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Stromal cell-derived CSF-1 blockade prolongs xenograft survival of CSF-1-negative neuroblastoma
Dietmar Abraham1, Karin Zins, Mouldy Sioud
1Laboratory for Cardiovascular Research, Vienna Medical University, A-1090Vienna, Austria.
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.
Insights
Host cells producing colony-stimulating factor-1 (CSF-1) enhance neuroblastoma growth by recruiting tumor-associated macrophages (TAMs). Blocking CSF-1 reduces tumor growth but improves survival only in neuroblastoma lacking CSF-1.
Area of Science:
- Oncology
- Immunology
- Molecular Biology
Background:
- Neuroblastoma (NB) invasiveness mechanisms are poorly understood.
- Cancer cells exploit host factors like colony-stimulating factor-1 (CSF-1) to recruit tumor-associated macrophages (TAMs), promoting tumor growth, angiogenesis, and extracellular matrix remodeling.
Purpose of the Study:
- To investigate the role of host CSF-1 in neuroblastoma growth and TAM recruitment.
- To evaluate the therapeutic potential of blocking CSF-1 in neuroblastoma.
Main Methods:
- Co-culturing neuroblastoma and stromal cells in vitro to assess macrophage recruitment.
- Utilizing in vivo xenograft models with CSF-1-expressing and CSF-1-negative neuroblastoma cells in mice.
- Administering intratumoral small interfering RNAs targeting mouse CSF-1.
- Analyzing TAM infiltration, matrix metalloproteinase (MMP)-12 levels, angiogenesis, and tissue inhibitors of MMPs.
- Employing confocal microscopy and flow cytometry to identify TAM subtypes.
Main Results:
- Host CSF-1 is crucial for macrophage recruitment to neuroblastoma cells in vitro.
- In vivo blockade of mouse CSF-1 significantly suppressed the growth of both CSF-1-expressing and CSF-1-negative neuroblastoma xenografts.
- CSF-1 blockade led to decreased TAM infiltration, MMP-12 levels, and angiogenesis, with increased tissue inhibitors of MMPs.
- Both Tie-2-positive and -negative TAMs were recruited by host CSF-1.
- Survival was prolonged only in CSF-1-negative neuroblastoma models following host CSF-1 blockade.
Conclusions:
- Increased CSF-1 production by host cells promotes TAM recruitment and neuroblastoma growth.
- The CSF-1 phenotype of neuroblastoma cells negatively impacts patient survival.
- Targeting host CSF-1 may be a viable therapeutic strategy, particularly for CSF-1-negative neuroblastomas.
