ORIGINAL PAPER Cilengitide affects tumor compartment, vascularization and microenvironment in experimental bone metastases as shown by longitudinal 18 F-FDG PET and gene expression analysis Maren Bretschi • Caixia Cheng • Hendrik Witt • Antonia Dimitrakopoulou-Strauss • Ludwig G. Strauss • Wolfhard Semmler • Tobias Ba ¨uerle Received: 6 October 2012 / Accepted: 26 November 2012 Ó Springer-Verlag Berlin Heidelberg 2012 Abstract Purpose Aim of this study was to investigate the specific treatment effects of inhibiting avb3/avb5 integrins by cilengitide in an animal model of breast cancer bone metastases using dynamic 18 F-FDG PET and gene expression analysis. Methods For this purpose, nude rats bearing bone metastases were treated with cilengitide, a small molecule inhibitor of avb3 and avb5 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 com- pared to control rats (n = 8). Dynamic 18 F-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 18 F-FDG PET study, the vas- cular 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 (avb5) as well as factors relevant for angiogenesis (avb3, VEGF, PDGF), bone resorption (PTHrP and RANKL), extracel- lular matrix remodeling (collagen, CD44) and bone mar- row 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 tran- scriptome analysis. Keywords Bone metastases Á Breast cancer Á 18 F-FDG PET Á Cilengitide Á Integrins Á Gene expression analysis Introduction In the pathogenesis of skeletal metastasis, the cross talk between tumor and stroma cells results in bone remodeling by osteoblasts and osteoclasts. Consequently, the micro- environment is enriched with bone-derived pathogenic factors that, in turn, enhance tumor signaling inducing progressed bone destruction. Novel therapies for metastatic disease in the skeleton target pivotal pathogenic factors such as RANKL (receptor activator of NF-jB ligand) that stimulate tumor-induced bone resorption (Weilbaecher M. Bretschi Á W. Semmler Á T. Ba ¨uerle (&) Department of Medical Physics in Radiology, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120 Heidelberg, Germany e-mail: t.baeuerle@dkfz.de C. Cheng Á A. Dimitrakopoulou-Strauss Á L. G. Strauss Clinical Cooperation Unit Nuclear Medicine, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120 Heidelberg, Germany H. Witt Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120 Heidelberg, Germany H. Witt Department of Pediatric Oncology, Hematology and Immunology, University Hospital Heidelberg, Im Neuenheimer Feld 430, 69120 Heidelberg, Germany 123 J Cancer Res Clin Oncol DOI 10.1007/s00432-012-1360-6