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Tumor Biology

, Volume 35, Issue 1, pp 791–798 | Cite as

Cytokines in osteoblast-conditioned medium promote the migration of breast cancer cells

  • Xiaojia Chen
  • Jia Lu
  • Yuhua Ji
  • An Hong
  • Qiuling Xie
Research Article

Abstract

Bone is one of the most common metastatic sites for breast cancer. In this study, we observed a promoting effect of osteoblast-conditioned medium (OCM) on the migration of MCF-7, a noninvasive cell line of breast cancer cells. Cytokine antibody array was used to compare the cytokines of OCM with the conditioned medium of non-differentiated osteoblast cells, which consequently revealed factors related to migration, such as IL8, IL6, CSF2 (G-CSF), CSF3 (GM-CSF), and TNFRSF11B (osteoprotegerin). The expression of genes related to migration was also estimated with a PCR array, which showed that 9 genes were upregulated and 26 genes downregulated. Moreover, activated p38, ERK, and AKT pathways were found in the OCM treatment group. This finding indicated the migration ability of breast cancer cells, which move toward the bone depending on the presence of specific cytokines in its surrounding microenvironment.

Keywords

Cytokines Osteoblast-conditioned medium (OCM) Breast cancer Bone microenvironment 

Abbreviations

OCM

Differentiated osteoblast-conditioned medium

CM

Undifferentiated osteoblast-conditioned medium

Notes

Acknowledgments

The authors thank Prof. Binqian Shen for the revisions on our paper. This work was supported by the Project of Production, Education and Research of Guangdong Province (2010B090400500) and the 211 Grant of the Ministry of Education of China. The funding agencies had no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript.

