Abstract
Prostate cancer (PCa) frequently metastasizes to bone resulting in a mixture of osteolytic and osteoblastic lesions. We have previously reported that monocyte chemotactic protein-1 (MCP-1) is chemotactic for PCa cells, and its receptor, CCR2 expression, correlates with pathological stages. However, the role of MCP-1/CCR2 axis on PCa progression in bone remains unclear. We first evaluated the serum levels of MCP-1 in patients with bone metastases or localized PCa by enzyme-linked immunosorbent assay. We found that MCP-1 levels were elevated in patients with bone metastases compared to localized PCa. We further determined the effects of knockdown CCR2 or MCP-1 on PCa cell invasion and the tumor cell-induced osteoclast activity in vitro, respectively. PCa C4-2B and PC3 cells were transfected stably with either CCR2 short hairpin RNA (shRNA) or a scrambled RNA. CCR2 knockdown significantly diminished the MCP-1-induced PCa cell invasion. In addition, the MCP-1 production was knocked down by MCP-1 shRNA in C4-2B and PC3 cells. Conditioned media (CM) was collected and determined for the CM-induced osteoclast formation in vitro. MCP-1 knockdown significantly decreased the PCa CM-induced osteoclast formation. Finally, MCP-1 knockdown PC3 cells were implanted into the tibia of SCID mice for 4 weeks. Tumor volume was determined by histopathology and bone histomorphometry. MCP-1 knockdown diminished PC3 tumor growth in bone. We concluded that activation of MCP-1/CCR2 axis promotes PCa growth in bone. This study suggests that MCP-1 may be a target for PCa progression.
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Abbreviations
- CM:
-
Conditioned media
- ECL:
-
Enhanced chemiluminescence
- ELISA:
-
Enzyme-linked immunosorbent assay
- H&E:
-
Hematoxylin and eosin
- IL-8:
-
Interleukin-8
- MCP-1:
-
Monocyte chemotactic protein-1
- M-CSF:
-
Macrophage colony-stimulating factor
- PCa:
-
Prostate cancer
- PVDF:
-
Polyvinylidine fluoride
- RANKL:
-
Receptor activator of nuclear factor kappa B ligand
- RT-PCR:
-
Reverse transcriptase-polymerase chain reaction
- SCID:
-
Severe combined immunodeficiency
- shRNA:
-
Short hairpin RNA
- TRAP:
-
Tartrate-resistant acid phosphatase
References
Roodman GD (2004) Mechanisms of bone metastasis. N Engl J Med 350(16):1655–1664. doi:10.1056/NEJMra030831
Keller ET, Zhang J, Cooper CR et al (2001) Prostate carcinoma skeletal metastases: cross-talk between tumor and bone. Cancer Metastasis Rev 20(3–4):333–349. doi:10.1023/A:1015599831232
Yoneda T, Hiraga T (2005) Crosstalk between cancer cells and bone microenvironment in bone metastasis. Biochem Biophys Res Commun 328(3):679–687. doi:10.1016/j.bbrc.2004.11.070
Martin J, Coleman R, Mundy G (2007) VIth meeting on cancer-induced bone disease. Expert Rev Anticancer Ther 7(4):461–464. doi:10.1586/14737140.7.4.461
O’Keefe RJ, and Guise TA (2003) Molecular mechanisms of bone metastasis and therapeutic implications. Clin Orthopaed Relat Res (415, Suppl):S100–S104. doi:10.1097/01.blo.0000093847.72468.2f
Morrissey C, Vessella RL (2007) The role of tumor microenvironment in prostate cancer bone metastasis. J Cell Biochem 101(4):873–886. doi:10.1002/jcb.21214
Taichman RS, Cooper C, Keller ET et al (2002) Use of the stromal cell-derived factor-1/CXCR4 pathway in prostate cancer metastasis to bone. Cancer Res 62(6):1832–1837
