This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Phadke, P. A. Articles by Welch, D. R. Search for Related Content PubMed PubMed Citation Articles by Phadke, P. A. Articles by Welch, D. R.

Kinetics of Metastatic Breast Cancer Cell Trafficking in Bone

Authors' Affiliations: Departments of ¹ Pathology and ² Medicine-Hematology/Oncology, ³ Comprehensive Cancer Center, ⁴ Center for Metabolic Bone Disease, ⁵ National Foundation for Cancer Research, Center for Metastasis Research, University of Alabama at Birmingham, Birmingham, Alabama, and ⁶ Department of Biochemistry and Molecular Biology, Pennsylvania State University, University Park, Pennsylvania

Requests for reprints: Danny R. Welch, Department of Pathology, University of Alabama at Birmingham, Volker Hall G-019A, 1670 University Boulevard, Birmingham, AL 35294-0019. Phone: 205-934-2961; Fax: 205-975-1126; E-mail: DanWelch{at}uab.edu.

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 1 hour 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 1 week, numerous foci (2-10 cells) were observed, mostly adjacent to osteoblast-like cells. By 2 weeks, fewer but larger foci (50 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 60% 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.

This article has been cited by other articles:

				D. R. Hurst, Y. Xie, K. S. Vaidya, A. Mehta, B. P. Moore, M. A. Accavitti-Loper, R. S. Samant, R. Saxena, A. C. Silveira, and D. R. Welch Alterations of BRMS1-ARID4A Interaction Modify Gene Expression but Still Suppress Metastasis in Human Breast Cancer Cells J. Biol. Chem., March 21, 2008; 283(12): 7438 - 7444. [Abstract] [Full Text] [PDF]

				P. A. Phadke, K. S. Vaidya, K. T. Nash, D. R. Hurst, and D. R. Welch BRMS1 Suppresses Breast Cancer Experimental Metastasis to Multiple Organs by Inhibiting Several Steps of the Metastatic Process Am. J. Pathol., March 1, 2008; 172(3): 809 - 817. [Abstract] [Full Text] [PDF]

				J. Zhu, X. Jia, G. Xiao, Y. Kang, N. C. Partridge, and L. Qin IMPLICATIONS FOR OSTEOLYTIC BONE METASTASES J. Biol. Chem., September 14, 2007; 282(37): 26656 - 26664. [Abstract] [Full Text] [PDF]

				M. A. Watson, L. R. Ylagan, K. M. Trinkaus, W. E. Gillanders, M. J. Naughton, K. N. Weilbaecher, T. P. Fleming, and R. L. Aft Isolation and Molecular Profiling of Bone Marrow Micrometastases Identifies TWIST1 as a Marker of Early Tumor Relapse in Breast Cancer Patients Clin. Cancer Res., September 1, 2007; 13(17): 5001 - 5009. [Abstract] [Full Text] [PDF]

				K. T. Nash, P. A. Phadke, J.-M. Navenot, D. R. Hurst, M. A. Accavitti-Loper, E. Sztul, K. S. Vaidya, A. R. Frost, J. C. Kappes, S. C. Peiper, et al. Requirement of KISS1 Secretion for Multiple Organ Metastasis Suppression and Maintenance of Tumor Dormancy J Natl Cancer Inst, February 21, 2007; 99(4): 309 - 321. [Abstract] [Full Text] [PDF]