title: Dissecting the autocrine and paracrine roles of the CCR2-CCL2 axis in tumor survival and angiogenesis.
abstract: The CCL2 CCR2 axis is likely to contributes to the development and progression of cancer diseases by two major mechanisms; autocrine effect of CCL2 as a survival/growth factor for CCR2+ cancer cells and, the attraction of CCR2+ CX₃CR1+tumor associated macrophages that in the absence of CCR2 hardly migrate. Thus far no in vivo system has been set up to differentiate the selective contribution of each of these features to cancer development. Here we employed a chimera animal model in which all non-malignant cells are CCR2-/-, but all cancer cells are CCR2+, combined with an adoptive transfer system of bone marrow (BM) CX₃CR1+ cells from CCR2+ mice harboring a targeted replacement of the CX₃CR1gene by an enhanced green fluorescent protein (EGFP) reporter gene (cx₃cr1(gfp)), together with the CD45.1 congene. Using this system we dissected the selective contribution of CX₃CR1+CCR2+ cells, which comprise only about 7% of CD11b+ BM cells, to tumor development and angiogenesis. Showing that aside for their direct pro-angiogenic effect they are essential for the recruitment of other CD11b+ cells to the tumor site. We further show that the administration of CCR2-Ig, that selectively and specifically neutralize CCL2, to mice in which CCR2 is expressed only on tumor cells, further suppressed tumor development, implicating for the key role of this chemokine supporting tumor survival in an autocrine manner. This further emphasizes the important role of CCL2 as a target for therapy of cancer diseases.
authors.affiliation: Department of Immunology, Rappaport Institute for Medical Research, Bruce Rappaport Faculty of Medicine, Technion, Haifa, Israel.
authors.forename: Liat
authors.initials: L
authors.lastname: Izhak
authors.forename: Gizi
authors.initials: G
authors.lastname: Wildbaum
authors.forename: Steffen
authors.initials: S
authors.lastname: Jung
authors.forename: Avi
authors.initials: A
authors.lastname: Stein
authors.forename: Yuval
authors.initials: Y
authors.lastname: Shaked
authors.forename: Nathan
authors.initials: N
authors.lastname: Karin
mesh_terms: D000818:Animals; D000943:Antigens, Differentiation / Q000378:metabolism; D019898:Autocrine Communication / Q000235:genetics / Q000502:physiology; D001854:Bone Marrow Cells / Q000378:metabolism; D039481:CD11b Antigen / Q000378:metabolism; D000073883:CX3C Chemokine Receptor 1; D045744:Cell Line, Tumor; D018932:Chemokine CCL2 / Q000235:genetics / Q000378:metabolism*; D018450:Disease Progression; D005260:Female; D007150:Immunohistochemistry; D008264:Macrophages / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009374:Neoplasms, Experimental / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D009389:Neovascularization, Pathologic / Q000235:genetics / Q000378:metabolism*; D019899:Paracrine Communication / Q000235:genetics / Q000502:physiology; D011485:Protein Binding; D054390:Receptors, CCR2 / Q000235:genetics / Q000378:metabolism*; D019707:Receptors, Chemokine / Q000378:metabolism; D016019:Survival Analysis; D047368:Tumor Burden; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
chemical_list: D000943:Antigens, Differentiation; D039481:CD11b Antigen; D000073883:CX3C Chemokine Receptor 1; C491768:Ccl2 protein, mouse; C515335:Ccr2 protein, mouse; D018932:Chemokine CCL2; C471885:Cx3cr1 protein, mouse; D054390:Receptors, CCR2; D019707:Receptors, Chemokine; D042461:Vascular Endothelial Growth Factor A; C036763:monocyte-macrophage differentiation antigen