Stromal cell-derived CSF-1 blockade prolongs xenograft survival of CSF-1-negative neuroblastoma

Int J Cancer. 2010 Mar 15;126(6):1339-52. doi: 10.1002/ijc.24859.

Abstract

The molecular mechanisms of tumor-host interactions that render neuroblastoma (NB) cells highly invasive are unclear. Cancer cells upregulate host stromal cell colony-stimulating factor-1 (CSF-1) production to recruit tumor-associated macrophages (TAMs) and accelerate tumor growth by affecting extracellular matrix remodeling and angiogenesis. By coculturing NB with stromal cells in vitro, we showed the importance of host CSF-1 expression for macrophage recruitment to NB cells. To examine this interaction in NB in vivo, mice bearing human CSF-1-expressing SK-N-AS and CSF-1-negative SK-N-DZ NB xenografts were treated with intratumoral injections of small interfering RNAs directed against mouse CSF-1. Significant suppression of both SK-N-AS and SK-N-DZ NB growth by these treatments was associated with decreased TAM infiltration, matrix metalloprotease (MMP)-12 levels and angiogenesis compared to controls, while expression of tissue inhibitors of MMPs increased following mouse CSF-1 blockade. Furthermore, Tie-2-positive and -negative TAMs recruited by host CSF-1 were identified in NB tumor tissue by confocal microscopy and flow cytometry. However, host-CSF-1 blockade prolonged survival only in CSF-1-negative SK-N-DZ NB. These studies demonstrated that increased CSF-1 production by host cells enhances TAM recruitment and NB growth and that the CSF-1 phenotype of NB tumor cells adversely affects survival.

Publication types

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

MeSH terms

  • Animals
  • Blotting, Western
  • Cell Communication
  • Cell Line
  • Cell Line, Tumor
  • Cell Movement
  • Coculture Techniques
  • Flow Cytometry
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Macrophage Colony-Stimulating Factor / genetics
  • Macrophage Colony-Stimulating Factor / metabolism*
  • Macrophages / cytology
  • Macrophages / metabolism
  • Male
  • Matrix Metalloproteinase 12 / metabolism
  • Mice
  • Mice, Nude
  • Microscopy, Confocal
  • Neuroblastoma / genetics
  • Neuroblastoma / metabolism
  • Neuroblastoma / pathology*
  • RNA Interference*
  • Receptor, TIE-2 / genetics
  • Receptor, TIE-2 / metabolism
  • Reverse Transcriptase Polymerase Chain Reaction
  • Stromal Cells / cytology
  • Stromal Cells / metabolism*
  • Survival Analysis
  • Tissue Inhibitor of Metalloproteinases / metabolism
  • Transplantation, Heterologous

Substances

  • Tissue Inhibitor of Metalloproteinases
  • Macrophage Colony-Stimulating Factor
  • Receptor, TIE-2
  • Matrix Metalloproteinase 12