Submitted in partial fulfillment of the Ph.D. thesis requirement of The Pennsylvania State University's Graduate Program in Pathobiology.
Osteoblasts are a major source of inflammatory cytokines in the tumor microenvironment of bone metastatic breast cancer
Article first published online: 3 AUG 2010
Copyright © 2010 Wiley-Liss, Inc.
Journal of Cellular Biochemistry
Volume 111, Issue 5, pages 1138–1148, 1 December 2010
How to Cite
Bussard, K. M., Venzon, D. J. and Mastro, A. M. (2010), Osteoblasts are a major source of inflammatory cytokines in the tumor microenvironment of bone metastatic breast cancer. J. Cell. Biochem., 111: 1138–1148. doi: 10.1002/jcb.22799
- Issue published online: 29 NOV 2010
- Article first published online: 3 AUG 2010
- Manuscript Accepted: 28 JUL 2010
- Manuscript Received: 27 JUL 2010
- U.S. Army Medical and Material Research Command Breast Cancer Program. Grant Numbers: DAMD 17-02-1-0358, W81XWH-06-1-0432, W81XWH-06-1-0363
- National Foundation for Cancer Research, Center for Metastasis Research
- The Susan G. Komen Breast Cancer Foundation. Grant Numbers: BCTR0601044, BCTR104406
- breast cancer;
Metastatic breast cancer cells co-opt the cells of the bone to increase their production of inflammatory cytokines. Here, we sought to identify key cytokines expressed by osteoblasts in vitro and in vivo in the presence of MDA-MB-231 metastatic breast cancer cells, including a bone-seeking variant. We hypothesized that osteoblast-derived cytokines increase in the presence of metastatic breast cancer cell conditioned medium (CM), act as chemoattractants for cancer cells, and enhance osteoclast formation. We detected increases in the concentrations of osteoblast-derived IL-6, MCP-1, VEGF, MIP-2, and KC in vitro in culture supernatants from MC3T3-E1 cells in the presence of metastatic breast cancer cell CM and from cancer-bearing femurs ex vivo. A comparison of cancer cell- and osteoblast-derived cytokines revealed that while breast cancer cells expressed the same or equivalent cytokines as the osteoblasts, the breast cancer cells only produced picogram quantities of MCP-1; osteoblasts expressed nanogram amounts. Bone-derived MCP-1 increased in the proximal metaphysis, an area where breast cancer cells preferentially trafficked following intracardiac inoculation in athymic mice. An MDA-MB-231 bone-seeking variant was not different from parental lines. Osteoblast CM was a potent chemoattractant for metastatic breast cancer cells. Furthermore, culture supernatants of osteoblasts treated with breast cancer cell CM enhanced osteoclast formation. These findings suggest that bone metastatic breast cancer cells utilize osteoblast-derived cytokines to facilitate breast cancer cell colonization and survival upon arrival in the bone microenvironment. J. Cell. Biochem. 111: 1138–1148, 2010. © 2010 Wiley-Liss, Inc.