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

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.
AuthorsDietmar Abraham, Karin Zins, Mouldy Sioud, Trevor Lucas, Romana Schäfer, E Richard Stanley, Seyedhossein Aharinejad
JournalInternational journal of cancer. Journal international du cancer (Int J Cancer) Vol. 126 Issue 6 Pg. 1339-52 (Mar 15 2010) ISSN: 1097-0215 [Electronic] United States
PMID19711348 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
Chemical References
  • Tissue Inhibitor of Metalloproteinases
  • Macrophage Colony-Stimulating Factor
  • Receptor, TIE-2
  • Matrix Metalloproteinase 12
  • 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, metabolism)
  • Macrophages (cytology, metabolism)
  • Male
  • Matrix Metalloproteinase 12 (metabolism)
  • Mice
  • Mice, Nude
  • Microscopy, Confocal
  • Neuroblastoma (genetics, metabolism, pathology)
  • RNA Interference
  • Receptor, TIE-2 (genetics, metabolism)
  • Reverse Transcriptase Polymerase Chain Reaction
  • Stromal Cells (cytology, metabolism)
  • Survival Analysis
  • Tissue Inhibitor of Metalloproteinases (metabolism)
  • Transplantation, Heterologous

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