Abstract
The paradigm of cancer development and metastasis is a comprehensive, complex series of events that ultimately reflects a coordinated interaction between the tumor cell and the microenvironment within which the tumor cell resides. Despite the realization that this relationship has changed the current paradigm of cancer research, the struggle continues to more completely understand the pathogenesis of the disease and the ability to appropriately identify and design novel targets for therapy. A particular area of research that has added a significant understanding to cancer metastasis is the role of chemokines and chemokine receptors. Here we review the current concepts of CCL2 (monoctye chemoattractant protein 1) and its role in tumor metastasis with particular interest to its role in the development of bone metastases.
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Paget, S. (1989). The distribution of secondary growths in cancer of the breast. 1889. Cancer Metastasis Reviews, 8(2), 98–101.
Loberg, R. D., Gayed, B. A., Olson, K. B., & Pienta, K. J. (2005). A paradigm for the treatment of prostate cancer bone metastases based on an understanding of tumor cell–microenvironment interactions. Journal of Cellular Biochemistry, 96(3), 439–446.
Shah, R. B., Mehra, R., Chinnaiyan, A. M., Shen, R., Ghosh, D., Zhou, M., et al. (2004). Androgen-independent prostate cancer is a heterogeneous group of diseases: Lessons from a rapid autopsy program. Cancer Research, 64(24), 9209–9216.
Posner, L. J., Miligkos, T., Gilles, J. A., Carnes, D. L., Taddeo, D. R., & Graves, D. T. (1997). Monocyte chemoattractant protein-1 induces monocyte recruitment that is associated with an increase in numbers of osteoblasts. Bone, 21(4):321–327.
Zheng, M. H., Fan, Y., Smith, A., Wysocki, S., Papadimitriou, J. M., & Wood, D. J. (1998). Gene expression of monocyte chemoattractant protein-1 in giant cell tumors of bone osteoclastoma: Possible involvement in CD68+ macrophage-like cell migration. Journal of Cellular Biochemistry, 70(1), 121–129.
Uguccioni, M., Loetscher, P., Forssmann, U., Dewald, B., Li, H., Lima, S. H., et al. (1996). Monocyte chemotactic protein 4 (MCP-4), a novel structural and functional analogue of MCP-3 and eotaxin. Journal of Experimental Medicine, 183(5):2379–2384.
Schall, T. J. (1991). Biology of the RANTES/SIS cytokine family. Cytokine, 3(3):165–183.
Sarafi, M. N., Garcia-Zepeda, E. A., MacLean, J. A., Charo, I. F., & Luster, A. D. (1997). Murine monocyte chemoattractant protein (MCP)-5: A novel CC chemokine that is a structural and functional homologue of human MCP-1. Journal of Experimental Medicine, 185(1), 99–109.
Van Damme, J., Proost, P., Lenaerts, J. P., & Opdenakker, G. (1992). Structural and functional identification of two human, tumor-derived monocyte chemotactic proteins (MCP-2 and MCP-3) belonging to the chemokine family. Journal of Experimental Medicine, 176(1), 59–65.
Vanderkerken, K., Vande Broek, I., Eizirik, D. L., Van Valckenborgh, E., Asosingh, K., Van Riet, I., et al. (2002). Monocyte chemoattractant protein-1 (MCP-1), secreted by bone marrow endothelial cells, induces chemoattraction of 5T multiple myeloma cells. Clinical & Experimental Metastasis, 19(1), 87–90.
Silvestris, F., Cafforio, P., Calvani, N., & Dammacco, F. (2004). Impaired osteoblastogenesis in myeloma bone disease: Role of upregulated apoptosis by cytokines and malignant plasma cells. British Journal of Haematology, 126(4), 475–486.
Leonard, E. J. (1997). Biological aspects of macrophage-stimulating protein (MSP) and its receptor. Ciba Foundation Symposium, 212, 183–191 (discussion 92–97).
Charo, I. F., Myers, S. J., Herman, A., Franci, C., Connolly, A. J., & Coughlin, S. R. (1994). Molecular cloning and functional expression of two monocyte chemoattractant protein 1 receptors reveals alternative splicing of the carboxyl-terminal tails. Proceedings of the National Academy of Science U.S.A., 91(7), 2752–2756.
Graves, D. T., Jiang, Y., &. Valente, A. J. (1999). The expression of monocyte chemoattractant protein-1 and other chemokines by osteoblasts. Frontier in Bioscience, 4, D571–D580.
Graves, D. T., Jiang, Y., & Valente, A. J. (1999). Regulated expression of MCP-1 by osteoblastic cells in vitro and in vivo. Histology and Histopathology, 14(4), 1347–1354.
