Abstract
Purpose
Aim of this study was to investigate the specific treatment effects of inhibiting αvβ3/αvβ5 integrins by cilengitide in an animal model of breast cancer bone metastases using dynamic 18F-FDG PET and gene expression analysis.
Methods
For this purpose, nude rats bearing bone metastases were treated with cilengitide, a small molecule inhibitor of αvβ3 and αvβ5 integrins, from day 30 to 55 after tumor cell inoculation of MDA-MB-231 breast cancer cells (25 mg/kg, 5 days per week; n = 8 rats) and compared to control rats (n = 8). Dynamic 18F-FDG PET data were assessed at days 30, 35 and 55 after tumor cell inoculation determining the vascular fraction VB and the metabolic variables k1–k4. At day 55, genome-wide mRNA expression analysis was performed to assess the treatment-specific expression changes from cilengitide-treated and control rats.
Results
In a longitudinal 18F-FDG PET study, the vascular fraction VB was significantly decreased in bone metastases between days 30/35, 30/55 and 35/55, whereas the kinetic parameters k1 and k4 were significantly decreased between days 30/55 in skeletal lesions of treated animals. Gene expression analysis from bone metastases at day 55 revealed that tumor-produced integrins (αvβ5) as well as factors relevant for angiogenesis (αvβ3, VEGF, PDGF), bone resorption (PTHrP and RANKL), extracellular matrix remodeling (collagen, CD44) and bone marrow microenvironment (CXCR4) were significantly reduced upon therapy with cilengitide.
Conclusions
Here, we provide evidence that cilengitide inhibits pivotal factors of all compartments of bone metastases including tumor cells, vasculature and bone microenvironment in vivo and by whole-genome transcriptome analysis.
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Acknowledgments
We thank Karin Leotta and Lisa Seyler for excellent technical assistance and Merck-Serono for providing cilengitide. For financial support, we thank the Deutsche Forschungsgemeinschaft (T.B., BA 4027/4-1).
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The authors declare that they have no conflict of interest.
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Bretschi, M., Cheng, C., Witt, H. et al. Cilengitide affects tumor compartment, vascularization and microenvironment in experimental bone metastases as shown by longitudinal 18F-FDG PET and gene expression analysis. J Cancer Res Clin Oncol 139, 573–583 (2013). https://doi.org/10.1007/s00432-012-1360-6
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DOI: https://doi.org/10.1007/s00432-012-1360-6