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: Jessica C Pahler, Simon Tazzyman, Neta Erez, Yung-Yi Chen, Craig Murdoch, Hiroaki Nozawa, Claire E Lewis, Douglas Hanahan
• Journal: Neoplasia (New York, N.Y.) (Neoplasia) Vol. 10 Issue 4 Pg. 329-40 (Apr 2008) ISSN: 1476-5586 [Electronic] United States
• PMID: 18392134 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Ccl2 protein, mouse
• Ccr2 protein, mouse
• Chemokine CCL2
• Receptors, CCR2
• Matrix Metalloproteinase 9

Topics

• Animals
• Carcinoma in Situ (immunology, metabolism)
• Cell Movement
• Chemokine CCL2 (physiology)
• Disease Models, Animal
• Disease Progression
• Female
• Humans
• Incidence
• Macrophages (physiology)
• Matrix Metalloproteinase 9 (metabolism)
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Monocytes (metabolism, pathology)
• Neovascularization, Pathologic
• Neutrophils (physiology)
• Precancerous Conditions (immunology, metabolism)
• Receptors, CCR2 (physiology)
• Reverse Transcriptase Polymerase Chain Reaction
• Spheroids, Cellular (pathology)
• Uterine Cervical Neoplasms (immunology, metabolism)
• Uterine Cervical Dysplasia (immunology, metabolism)