Wong, L. M., Myers, S. J., Tsou, C. L., Gosling, J., Arai, H., & Charo, I. F. (1997). Organization and differential expression of the human monocyte chemoattractant protein 1 receptor gene. Evidence for the role of the carboxyl-terminal tail in receptor trafficking. Journal of Biological Chemistry, 272(2), 1038–1045.
Rollins, B. J. (1997). Chemokines. Blood, 90(3), 909–928.
Baggiolini, M., Dewald, B., & Moser, B. (1997). Human chemokines: An update. Annual Review of Immunology, 15, 675–705.
Loberg, R. D., Day, L. L., Harwood, J., Ying, C., St John, L. N., Giles, R., et al. (2006). CCL2 is a potent regulator of prostate cancer cell migration and proliferation. Neoplasia, 8(7), 578–586.
Silvestris, F., Cafforio, P., Tucci, M., Grinello, D., & Dammacco, F. (2003) Upregulation of osteoblast apoptosis by malignant plasma cells: A role in myeloma bone disease. Britist Journal of Haematology, 122(1), 39–52.
Arendt, B. K., Velazquez-Dones, A., Tschumper, R. C., Howell, K. G., Ansell, S. M., Witzig, T. E., & Jelinek, D. F. (2002). Interleukin 6 induces monocyte chemoattractant protein-1 expression in myeloma cells. Leukemia, 16(10), 2142–2147.
Vande Broek, I., Asosingh, K., Vanderkerken, K., Straetmans, N., Van Camp, B., & Van Riet, I. (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. British Journal of Cancer, 88(6), 855–862.
Johrer, K., Janke, K., Krugmann, J., Fiegl, M., & Greil, R. (2004). Transendothelial migration of myeloma cells is increased by tumor necrosis factor (TNF)-alpha via TNF receptor 2 and autocrine up-regulation of MCP-1. Clinical Cancer Research, 10(6), 1901–1910.
Pellegrino, A., Ria, R., Di Pietro, G., Cirulli, T., Surico, G., Pennisi, A., Morabito, F., Ribatti, D., Vacca, A. (2005). Bone marrow endothelial cells in multiple myeloma secrete CXC-chemokines that mediate interactions with plasma cells. British Journal of Haematology, 129(2), 248–256.
Soule, H. D., Vazguez, J., Long, A., Albert, S., & Brennan, M. (1973). A human cell line from a pleural effusion derived from a breast carcinoma. Journal of the National Cancer Institute, 51(5), 1409–1416.
Engel, L. W., Young, N. A., Tralka, T. S., Lippman, M. E., O’Brien, S. J., & Joyce, M. J. (1978). Establishment and characterization of three new continuous cell lines derived from human breast carcinomas. Cancer Research 38(10), 3352–3364.
Youngs, S. J., Ali, S. A., Taub, D. D., & Rees, R. C. (1997). Chemokines induce migrational responses in human breast carcinoma cell lines. International Journal of Cancer, 71(2):257–266.
Keydar, I., Chen, L., Karby, S., Weiss, F. R., Delarea, J., Radu, M., et al. (1975). Establishment and characterization of a cell line of human breast carcinoma origin. European Journal of Cancer, 15(5), 659–670.
Ueno, T., Toi, M., Saji, H., Muta, M., Bando, H., Kuroi, K., et al. (2000). Significance of macrophage chemoattractant protein-1 in macrophage recruitment, angiogenesis, and survival in human breast cancer. Clinical Cancer Research, 6(8), 3282–3289.
Saji, H., Koike, M., Yamori, T., Saji, S., Seiki, M., Matsushima, K., et al. (2001). Significant correlation of monocyte chemoattractant protein-1 expression with neovascularization and progression of breast carcinoma. Cancer, 92(5), 1085–1091.
Lebrecht, A., Grimm, C., Lantzsch, T., Ludwig, E., Hefler, L., Ulbrich, E., et al. (2004). Monocyte chemoattractant protein-1 serum levels in patients with breast cancer. Tumour Biology, 25(1–2), 14–17.
Ferrero, E., Fabbri, M., Poggi, A., Galati, G., Bernasconi, S., & Zocchi, M. R. (1998). Tumor-driven matrix invasion by infiltrating lymphocytes: Involvement of the alpha1 integrin I-domain. European Journal of Immunology, 28(8), 2530–2536.
Amann, B., Perabo, F. G., Wirger, A., Hugenschmidt, H., & Schultze-Seemann, W. (1998). Urinary levels of monocyte chemo-attractant protein-1 correlate with tumour stage and grade in patients with bladder cancer. British Journal of Urology, 82(1), 118–121.
