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.
Abraham
Dietmar
D
Laboratory for Cardiovascular Research, Vienna Medical University, A-1090Vienna, Austria.
Zins
Karin
K
Sioud
Mouldy
M
Lucas
Trevor
T
Schäfer
Romana
R
Stanley
E Richard
ER
Aharinejad
Seyedhossein
S
D000818:Animals; D015153:Blotting, Western; D002450:Cell Communication; D002460:Cell Line; D045744:Cell Line, Tumor; D002465:Cell Movement; D018920:Coculture Techniques; D005434:Flow Cytometry; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D016173:Macrophage Colony-Stimulating Factor / Q000235:genetics / Q000378:metabolism*; D008264:Macrophages / Q000166:cytology / Q000378:metabolism; D008297:Male; D053508:Matrix Metalloproteinase 12 / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D018613:Microscopy, Confocal; D009447:Neuroblastoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D034622:RNA Interference; D042787:Receptor, TIE-2 / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D017154:Stromal Cells / Q000166:cytology / Q000378:metabolism*; D016019:Survival Analysis; D019714:Tissue Inhibitor of Metalloproteinases / Q000378:metabolism; D014183:Transplantation, Heterologous
D019714:Tissue Inhibitor of Metalloproteinases; D016173:Macrophage Colony-Stimulating Factor; D042787:Receptor, TIE-2; D053508:Matrix Metalloproteinase 12