Breast cancer cells induce osteoblast apoptosis: A possible contributor to bone degradation

Mastro, Andrea M.; Welch, Danny R.; Donahue, Henry J.; Jewell, Jennifer; Mercer, Robyn R.; DiGirolamo, Douglas J.; Chislock, Elizabeth M.; Guttridge, Kristin

doi:10.1002/jcb.10746

Cited by 79 publications

(73 citation statements)

References 36 publications

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“…Moreover, we have shown that NOG is a driver of this effect because the activation was observed in the presence of NOG and it was lost when NOG was depleted. Previous studies have shown that conditioned medium of MDA-231 breast cancer cells induce osteoblast apoptosis in vitro (35,36), which under certain circumstances might add on the NOG phenotype described herein.…”

Section: Discussionmentioning

confidence: 73%

Identification of NOG as a Specific Breast Cancer Bone Metastasis-supporting Gene

Tarragona

Pavlović

Arnal-Estapé

et al. 2012

Journal of Biological Chemistry

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Background: NOG gene is required for accumulation of mature osteoclasts and proper skeletal development. Results: NOG mediates breast cancer metastatic bone colonization by osteoclast differentiation and self-renewal metastatic properties. Conclusion: Expression of NOG in breast metastatic cancer cells provides them with bone colonization capabilities. Significance: The interplay of bone microenvironment and cancer cell autonomous functions define the selection of genes that lead to bone metastasis development.

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Section: Discussionmentioning

confidence: 73%

Identification of NOG as a Specific Breast Cancer Bone Metastasis-supporting Gene

Tarragona

Pavlović

Arnal-Estapé

et al. 2012

Journal of Biological Chemistry

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“…In particular, tumor cell activation of osteoclasts via the ''vicious cycle'' of secretion of PTHrP or RANK ligand has been implicated in bone resorption (4,19,42). However, we previously hypothesized that the balance of bone deposition and resorption could be altered as well by reducing osteoblast number or differentiation and/or activity (33). In vitro coculture of metastatic human breast carcinoma cells or their conditioned medium with human osteoblasts resulted in apoptosis of the osteoblasts (33).…”

Section: Discussionmentioning

confidence: 99%

Kinetics of Metastatic Breast Cancer Cell Trafficking in Bone

Phadke¹,

Mercer

Harms³

et al. 2006

Clinical Cancer Research

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111

132

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Purpose: In vivo studies have focused on the latter stages of the bone metastatic process (osteolysis), whereas little is known about earlier events, e.g., arrival, localization, and initial colonization. Defining these initial steps may potentially identify the critical points susceptible to therapeutic intervention. Experimental Design: MDA-MB-435 human breast cancer cells engineered with green fluorescent protein were injected into the cardiac left ventricle of athymic mice. Femurs were analyzed by fluorescence microscopy, immunohistochemistry, real-time PCR, flow cytometry, and histomorphometry at times ranging from 1hour to 6 weeks. Results: Single cells were found in distal metaphyses at 1 hour postinjection and remained as single cells up to 72 hours. Diaphyseal arrest occurred rarely and few cells remained there after 24 hours. At 1week, numerous foci (2-10 cells) were observed, mostly adjacent to osteoblast-like cells. By 2 weeks, fewer but larger foci (z50 cells) were seen. Most bones had a single large mass at 4 weeks (originating from a colony or coalescing foci) which extended into the diaphysis by 4 to 6 weeks. Little change (<20%) in osteoblast or osteoclast numbers was observed at 2 weeks, but at 4 to 6 weeks, osteoblasts were dramatically reduced (8% of control), whereas osteoclasts were reduced modestly (to f60% of control). Conclusions: Early arrest in metaphysis and minimal retention in diaphysis highlight the importance of the local milieu in determining metastatic potential.These results extend the Seed and Soil hypothesis by demonstrating both intertissue and intratissue differences governing metastatic location. Ours is the first in vivo evidence that tumor cells influence not only osteoclasts, as widely believed, but also eliminate functional osteoblasts, thereby restructuring the bone microenvironment to favor osteolysis.The data may also explain why patients receiving bisphosphonates fail to heal bone despite inhibiting resorption, implying that concurrent strategies that restore osteoblast function are needed to effectively treat osteolytic bone metastases.Breast cancer has a remarkable predilection to colonize bone, with an incidence between 70% and 85% in patients (1-3). At the time of death, metastatic bone disease accounts for the bulk of tumor burden (4). For women with bone metastases, the complications-severe, often intractable pain, pathologic fractures, and hypercalcemia-are catastrophic. Despite its obvious clinical importance, very little is understood about the fundamental mechanisms responsible for breast cancer metastasis to bone. Research progress has been hampered by the dearth of, and technical difficulties inherent in, the current models.Most models of metastasis poorly recapitulate the pathogenesis of breast cancer. The ideal model would involve dissemination from an orthotopic site (i.e., mammary fat pad), colonization, and osteolysis. None of the currently available human breast xenograft models spread to bone following orthotopic implantation and only on...

