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Fibroblasts Isolated from Common Sites of Breast Cancer Metastasis Enhance Cancer Cell Growth Rates and Invasiveness in an Interleukin-6–Dependent Manner

¹ Center for Childhood Cancer, Children's Research Institute; ² Department of Veterinary Biosciences, College of Veterinary Medicine, ³ Integrated Biomedical Science Graduate Program, Department of Pediatrics, School of Medicine and Public Health, and ⁴ Department of Molecular Virology, Immunology, and Medical Genetics, Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio; ⁵ Center for Applied Biomedical Research, St. Orsola-Malpighi University Hospital, ⁶ Department of Experimental Pathology, ⁷ Department of Pharmacology and Toxicology, and ⁸ Departments of Experimental and Evolutionary Biology, University of Bologna, Bologna, Italy; ⁹ Department of Life Science, National Chung Cheng University, Chia-Yi, Taiwan, Republic of China; and ¹⁰ Department of Blood and Bone Marrow Transplantation, University of Texas M. D. Anderson Cancer Center, Houston, Texas

Requests for reprints: Brett M. Hall, Center for Childhood Cancer, WA5015, Nationwide Children's Hospital, 700 Children's Drive, Columbus, OH 43205. Phone: 614-355-2650; Fax: 614-722-5895; E-mail: hall.125{at}osu.edu or Massimiliano Bonafé, Department of Experimental Pathology, University of Bologna, Via S. Giacomo 12, 40126 Bologna, Italy. Phone: 39-051-636-4009; Fax: 39-051-636-3902; E-mail: massimiliano.bonafe{at}unibo.it.

Key Words: fibroblast • tumor microenvironment • breast cancer • metastasis • interleukin-6 • seed and soil • three-dimensional

Common sites of breast cancer metastasis include the lung, liver, and bone, and of these secondary metastatic sites, estrogen receptor (ER)–positive breast cancer often favors bone. Within secondary organs, cancer cells would predictably encounter tissue-specific fibroblasts or their soluble factors, yet our understanding of how tissue-specific fibroblasts directly affect cancer cell growth rates and survival remains largely unknown. Therefore, we tested the hypothesis that mesenchymal fibroblasts isolated from common sites of breast cancer metastasis provide a more favorable microenvironment with respect to tumor growth rates. We found a direct correlation between the ability of breast, lung, and bone fibroblasts to enhance ER-positive breast cancer cell growth and the level of soluble interleukin-6 (IL-6) produced by each organ-specific fibroblast, and fibroblast-mediated growth enhancement was inhibited by the removal or inhibition of IL-6. Interestingly, mice coinjected with MCF-7 breast tumor cells and senescent skin fibroblasts, which secrete IL-6, developed tumors, whereas mice coinjected with presenescent skin fibroblasts that produce little to no IL-6 failed to form xenograft tumors. We subsequently determined that IL-6 promoted growth and invasion of breast cancer cells through signal transducer and activator of transcription 3–dependent up-regulation of Notch-3, Jagged-1, and carbonic anhydrase IX. These data suggest that tissue-specific fibroblasts and the factors they produce can promote breast cancer disease progression and may represent attractive targets for development of new therapeutics. [Cancer Res 2008;68(21):9087–95]