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The Influence of Metastatic Breast Cancer on the Bone Microenvironment

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Signaling Pathways and Molecular Mediators in Metastasis

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Abstract

The bone is a welcoming microenvironment for metastases from many cancers including breast cancer. Cancer cells can easily enter the bone marrow cavity due to its vasculature; there they are exposed to the many growth factors and cytokines that are part of the continuous bone remodeling process. In addition, the cancer cells interact with the resident bone cells, osteoblasts and osteoclasts, to modify the microenvironment resulting in cancer cell colonization and eventually bone degradation. Osteoclasts release numerous molecules such as insulin-like growth factors (IGFs) and transforming growth factor beta (TGF-β) from the matrix. Osteoblasts undergo an inflammatory stress response and produce a set of cytokines that are osteoclastogenic. These cytokines include IL-6, IL-8 (murine homologue MIP-2), VEGF, MCP-1, MIG and LIX. Several of these molecules also are secreted by cancer cells. One notable exception is MCP-1 which is made only in small quantities. During the course of metastasis, osteoblast differentiation is suppressed and the prevalence of osteoblast apopotosis increases. Thus the bone microenvironment is modified by the interaction of cancer cells with both osteoblasts and osteoclasts. Bone loss results from hyperactive osteoclasts and hypoactive osteoblasts. This chapter summarizes the results of studies of osteoblast and breast cancer cell interactions that have been performed in cell culture, in mice and in a novel three dimensional culture bioreactor.

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Abbreviations

COX-2:

Cyclooxygenase-2

DAB:

3,3′- Diaminobenzidine

ECM:

Extracellular matrix

G-CSF:

Granulocyte-colony stimulating factor

GM-CSF:

Granulocyte macrophage-colony stimulating factor

GFP:

Green fluorescent protein

GRO-a:

Growth related oncogene alpha

IFN:

Interferon

IGFs:

Insulin-like growth factors

IL:

Interleukin

KC:

Keratinocyte chemoattractant

LIX:

LPS induced CXC chemokine

M-CSF:

Macrophage-colony stimulating factor

MCP-1:

Monocyte chemotactic protein 1

MIG:

Monokine induced by interferon gamma

MIP-2:

Macrophage inflammatory protein

MMP:

Matrix metalloproteinase

OPG:

Osteoprotogerin

PDGF:

Platelet derived growth factor

PGE:

Prostaglandin

PTHrP:

Parathyroid hormone related peptide

RANKL:

Receptor activator of NFκB ligand

TGF-β:

Transforming growth factor beta

TNF:

Tumor necrosis factor

TRAP:

Tartrate resistant acid phosphatase

TUNEL:

Terminal deoxynucleotidyl transferase dUTP nick end labeling

VEGF:

Vasular endothelial growth factor

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Acknowledgements

This work was supported through grants from the U.S. Army Medical and Materiel Command Breast Cancer Research Program (WX81XWH-06-1-0432 and WX81XWH-0801-0448), The Susan G. Koman Breast Cancer Foundation (BCTR 0601044), with help from The National Foundation for Cancer Research, and The Penn State Hershey Cancer Institute. We would like to thank Erwin Vogler, Carol Gay, Ravi Dhurjati, and Laurie Shuman for their work with various aspects of the projects.

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Authors and Affiliations

  1. Department of Biochemistry, 431 S. Frear Building, University Park, PA, 16802, USA

    Andrea M. Mastro, Donna M. Sosnoski & Venkatesh Krishnan

  2. Mammary Biology and Tumorigenesis Laboratory, NCI, NIH, Room 1112, Building 37, 37 Convent Drive, Bethesda, MD, 20892, USA

    Karen M. Bussard

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  1. Andrea M. Mastro
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  2. Donna M. Sosnoski
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  3. Venkatesh Krishnan
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  4. Karen M. Bussard
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Correspondence to Andrea M. Mastro .

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  1. Drexel University College of Medicine, N. 15th Street 245, Philadelphia, 19102, Pennsylvania, USA

    Alessandro Fatatis

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Mastro, A.M., Sosnoski, D.M., Krishnan, V., Bussard, K.M. (2011). The Influence of Metastatic Breast Cancer on the Bone Microenvironment. In: Fatatis, A. (eds) Signaling Pathways and Molecular Mediators in Metastasis. Springer, Dordrecht. https://doi.org/10.1007/978-94-007-2558-4_15

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