Plasticity in tumor-promoting inflammation: impairment of macrophage recruitment evokes a compensatory neutrophil response

Neoplasia. 2008 Apr;10(4):329-40. doi: 10.1593/neo.07871.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Carcinoma in Situ / immunology*
  • Carcinoma in Situ / metabolism
  • Cell Movement
  • Cervical Intraepithelial Neoplasia / immunology*
  • Cervical Intraepithelial Neoplasia / metabolism
  • 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
  • Monocytes / pathology
  • Neovascularization, Pathologic
  • Neutrophils / physiology*
  • Precancerous Conditions / immunology
  • Precancerous Conditions / metabolism
  • Receptors, CCR2 / physiology
  • Reverse Transcriptase Polymerase Chain Reaction
  • Spheroids, Cellular / pathology
  • Uterine Cervical Neoplasms / immunology*
  • Uterine Cervical Neoplasms / metabolism

Substances

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