title: Plasticity in tumor-promoting inflammation: impairment of macrophage recruitment evokes a compensatory neutrophil response.
abstract: Previous studies in the K14-HPV/E(2) mouse model of cervical carcinogenesis demonstrated that infiltrating macrophages are the major source of matrix metalloproteinase 9 (MMP-9), a metalloprotease important for tumor angiogenesis and progression. We observed increased expression of the macrophage chemoattractant, CCL2, and its receptor, CCR2, concomitant with macrophage influx and MMP-9 expression. To study the role of CCL2-CCR2 signaling in cervical tumorigenesis, we generated CCR2-deficient K14-HPV/E(2) mice. Cervixes of CCR2-null mice contained significantly fewer macrophages. Surprisingly, there was only a modest delay in time to progression from dysplasia to carcinoma in the CCR2-deficient mice, and no difference in end-stage tumor incidence or burden. Moreover, there was an unexpected persistence of MMP-9 activity, associated with increased abundance of MMP-9(+) neutrophils in tumors from CCR2-null mice. In vitro bioassays revealed that macrophages produce soluble factor(s) that can suppress neutrophil dynamics, as evidenced by reduced chemotaxis in response to CXCL8, and impaired invasion into three-dimensional tumor masses grown in vitro. Our data suggest a mechanism whereby CCL2 attracts proangiogenic CCR2(+) macrophages with the ancillary capability to limit infiltration by neutrophils. If such tumor-promoting macrophages are suppressed, MMP-9(+) neutrophils are then recruited, providing alternative paracrine support for tumor angiogenesis and progression.
authors.affiliation: Department of Biochemistry and Biophysics, Comprehensive Cancer Center, University of California - San Francisco, San Francisco, CA 94143, USA.
authors.forename: Jessica C
authors.initials: JC
authors.lastname: Pahler
authors.forename: Simon
authors.initials: S
authors.lastname: Tazzyman
authors.forename: Neta
authors.initials: N
authors.lastname: Erez
authors.forename: Yung-Yi
authors.initials: YY
authors.lastname: Chen
authors.forename: Craig
authors.initials: C
authors.lastname: Murdoch
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Nozawa
authors.forename: Claire E
authors.initials: CE
authors.lastname: Lewis
authors.forename: Douglas
authors.initials: D
authors.lastname: Hanahan
mesh_terms: D000818:Animals; D002278:Carcinoma in Situ / Q000276:immunology* / Q000378:metabolism; D002465:Cell Movement; D018932:Chemokine CCL2 / Q000502:physiology; D004195:Disease Models, Animal; D018450:Disease Progression; D005260:Female; D006801:Humans; D015994:Incidence; D008264:Macrophages / Q000502:physiology*; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009000:Monocytes / Q000378:metabolism / Q000473:pathology; D009389:Neovascularization, Pathologic; D009504:Neutrophils / Q000502:physiology*; D011230:Precancerous Conditions / Q000276:immunology / Q000378:metabolism; D054390:Receptors, CCR2 / Q000502:physiology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D018874:Spheroids, Cellular / Q000473:pathology; D002583:Uterine Cervical Neoplasms / Q000276:immunology* / Q000378:metabolism; D002578:Uterine Cervical Dysplasia / Q000276:immunology* / Q000378:metabolism
chemical_list: C491768:Ccl2 protein, mouse; C515335:Ccr2 protein, mouse; D018932:Chemokine CCL2; D054390:Receptors, CCR2; D020780:Matrix Metalloproteinase 9