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Interference with the Microenvironmental Support Impairs the De novo Formation of Bone Metastases In vivo

¹ Department of Endocrinology, Leiden University Medical Center, Leiden, the Netherlands and ² Departments of Clinical Research and Urology, Faculty of Medicine, University of Bern, Bern, Switzerland

Requests for reprints: Gabri van der Pluijm, Department of Endocrinology, Leiden University Medical Center, C4-86, Albinusdreef 2, 233 ZA Leiden, the Netherlands. Phone: 31-71-5263779; Fax: 31-71-5248136; E-mail: G.van_der_Pluijm{at}lumc.nl.

Interference with the microenvironmental growth support is an attractive therapeutic strategy for repressing metastatic tumor growth. Bone is a highly dynamic tissue that is continuously remodeled by bone resorption and subsequent bone formation. Growth factors supporting bone metastatic growth are released especially during bone resorption. Differently from most other tissues, drugs that can limit local turnover, such as bisphosphonates, are available for bone. In the present study, we tested the hypothesis that inhibition of bone turnover can affect development and growth progression of experimental bone metastasis. Whole-body bioluminescent reporter imaging was used for the detection, monitoring, and quantification in vivo of the growth progression of bone metastases induced by intracardiac or intraosseous injection of luciferase-transfected breast cancer cells (MDA-231-B/luc⁺) to nude mice. Suppression of bone turnover by bisphosphonates, before bone colonization by cancer cells, inhibited by a great extent the number of developing bone metastasis. Tumor growth in the few, but still developing, bone metastases was affected only transiently. Reduction of bone turnover had no effect on growth progression of bone metastases, which were already established when bisphosphonate treatment was initiated, despite a substantial reduction in osteolysis. Therefore, cancer cells metastatic to bone, after an initial growth phase that depends on the interaction with the local stroma, become independent of microenvironmental growth factor support and progress autonomously. Inhibition of bone turnover may represent a useful adjuvant therapy especially for cancer patients at risk to develop bone metastasis.

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