References

  1. 1.
    McKnight DAC, Sosnoski DM, Koblinski JE, Gay CV. Roles of osteonectin in the migration of breast cancer cells into bone. Journal of Cellular Biochemistry. 2006;97:288–302.CrossRefGoogle Scholar
  2. 2.
    Mundy GR. Metastasis: metastasis to bone: causes, consequences and therapeutic opportunities. Nature Reviews Cancer. 2002;2:584–93.PubMedCrossRefGoogle Scholar
  3. 3.
    Shan H, Takahashi T, Bando Y, Izumi K, Uehara H. Inhibitory effect of soluble platelet-derived growth factor receptor β on intraosseous growth of breast cancer cells in nude mice. Cancer Science. 2011;102:1904–10.PubMedCrossRefGoogle Scholar
  4. 4.
    Roodman GD. Mechanisms of bone metastasis. New England Journal of Medicine. 2004;350:1655–64.PubMedCrossRefGoogle Scholar
  5. 5.
    Tang CH, Chuang JY, Fong YC, Maa MC, Way TD, Hung CH. Bone-derived SDF-1 stimulates IL-6 release via CXCR4, ERK and NF-κB pathways and promotes osteoclastogenesis in human oral cancer cells. Carcinogenesis. 2008;29:1483–92.PubMedCrossRefGoogle Scholar
  6. 6.
    Mundy GR, Yoneda T. Facilitation and suppression of bone metastasis. Clin Orthop. 1995;312:34–44.PubMedGoogle Scholar
  7. 7.
    Thomas RJ, Guise T, Yin JJ, Elliott J, Horwood NJ, Martin TJ, et al. Breast cancer cells interact with osteoblasts to support osteoclast formation. Endocrinology. 1999;140:4451–8.PubMedGoogle Scholar
  8. 8.
    Kakonen S-M, Mundy GR. Mechanisms of osteolytic bone metastases in breast carcinoma. Cancer. 2003;97:834–9.PubMedCrossRefGoogle Scholar
  9. 9.
    Vurusaner B, Poli G, Basaga H. Tumor suppressor genes and ROS: complex networks of interactions. Free Radic Biol Med. 2012;52:7–18.PubMedCrossRefGoogle Scholar
  10. 10.
    Wei Y-Y, Chen Y-J, Hsiao Y-C, Huang Y-C, Lai T-H, Tang C-H. Osteoblasts-derived TGF-β1 enhance motility and integrin upregulation through Akt, ERK, and NF-κB-dependent pathway in human breast cancer cells. Molecular Carcinogenesis. 2008;47:526–37.PubMedCrossRefGoogle Scholar
  11. 11.
    Hanahan D, Weinberg RA. The hallmarks of cancer. Cell. 2000;100:57–70.PubMedCrossRefGoogle Scholar
  12. 12.
    Liu C, Dalby B, Chen W, Kilzer JM, Chiou HC. Transient transfection factors for high-level recombinant protein production in suspension cultured mammalian cells. Molecular Biotechnology. 2008;39:141–53.PubMedCrossRefGoogle Scholar
  13. 13.
    Makuch LA, Sosnoski DM, Gay CV. Osteoblast-conditioned media influence the expression of E-selectin on bone-derived vascular endothelial cells. Journal of Cellular Biochemistry. 2006;98:1221–9.PubMedCrossRefGoogle Scholar
  14. 14.
    Brama M, Basciani S, Cherubini S, Mariani S, Migliaccio S, Arizzi M, et al. Osteoblast-conditioned medium promotes proliferation and sensitizes breast cancer cells to imatinib treatment. Endocrine Related Cancer. 2007;14:61–72.PubMedCrossRefGoogle Scholar
  15. 15.
    Lai T-H, Fong Y-C, Fu W-M, Yang R-S, Tang C-H. Osteoblasts-derived BMP-2 enhances the motility of prostate cancer cells via activation of integrins. The Prostate. 2008;68:1341–53.PubMedCrossRefGoogle Scholar
  16. 16.
    Fong Y-C, Maa M-C, Tsai F-J, Chen W-C, Lin J-G, Jeng L-B, et al. Osteoblast-derived TGF-β1 stimulates IL-8 release through AP-1 and NF-κB in human cancer cells. Journal of Bone and Mineral Research. 2008;23:961–70.PubMedCrossRefGoogle Scholar
  17. 17.
    Nannuru KC, Sharma B, Varney ML, Singh RK. Role of chemokine receptor CXCR2 expression in mammary tumor growth, angiogenesis and metastasis. J Carcinog. 2011;10:40.PubMedCentralPubMedCrossRefGoogle Scholar
  18. 18.
    Soikkeli J, Podlasz P, Yin M, Nummela P, Jahkola T, Virolainen S, et al. Metastatic outgrowth encompasses COL-I, FN1, and POSTN up-regulation and assembly to fibrillar networks regulating cell adhesion, migration, and growth. Am J Pathol. 2010;177:387–403.PubMedCrossRefGoogle Scholar
