Thorsten Heilmann1,2, Anna-Lena Rumpf3, Marijke Roscher3, Maren Tietgen4, Olga Will4, Mirko Gerle5, Timo Damm4, Christoph Borzikowsky6, Nicolai Maass3, Claus-Christian Glüer4, Sanjay Tiwari4, Anna Trauzold7, Christian Schem3,8. 1. Department of Gynecology and Obstetrics, University Hospital Schleswig-Holstein, Arnold-Heller-Straße 3, 24105, Kiel, Germany. thorsten.heilmann@uksh.de. 2. Institute for Experimental Cancer Research, Christian-Albrechts-University of Kiel, Kiel, Germany. thorsten.heilmann@uksh.de. 3. Department of Gynecology and Obstetrics, University Hospital Schleswig-Holstein, Arnold-Heller-Straße 3, 24105, Kiel, Germany. 4. Section Biomedical Imaging, Department of Radiology and Neuroradiology, University Hospital Schleswig-Holstein, Kiel, Germany. 5. Department of Oral and Maxillofacial Surgery, University Hospital Schleswig-Holstein, Kiel, Germany. 6. Institute of Medical Informatics and Statistics, Christian-Albrechts-University of Kiel, Kiel, Germany. 7. Institute for Experimental Cancer Research, Christian-Albrechts-University of Kiel, Kiel, Germany. 8. Mammazentrum am Krankenhaus Jerusalem, Hamburg, Germany.
Abstract
PURPOSE: Bone metastasis in breast cancer has been linked to activity of c-Src kinase, one of the extensively explored tyrosine kinases in cell biology. The impact of TNF-related apoptosis inducing ligand (TRAIL) and TRAIL receptors has just recently been integrated into this conception. METHODS: An osteotropic clone of MDA-MB-231 cells simulated a model for bone metastasis of triple-negative breast cancer (TNBC). The effects of Dasatinib, a clinically established inhibitor of Src kinases family and Abl were evaluated in vitro and in vivo. In vivo effects of Dasatinib treatment on the occurrence of skeletal metastases were tested in a xenograft mouse model after intra-cardiac injection of osteotropic MDA-MB-231-cells. Ex vivo analyses of the bone sections confirmed intraosseous growth of metastases and allowed determination of osteoclastic activity. RESULTS: Treatment of osteotropic MDA-MB-231 cells with Dasatinib inhibited proliferation rates in vitro. A shift in TRAIL-receptor expression towards an induction of oncogenic TRAIL-R2 was observed. In vivo, 15 of 30 mice received an intra-peritoneal treatment with Dasatinib. These mice showed significantly less skeletal metastases in bioluminescence scans. Moreover, a pronounced increase in bone volume was observed in the treatment group, as detected by µ-Computed Tomography. Dasatinib treatment also led to a greater increase in bone density in tibiae without metastatic affection, which was accompanied by reduced recruitment of osteoclasts. CONCLUSION: Our observations support the concept of utilizing Dasatinib in targeting early-stage bone metastatic TNBC and sustaining bone health.
PURPOSE: Bone metastasis in breast cancer has been linked to activity of c-Src kinase, one of the extensively explored tyrosine kinases in cell biology. The impact of TNF-related apoptosis inducing ligand (TRAIL) and TRAIL receptors has just recently been integrated into this conception. METHODS: An osteotropic clone of MDA-MB-231 cells simulated a model for bone metastasis of triple-negative breast cancer (TNBC). The effects of Dasatinib, a clinically established inhibitor of Src kinases family and Abl were evaluated in vitro and in vivo. In vivo effects of Dasatinib treatment on the occurrence of skeletal metastases were tested in a xenograft mouse model after intra-cardiac injection of osteotropic MDA-MB-231-cells. Ex vivo analyses of the bone sections confirmed intraosseous growth of metastases and allowed determination of osteoclastic activity. RESULTS: Treatment of osteotropic MDA-MB-231 cells with Dasatinib inhibited proliferation rates in vitro. A shift in TRAIL-receptor expression towards an induction of oncogenic TRAIL-R2 was observed. In vivo, 15 of 30 mice received an intra-peritoneal treatment with Dasatinib. These mice showed significantly less skeletal metastases in bioluminescence scans. Moreover, a pronounced increase in bone volume was observed in the treatment group, as detected by µ-Computed Tomography. Dasatinib treatment also led to a greater increase in bone density in tibiae without metastatic affection, which was accompanied by reduced recruitment of osteoclasts. CONCLUSION: Our observations support the concept of utilizing Dasatinib in targeting early-stage bone metastatic TNBC and sustaining bone health.
Entities:
Keywords:
Bone metastases; Breast cancer; Dasatinib; Src; TRAIL; TRAIL receptor
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