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Section: Discussionmentioning

confidence: 99%

The Role of Osteoblast-Derived Cytokines in Bone Metastatic Breast Cancer

Bussard¹

2007

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Public reporting burden for this collection of information is estimated to average 1 hour per response, including the time for reviewing instructions, searching existing data sources, gathering and maintaining the data needed, and completing and reviewing this collection of information. Send comments regarding this burden estimate or any other aspect of this collection of information, including suggestions for reducing this burden to Department of Defense, Washington Headquarters Services, Directorate for Information Operations and Reports (0704-0188), 1215 Jefferson Davis Highway, Suite 1204, Arlington, VA 22202-4302. Respondents should be aware that notwithstanding any other provision of law, no person shall be subject to any penalty for failing to comply with a collection of information if it does not display a currently valid OMB control number. PLEASE DO NOT RETURN YOUR FORM TO THE ABOVE ADDRESS. REPORT DATE (DD-MM-YYYY)01/03/07 REPORT TYPE Annual Summary DATES COVERED (From SPONSOR/MONITOR'S REPORT NUMBER(S) DISTRIBUTION / AVAILABILITY STATEMENTApproved for Public Release; Distribution Unlimited SUPPLEMENTARY NOTES ABSTRACT:Breast cancer (BC) metastasizes to bone. It is likely bone provides a hospitable environment that attracts BC cells and allows them to colonize and grow. Current models suggest BC-derived cytokines are key to understanding BC metastasis. We hypothesize that osteoblasts can be directed by metastatic BC cells to produce cytokines that are chemoattractants for osteoclasts and cancer cells, and growth or maintenance factors for BC cells. Our purpose is to determine how osteoblast-derived cytokines influence BC metastases to bone. Goals include investigating the production of osteoblast-derived cytokines in response to BC cells or their conditioned medium (CM), the production of bone-derived cytokines in response to BC cells in vivo, and the presence of functional cytokine receptors on osteoblasts and BC cells. Using murine osteoblasts, and human metastatic BC and non-metastatic cells, we found that BC CM treatment increased osteoblast-derived cytokine secretion of IL-6, KC, VEGF, MIP-2, and MCP-1. Maximum induction of osteoblast-derived cytokine secretion occurred with 20 day old cells. Treatment with CM of a bone-seeking cancer variant enhanced osteoblast-derived cytokine production at Day 20. Murine-specific ELISAs showed osteoblast-derived cytokine secretion to MDA-231 variant CM was dose-dependent. No significant changes in osteoblast-derived cytokine secretion were observed in 4 day old cells.

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Breast cancer cells induce osteoblast apoptosis: A possible contributor to bone degradation

Cited by 79 publications

References 36 publications

Identification of NOG as a Specific Breast Cancer Bone Metastasis-supporting Gene

Identification of NOG as a Specific Breast Cancer Bone Metastasis-supporting Gene

Kinetics of Metastatic Breast Cancer Cell Trafficking in Bone

The Role of Osteoblast-Derived Cytokines in Bone Metastatic Breast Cancer

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