hypothesized that CEACAM1 would regulate Bv8 production in these cells. In support of this hypothesis, we found that Bv8 expression was elevated in Gr1(+)CD11b(+) cells from Ceacam1-deficient mice implanted with B16 melanoma, increasing the infiltration of Gr1(+)CD11b(+) myeloid cells in melanoma tumors and enhancing their growth and angiogenesis. Furthermore, treatment with anti-Gr1 or anti-Bv8 or anti-G-CSF monoclonal antibody reduced myeloid cell infiltration, tumor growth, and angiogenesis to levels observed in tumor-bearing wild-type (WT) mice. Reconstitution of CEACAM1-deficient mice with WT bone marrow cells restored tumor infiltration of Gr1(+)CD11b(+) cells along with tumor growth and angiogenesis to WT levels. Treatment of tumor-bearing WT mice with anti-CEACAM1 antibody limited tumor outgrowth and angiogenesis, albeit to a lesser extent. Tumor growth in Ceacam1-deficient mice was not affected significantly in Rag(-/-) background, indicating that CEACAM1 expression in T and B lymphocytes had a negligible role in this pathway. Together, our findings show that CEACAM1 negatively regulates Gr1(+)CD11b(+) myeloid cell-dependent tumor angiogenesis by inhibiting the G-CSF-Bv8 signaling pathway.
authors.affiliation: City of Hope Irell & Manella Graduate School of Biological Sciences, Duarte, California, USA.
authors.forename: Rongze
authors.initials: R
authors.lastname: Lu
authors.forename: Maciej
authors.initials: M
authors.lastname: Kujawski
authors.forename: Hao
authors.initials: H
authors.lastname: Pan
authors.forename: John E
authors.initials: JE
authors.lastname: Shively
mesh_terms: D000818:Animals; D000906:Antibodies / Q000276:immunology / Q000494:pharmacology; D001402:B-Lymphocytes / Q000473:pathology; D039481:CD11b Antigen / Q000096:biosynthesis; D002272:Carcinoembryonic Antigen / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D048708:Cell Growth Processes / Q000502:physiology; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms / Q000098:blood supply* / Q000235:genetics / Q000473:pathology; D005768:Gastrointestinal Hormones / Q000096:biosynthesis; D007150:Immunohistochemistry; D008546:Melanoma, Experimental / Q000098:blood supply* / Q000235:genetics / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D022423:Myeloid Cells / Q000276:immunology / Q000378:metabolism / Q000473:pathology*; D009389:Neovascularization, Pathologic / Q000235:genetics / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D009479:Neuropeptides / Q000096:biosynthesis; D013601:T-Lymphocytes / Q000473:pathology
chemical_list: D000906:Antibodies; D039481:CD11b Antigen; D002272:Carcinoembryonic Antigen; C486183:Ceacam1 protein, mouse; D005768:Gastrointestinal Hormones; D009479:Neuropeptides; C486586:Prok2 protein, mouse