It is commonly accepted that cancer cells interact with host cells to create a microenvironment favoring malignant colonization. The complex bone microenvironment produces an ever changing array of cytokines and growth factors. In this study, we examined levels of MCP-1, IL-6, KC, MIP-2, VEGF, MIG, and eotaxin in femurs of athymic nude mice inoculated via intracardiac injection with MDA-MB- human metastatic breast cancer cells, MDA-MB-231BRMS , a metastasis suppressed variant, or PBS. Animals were euthanized (day 3, 11, 19, 27 after injection) to examine femoral cytokine levels at various stages of cancer cell colonization. The epiphysis contained significantly more cytokines than the diaphysis except for MIG which was similar throughout the bone. Variation among femurs was evident within all groups. By day 27, MCP-1, MIG, VEGF and eotaxin levels were significantly greater in femurs of cancer cell-inoculated mice. These pro-osteoclastic and angiogenic cytokines may manipulate the bone microenvironment to enhance cancer cell colonization. 1. Introduction The colonization and growth of cancer metastases in the bone depends on a cooperative interaction of the cancer cells with the host cells in the bone microenvironment. This microenvironment includes the resident osteoblasts, osteoclasts, endothelial cells, bone-lining cells, stromal cells, hematopoietic stem cells, and transient cells such as macrophages, lymphocytes, neutrophils, and other blood cells. While cell-cell contacts are established between cancer cells and bone cells via adhesion molecules, a wider network of communication occurs through secreted cytokines and growth factors. These soluble molecules play a critical role in the normal bone remodeling process as well as in cancer cell colonization of the bone marrow. The interplay of the cancer cells with the cells of the bone marrow cavity has been described in terms of a vicious cycle [1]. In brief, cytokines or growth factors secreted by invading cancer cells (e.g., parathyroid hormone-related protein, PTHrP) act to stimulate osteoblasts to produce more receptor activator of nuclear factor kappa-B ligand (RANKL) and less osteoprotegerin (OPG), a decoy receptor for RANKL. The RANKL binds to RANK on osteoclast precursors leading to differentiation and activation of osteoclasts. Activated osteoclasts degrade bone matrix releasing growth factors such as transforming growth factor beta (TGF-β) and insulin-like growth factor (IGF). These molecules, in turn, stimulate further cancer cell growth. This series of events provides an explanation of the
References
[1]
T. A. Guise and G. R. Mundy, “Cancer and bone,” Endocrine Reviews, vol. 19, no. 1, pp. 18–54, 1998.
[2]
R. R. Mercer, C. Miyasaka, and A. M. Mastro, “Metastatic breast cancer cells suppress osteoblast adhesion and differentiation,” Clinical and Experimental Metastasis, vol. 21, no. 5, pp. 427–435, 2004.
[3]
R. R. Mercer and A. M. Mastro, “Cytokines secreted by bone-metastatic breast cancer cells alter the expression pattern of f-actin and reduce focal adhesion plaques in osteoblasts through PI3K,” Experimental Cell Research, vol. 310, no. 2, pp. 270–281, 2005.
[4]
P. A. Phadke, R. R. Mercer, J. F. Harms et al., “Kinetics of metastatic breast cancer cell trafficking in bone,” Clinical Cancer Research, vol. 12, no. 5, pp. 1431–1440, 2006.
[5]
K. M. Bussard, D. J. Venzon, and A. M. Mastro, “Osteoblasts are a major source of inflammatory cytokines in the tumor microenvironment of bone metastatic breast cancer,” Journal of Cellular Biochemistry, vol. 111, no. 5, pp. 1138–1148, 2010.
[6]
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,” American Journal of Pathology, vol. 172, no. 3, pp. 809–817, 2008.
[7]
M. Kinder, E. Chislock, K. M. Bussard, L. Shuman, and A. M. Mastro, “Metastatic breast cancer induces an osteoblast inflammatory response,” Experimental Cell Research, vol. 314, no. 1, pp. 173–183, 2008.
[8]
H. B. Kwak, S. W. Lee, H. M. Jin et al., “Monokine induced by interferon-γ is induced by receptor activator of nuclear factor κB ligand and is involved in osteoclast adhesion and migration,” Blood, vol. 105, no. 7, pp. 2963–2969, 2005.