Dwinell MB, Eckmann L, Leopard JD et al (1999) Chemokine receptor expression by human intestinal epithelial cells. Gastroenterology 117(2):359–367. doi:10.1053/gast.1999.0029900359
Soejima K, Rollins BJ (2001) A functional IFN-gamma-inducible protein-10/CXCL10-specific receptor expressed by epithelial and endothelial cells that is neither CXCR3 nor glycosaminoglycan. J Immunol (Baltimore:1950) 167(11):6576–6582
Scotton C, Milliken D, Wilson J et al (2001) Analysis of CC chemokine and chemokine receptor expression in solid ovarian tumours. Br J Cancer 85(6):891–897. doi:10.1054/bjoc.2001.2020
Shulby SA, Dolloff NG, Stearns ME et al (2004) CX3CR1-fractalkine expression regulates cellular mechanisms involved in adhesion, migration, and survival of human prostate cancer cells. Cancer Res 64(14):4693–4698. doi:10.1158/0008-5472.CAN-03-3437
Shariat SF, Andrews B, Kattan MW et al (2001) Plasma levels of interleukin-6 and its soluble receptor are associated with prostate cancer progression and metastasis. Urology 58(6):1008–1015. doi:10.1016/S0090-4295(01)01405-4
Inoue K, Slaton JW, Kim SJ et al (2000) Interleukin 8 expression regulates tumorigenicity and metastasis in human bladder cancer. Cancer Res 60(8):2290–2299
Reiland J, Furcht LT, McCarthy JB (1999) CXC-chemokines stimulate invasion and chemotaxis in prostate carcinoma cells through the CXCR2 receptor. The Prostate 41(2):78–88. doi:10.1002/(SICI)1097-0045(19991001)41:2<78::AID-PROS2>3.0.CO;2-P
Lu Y, Cai Z, Galson DL et al (2006) Monocyte chemotactic protein-1 (MCP-1) acts as a paracrine and autocrine factor for prostate cancer growth and invasion. The Prostate 66(12):1311–1318. doi:10.1002/pros.20464
Loberg RD, Ying C, Craig M et al (2007) Targeting CCL2 with systemic delivery of neutralizing antibodies induces prostate cancer tumor regression in vivo. Cancer Res 67(19):9417–9424. doi:10.1158/0008-5472.CAN-07-1286
Muller A, Homey B, Soto H et al (2001) Involvement of chemokine receptors in breast cancer metastasis. Nature 410(6824):50–56. doi:10.1038/35065016
Lu Y, Cai Z, Xiao G et al (2007) CCR2 expression correlates with prostate cancer progression. J Cell Biochem 101(3):676–685. doi:10.1002/jcb.21220
Salcedo R, Ponce ML, Young HA et al (2000) Human endothelial cells express CCR2 and respond to MCP-1: direct role of MCP-1 in angiogenesis and tumor progression. Blood 96(1):34–40
Vande Broek I, Asosingh K, Vanderkerken K et al (2003) Chemokine receptor CCR2 is expressed by human multiple myeloma cells and mediates migration to bone marrow stromal cell-produced monocyte chemotactic proteins MCP-1, -2 and -3. Br J Cancer 88(6):855–862. doi:10.1038/sj.bjc.6600833
Janis K, Hoeltke J, Nazareth M et al (2004) Estrogen decreases expression of chemokine receptors, and suppresses chemokine bioactivity in murine monocytes. Am J Reprod Immunol (New York) 51(1):22–31. doi:10.1046/j.8755-8920.2003.00117.x
Lebrecht A, Hefler L, Tempfer C et al (2001) Serum cytokine concentrations in patients with cervical cancer: interleukin-4, interferon-gamma, and monocyte chemoattractant protein-1. Gynecol Oncol 83(1):170–171. doi:10.1006/gyno.2001.6361
Hefler L, Tempfer C, Heinze G et al (1999) Monocyte chemoattractant protein-1 serum levels in ovarian cancer patients. Br J Cancer 81(5):855–859. doi:10.1038/sj.bjc.6690776
Dwyer RM, Potter-Beirne SM, Harrington KA et al (2007) Monocyte chemotactic protein-1 secreted by primary breast tumors stimulates migration of mesenchymal stem cells. Clin Cancer Res 13(17):5020–5027. doi:10.1158/1078-0432.CCR-07-0731