  19. 19.
    Zeng G, Cai S, Liu Y, Wu GJ. METCAM/MUC18 augments migration, invasion, and tumorigenicity of human breast cancer SK-BR-3 cells. Gene. 2012;492:229–38.PubMedCrossRefGoogle Scholar
  20. 20.
    Poettler M, Unseld M, Mihaly-Bison J, Uhrin P, Koban F, Binder BR, et al. The urokinase receptor (CD87) represents a central mediator of growth factor-induced endothelial cell migration. Thromb Haemost. 2012;108:357–66.PubMedCrossRefGoogle Scholar
  21. 21.
    Christgen M, Bruchhardt H, Ballmaier M, Krech T, Langer F, Kreipe H, et al. KAI1/CD82 is a novel target of estrogen receptor-mediated gene repression and downregulated in primary human breast cancer. Int J Cancer. 2008;123:2239–46.PubMedCrossRefGoogle Scholar
  22. 22.
    Cho SG, Li D, Stafford LJ, Luo J, Rodriguez-Villanueva M, Wang Y, et al. KiSS1 suppresses TNFalpha-induced breast cancer cell invasion via an inhibition of RhoA-mediated NF-kappaB activation. J Cell Biochem. 2009;107:1139–49.PubMedCentralPubMedCrossRefGoogle Scholar
  23. 23.
    Mahabeleshwar GH, Kundu GC. Syk, a protein-tyrosine kinase, suppresses the cell motility and nuclear factor kappa b-mediated secretion of urokinase type plasminogen activator by inhibiting the phosphatidylinositol 3′-kinase activity in breast cancer cells. J Biol Chem. 2003;278:6209–21.PubMedCrossRefGoogle Scholar
  24. 24.
    Palena C, Hamilton DH, Fernando RI. Influence of IL-8 on the epithelial-mesenchymal transition and the tumor microenvironment. Future Oncol. 2012;8:713–22.PubMedCentralPubMedCrossRefGoogle Scholar
  25. 25.
    Lei X, Pathak SP, Fukumura D. Hypoxia-induced activation of p38 mitogen-activated protein kinase and phosphatidylinositol 3′-kinase signaling pathways contributes to expression of interleukin 8 in human ovarian carcinoma cells. Clinical Cancer Research. 2004;10:701–7.CrossRefGoogle Scholar
  26. 26.
    Benoy IH. Increased serum interleukin-8 in patients with early and metastatic breast cancer correlates with early dissemination and survival. Clinical Cancer Research. 2004;10:7157–62.PubMedCrossRefGoogle Scholar
  27. 27.
    Veltri RW, Miller MC, Zhao G, NG A, Marley GM, Wright GL, et al. Interleukin-8 serum levels in patients with benigh prostatic hyperplasia and prostate cancer. UROLOGY. 1999;53:139–47.PubMedCrossRefGoogle Scholar
  28. 28.
    Xu L, Fidler IJ. Acidic pH-induced elevation in interleukin 8 expression by human ovarian carcinoma cells. Cancer Research. 2000;60:4610–6.PubMedGoogle Scholar
  29. 29.
    Singh RK, Gutman M, Radinsky R, Bucana CD, FidIer IJ. Expression of interleukin 8 correlates with the metastatic potential of human melanoma cells in nude mice. Cancer Research. 1994;54:3242–7.PubMedGoogle Scholar
  30. 30.
    Brat DJ, Bellai AC, Meir EGV. The role of interleukin-8 and its receptors in gliomagenesis and tumoral angiogenesis. Neuro-Oncology. 2005;7:122–33.PubMedCentralPubMedCrossRefGoogle Scholar
  31. 31.
    Tedgui A, Mallat Z. Cytokines in atherosclerosis: pathogenic and regulatory pathways. Physiol Rev. 2006;86:515–81.PubMedCrossRefGoogle Scholar
  32. 32.
    Inoue K, Slaton JW, Kim SJ, Perrotte P, Eve BY, Bar-Eli M, et al. Interleukin 8 expression regulates tumorigenicity and metastasis in human bladder cancer. Cancer Research. 2000;60:2290–9.PubMedGoogle Scholar
  33. 33.
    De Larco JE. The potential role of neutrophils in promoting the metastatic phenotype of tumors releasing interleukin-8. Clinical Cancer Research. 2004;10:4895–900.PubMedCrossRefGoogle Scholar
  34. 34.
