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Osteoblasts modulate Ca2+ signaling in bone-metastatic prostate and breast cancer cells

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Abstract

Metastatic prostate and breast cancers display a predilection for the skeleton. The high incidence of skeletal metastasis may be a reflection of favorable reciprocal interactions between the bone microenvironment and disseminated cancer cells. Here we show that bone-metastatic PC3-ML prostate cancer cells and MDA-231 breast cancer cells—when co-cultured with human osteoblasts—down-regulate the increase in cytosolic free calcium (Ca2+) induced by agonist stimulation. This osteoblast promoted alteration of Ca2+ signaling develops and reverts in a time-dependent manner. Most importantly, the Ca2+ responses of cancer cells lacking bone metastatic potential are not affected by osteoblasts. The limited increase in cytosolic Ca2+ observed in bone-metastatic cells does not result from depleted intracellular Ca2+ stores but rather a decreased entry of Ca2+ from the extracellular space. Interestingly, the inhibition of histone deacetylase in cancer cells replicates the changes in Ca2+ signaling induced by osteoblasts, suggesting the participation of epigenetic mechanisms. Finally, cancer cells harvested from skeletal metastases induced in mice showed Ca2+ responses identical to cells co-cultured with osteoblasts. However, Ca2+ signaling in cancer cells recovered from metastases to soft-tissues was not affected, emphasizing the role of the bone microenvironment in regulating the functional behavior of bone-metastatic cells. We propose that osteoblasts protect selected malignant phenotypes from cell death caused by an excessive increase in cytosolic Ca2+, thereby facilitating their progression into macroscopic skeletal metastases.

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Acknowledgments

This work was supported in part by the W. W. Smith Charitable Trust Foundation and NIH (grant GM067892 to A.F.). The authors wish to thank Dr. Olimpia Meucci for critically reading the manuscript, Whitney Jamieson and Mike Russell in Fatatis laboratory for cancer cell inoculation and members of Meucci laboratory for helpful discussion.

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Authors and Affiliations

  1. Department of Pharmacology and Physiology, Drexel University College of Medicine, 245 N. 15th Street, New College Building, MS488, Philadelphia, PA, 19102, USA

    Julia D’Ambrosio & Alessandro Fatatis

  2. Department of Pathology and Laboratory Medicine, Drexel University College of Medicine, Philadelphia, PA, 19102, USA

    Alessandro Fatatis

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  1. Julia D’Ambrosio
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  2. Alessandro Fatatis
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Correspondence to Alessandro Fatatis.

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D’Ambrosio, J., Fatatis, A. Osteoblasts modulate Ca2+ signaling in bone-metastatic prostate and breast cancer cells. Clin Exp Metastasis 26, 955–964 (2009). https://doi.org/10.1007/s10585-009-9286-3

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  • DOI: https://doi.org/10.1007/s10585-009-9286-3

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