Koide N, Nishio A, Sato T et al (2004) Significance of macrophage chemoattractant protein-1 expression and macrophage infiltration in squamous cell carcinoma of the esophagus. Am J Gastroenterol 99(9):1667–1674. doi:10.1111/j.1572-0241.2004.30733.x
Lu Y, Xiao G, Galson DL et al (2007) PTHrP-induced MCP-1 production by human bone marrow endothelial cells and osteoblasts promotes osteoclast differentiation and prostate cancer cell proliferation and invasion in vitro. Int J Cancer 121(4):724–733. doi:10.1002/ijc.22704
Zhang J, Dai J, Qi Y et al (2001) Osteoprotegerin inhibits prostate cancer-induced osteoclastogenesis and prevents prostate tumor growth in the bone. J Clin Invest 107(10):1235–1244. doi:10.1172/JCI11685
Zhang J, Dai J, Yao Z et al (2003) Soluble receptor activator of nuclear factor kappaB Fc diminishes prostate cancer progression in bone. Cancer Res 63(22):7883–7890
Lu Y, Cai Z, Xiao G et al (2007) Monocyte chemotactic protein-1 mediates prostate cancer-induced bone resorption. Cancer Res 67(8):3646–3653. doi:10.1158/0008-5472.CAN-06-1210
Loberg RD, Day LL, Harwood J et al (2006) CCL2 is a potent regulator of prostate cancer cell migration and proliferation. Neoplasia (New York) 8(7):578–586. doi:10.1593/neo.06280
Conti I, Rollins BJ (2004) CCL2 (monocyte chemoattractant protein-1) and cancer. Semin Cancer Biol 14(3):149–154. doi:10.1016/j.semcancer.2003.10.009
Youngs SJ, Ali SA, Taub DD et al (1997) Chemokines induce migrational responses in human breast carcinoma cell lines. Int J Cancer 71(2):257–266. doi:10.1002/(SICI)1097-0215(19970410)71:2<257::AID-IJC22>3.0.CO;2-D
Bottazzi B, Colotta F, Sica A et al (1990) A chemoattractant expressed in human sarcoma cells (tumor-derived chemotactic factor, TDCF) is identical to monocyte chemoattractant protein-1/monocyte chemotactic and activating factor (MCP-1/MCAF). Int J Cancer 45(4):795–797. doi:10.1002/ijc.2910450436
Mantovani A, Sozzani S, Bottazzi B et al (1993) Monocyte chemotactic protein-1 (MCP-1): signal transduction and involvement in the regulation of macrophage traffic in normal and neoplastic tissues. Adv Exp Med Biol 351:47–54
Mantovani A, Allavena P, Sica A (2004) Tumour-associated macrophages as a prototypic type II polarised phagocyte population: role in tumour progression. Eur J Cancer 40(11):1660–1667. doi:10.1016/j.ejca.2004.03.016
Kinder M, Chislock E, Bussard KM et al (2008) Metastatic breast cancer induces an osteoblast inflammatory response. Exp Cell Res 314(1):173–183. doi:10.1016/j.yexcr.2007.09.021
Taichman RS, Loberg RD, Mehra R et al (2007) The evolving biology and treatment of prostate cancer. J Clin Invest 117(9):2351–2361. doi:10.1172/JCI31791
Acknowledgments
The authors thank Dr. G. David Roodman for his helpful discussion, Dr. Zhong Cai for his technical help, and Mrs. Donna Gaspich for her editing. This study was supported by Department of Defense PC061231 and University of Pittsburgh Cancer Institute CCSG (J. Zhang).
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Lu, Y., Chen, Q., Corey, E. et al. Activation of MCP-1/CCR2 axis promotes prostate cancer growth in bone. Clin Exp Metastasis 26, 161–169 (2009). https://doi.org/10.1007/s10585-008-9226-7
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DOI: https://doi.org/10.1007/s10585-008-9226-7