    Luca M, Huang S, Gershenwald JE, Singh RK, Reicht R, Bar-Eli M. Expression of interleukin-8 by human melanoma cells up-regulates MMP-2 activity and increases tumor growth and metastasis. American Journal of Pathology. 1997;151:1105–13.PubMedGoogle Scholar
  35. 35.
    Yatsunamia J, Tsurutaa N, Ogataa K, Wakamatsua K, Takayamaa K, Kawasakia M, et al. Interleukin-8 participates in angiogenesis in non-small cell, but not small cell carcinoma of the lung. Cancer Letters. 1997;120:101–8.CrossRefGoogle Scholar
  36. 36.
    Araki S, Omori Y, Lyn D, Singh RK, Meinbach DM, Sandman Y, et al. Interleukin-8 is a molecular determinant of androgen independence and progression in prostate cancer. Cancer Research. 2007;67:6854–62.PubMedCrossRefGoogle Scholar
  37. 37.
    Yao C, Lin Y, Chua M-S, Ye C-S, Bi J, Li W, et al. Interleukin-8 modulates growth and invasiveness of estrogen receptor-negative breast cancer cells. International Journal of Cancer. 2007;121:1949–57.CrossRefGoogle Scholar
  38. 38.
    Chaudhary LR, Avioli LV. Dexamethasone regulates IL-1β and TNF-α induced interleukin-8 production in human bone marrow stromal and osteoblast-like cells. Calcif Tissue Int. 1994;55:16–20.PubMedCrossRefGoogle Scholar
  39. 39.
    Collin-Osdoby RL, Chen Y, Sunyer T, Chaudhary L, Tsay A, Goldring S, et al. Human osteoclasts and osteoclastlike cells synthesize and release high basal and inflammatory stimulated levels of the potent chemokine interleukin-8. Endocrinology. 1998;139:4353–63.PubMedGoogle Scholar
  40. 40.
    Bronner F, Farach-Carson MC. Inflammatory cytokines and their role in bone metastasis and osteolysis. Bone and Cancer. 2009;5:141–55.Google Scholar
  41. 41.
    Nishizuka I, Ishikawa T, Hamaguchi Y, Kamiyama M, Ichikawa Y, Kadota K, et al. Analysis of gene expression involved in brain metastasis from breast cancer using CDNA microarray. Breast Cancer. 2002;9:26–32.PubMedCrossRefGoogle Scholar
  42. 42.
    Waugh DJJ, Wilson C. The interleukin-8 pathway in cancer. Clinical Cancer Research. 2008;14:6735–41.PubMedCrossRefGoogle Scholar
  43. 43.
    Santini D, Schiavon G, Vincenzi B, Gaeta L, Pantano F, Russo A, et al. Receptor activator of NF-kB (RANK) expression in primary tumors associates with bone metastasis occurrence in breast cancer patients. PLoS One. 2011;6:1–9.Google Scholar
  44. 44.
    Eubank TD, Roberts RD, Khan M, Curry JM, Nuovo GJ, Kuppusamy P, et al. Granulocyte macrophage colony-stimulating factor inhibits breast cancer growth and metastasis by invoking an anti-angiogenic program in tumor-educated macrophages. Cancer Research. 2009;69:2133–40.PubMedCentralPubMedCrossRefGoogle Scholar
  45. 45.
    Kohn EC, Hollister GH, DiPersio JD, Wahl S, Liotta LA, Schiffmann E. Granulocyte–macrophage colony-stimulating factor induces human melanoma-cell migration. Int J Cancer. 1993;53:968–72.PubMedCrossRefGoogle Scholar
  46. 46.
    Jiang W, Xiang C, Cazacu S, Brodie C, Mikkelsen T. Insulin-like growth factor binding protein 7 mediates glioma cell growth and migration. Neoplasia. 2008;10:1335–42.PubMedCentralPubMedGoogle Scholar
  47. 47.
    Amemiya Y, Yang W, Benatar T, Nofech-Mozes S, Yee A, Kahn H, et al. Insulin like growth factor binding protein-7 reduces growth of human breast cancer cells and xenografted tumors. Breast Cancer Research and Treatment. 2011;126:373–84.PubMedCrossRefGoogle Scholar

Copyright information

© International Society of Oncology and BioMarkers (ISOBM) 2013

Authors and Affiliations

  • Xiaojia Chen
    • 1
    • 2
  • Jia Lu
    • 1
    • 2
  • Yuhua Ji
    • 1
    • 2
  • An Hong
    • 1
    • 2
  • Qiuling Xie
    • 1
    • 2
  1. 1.Guangdong Provincial Key Laboratory of Bioengineering MedicineGuangzhouChina
  2. 2.China National Engineering Research Center of Genetic MedicineGuangzhouChina

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