[9]
Z. A. Dehqanzada, C. E. Storrer, M. T. Hueman et al., “Assessing serum cytokine profiles in breast cancer patients receiving a HER2/neu vaccine using Luminex technology,” Oncology Reports, vol. 17, no. 3, pp. 687–694, 2007.
[10]
Y. Cao, T. Luetkens, S. Kobold et al., “The cytokine/chemokine pattern in the bone marrow environment of multiple myeloma patients,” Experimental Hematology, vol. 38, no. 10, pp. 860–867, 2010.
[11]
B. P. Schneider and K. D. Miller, “Angiogenesis of breast cancer,” Journal of Clinical Oncology, vol. 23, no. 8, pp. 1782–1790, 2005.
[12]
R. D. Rubens and G. R. Mundy, Cancer and the Skeleton, Martin Dunitz Ltd, London, UK, 2000.
[13]
G. Lisignoli, S. Toneguzzi, A. Piacentini et al., “Recruitment and Proliferation of T Lymphocytes Is Supported by IFNγ- and TNFα-Activated Human Osteoblasts: involvement of CD54 (ICAM-1) and CD106 (VCAM-1) Adhesion Molecules and CXCR3 Chemokine Receptor,” Journal of Cellular Physiology, vol. 198, no. 3, pp. 388–398, 2004.
[14]
L. Penolazzi, E. Lambertini, E. Tavanti et al., “Evaluation of chemokine and cytokine profiles in osteoblast progenitors from umbilical cord blood stem cells by BIO-PLEX technology,” Cell Biology International, vol. 32, no. 2, pp. 320–325, 2008.
[15]
B. J. Votta, J. R. White, R. A. Dodds et al., “CKβ-8 [CCL23], a novel CC chemokine, is chemotactic for human osteoclast precursors and is expressed in bone tissues,” Journal of Cellular Physiology, vol. 183, no. 2, pp. 196–207, 2000.
[16]
G. D. Roodman, “Role of stromal-derived cytokines and growth factors in bone metastasis,” Cancer, vol. 97, no. 3, pp. 733–738, 2003.
[17]
E. A. Fritz, T. T. Glant, C. Vermes, J. J. Jacobs, and K. A. Roebuck, “Chemokine gene activation in human bone marrow-derived osteoblasts following exposure to particulate wear debris,” Journal of Biomedical Materials Research—Part A, vol. 77, no. 1, pp. 192–201, 2006.
[18]
I. Marriott, “Osteoblast responses to bacterial pathogens: a previously unappreciated role for bone-forming cells in host defense and disease progression,” Immunologic Research, vol. 30, no. 3, pp. 291–308, 2004.
[19]
R. Salcedo, H. A. Young, M. L. Ponce et al., “Eotaxin (CCL11) induces in vivo angiogenic responses by human CCR3+ endothelial cells,” Journal of Immunology, vol. 166, no. 12, pp. 7571–7578, 2001.
[20]
M. J. Voss, M. F. M？ller, D. G. Powe, B. Niggemann, K. S. Z？nker, and F. Entschladen, “Luminal and basal-like breast cancer cells show increased migration induced by hypoxia, mediated by an autocrine mechanism,” BMC Cancer, vol. 11, pp. 158–169, 2011.
[21]
G. R. Mundy, “Metastasis to bone: causes, consequences and therapeutic opportunities,” Nature Reviews Cancer, vol. 2, no. 8, pp. 584–593, 2002.
[22]
A. Müller, B. Homey, H. Soto et al., “Involvement of chemokine receptors in breast cancer metastasis,” Nature, vol. 410, no. 6824, pp. 50–56, 2001.
[23]
A. Taherian, X. Li, Y. Liu, and T. A. Haas, “Differences in integrin expression and signaling within human breast cancer cells,” BMC Cancer, vol. 11, pp. 293–307, 2011.
[24]
S. Y. Shin, J. S. Nam, Y. Lim, and Y. H. Lee, “TNFα-exposed bone marrow-derived mesenchymal stem cells promote locomotion of MDA-MB-231 breast cancer cells through transcriptional activation of CXCR3 ligand chemokines,” The Journal of Biological Chemistry, vol. 285, no. 40, pp. 30731–30740, 2010.
[25]
K. Fitzgerald, L. O'Neill, A. Gearing, and R. Callard, The Cytokine Facts Book, Academic Press, New York, NY, USA, 2001.