Luciani, M. G., Stoppacciaro, A., Peri, G., Mantovani, A., & Ruco, L. P. (1998). The monocyte chemotactic protein a (MCP-1) and interleukin 8 (IL-8) in Hodgkin’s disease and in solid tumours. Molecular Pathology, 51(5):273–276.
Baier, P. K., Eggstein, S., Wolff-Vorbeck, G., Baumgartner, U., & Hopt, U. T. (2005). Chemokines in human colorectal carcinoma. Anticancer Research, 25(5), 3581–3584.
Lu, Y., Cai, Z., Galson, D. L., Xiao, G., Liu, Y., George, D. E., et al. (2006). Monocyte chemotactic protein-1 (MCP-1) acts as a paracrine and autocrine factor for prostate cancer growth and invasion. Prostate, 66(12), 1311–1318.
Kim, M. S., Day, C. J., & Morrison, N. A. (2005). MCP-1 is induced by receptor activator of nuclear factor-{kappa}B ligand, promotes human osteoclast fusion, and rescues granulocyte macrophage colony-stimulating factor suppression of osteoclast formation. Journal of Biology Chemistry, 280(16), 16163–16169.
Kim, M. S., Day, C. J., Selinger, C. I., Magno, C. L., Stephens, S. R., & Morrison, N. A. (2006). MCP-1-induced human osteoclast-like cells are tartrate-resistant acid phosphatase, NFATc1, and calcitonin receptor-positive but require receptor activator of NFkappaB ligand for bone resorption. Journal of Biology Chemistry, 281(2), 1274–1285.
Kim, M. S., Magno, C. L., Day, C. J., & Morrison, N. A. (2006). Induction of chemokines and chemokine receptors CCR2b and CCR4 in authentic human osteoclasts differentiated with RANKL and osteoclast like cells differentiated by MCP-1 and RANTES. Journal of Cellular Biochemistry, 97(3), 512–518.
Muta, M., Matsumoto, G., Nakashima, E., & Toi, M. (2006). Mechanical analysis of tumor growth regression by the cyclooxygenase-2 inhibitor, DFU, in a Walker256 rat tumor model: importance of monocyte chemoattractant protein-1 modulation. Clinical Cancer Research, 12(1), 264–272.
Broxmeyer, H. E., Pelus, L. M., Kim, C. H., Hangoc, G., Cooper, S., & Hromas, R. (2006). Synergistic inhibition in vivo of bone marrow myeloid progenitors by myelosuppressive chemokines and chemokine-accelerated recovery of progenitors after treatment of mice with ara-C. Experimental Hematology, 34(8), 1069–1077.
Broxmeyer, H. E., Cooper, S., Hangoc, G., & Kim, C. H. (2005). Stromal cell-derived factor-1/CXCL12 selectively counteracts inhibitory effects of myelosuppressive chemokines on hematopoietic progenitor cell proliferation in vitro. Stem Cells and Development, 14(2), 199–203.
Cashman, J. D., Eaves, C. J., Sarris, A. H., & Eaves, A. C. (1998). MCP-1, not MIP-1alpha, is the endogenous chemokine that cooperates with TGF-beta to inhibit the cycling of primitive normal but not leukemic (CML) progenitors in long-term human marrow cultures. Blood, 92(7), 2338–2344.
Xu, Y. X., Talati, B. R., Janakiraman, N., Chapman, R. A., & Gautam, S. C. (1999). Growth factors: Production of monocyte chemotactic protein-1 (MCP-1/JE) by bone marrow stromal cells: Effect on the migration and proliferation of hematopoietic progenitor cells. Hematology, 4(4), 345–356.
Kurihara, T., Warr, G., Loy, J., & Bravo, R. (1997). Defects in macrophage recruitment and host defense in mice lacking the CCR2 chemokine receptor. Journal of Experimental Medicine, 186(10), 1757–1762.
Dzenko, K. A., Song, L., Ge, S., Kuziel, W. A., & Pachter, J. S. (2005). CCR2 expression by brain microvascular endothelial cells is critical for macrophage transendothelial migration in response to CCL2. Microvascular Research, 70(1–2), 53–64.
Yang, X., Lu, P., Ishida, Y., Kuziel, W. A., Fujii, C., & Mukaida, N. (2006). Attenuated liver tumor formation in the absence of CCR2 with a concomitant reduction in the accumulation of hepatic stellate cells, macrophages and neovascularization. International Journal Cancer, 118(2), 335–345.
Huang, S., Singh, R. K., Xie, K., Gutman, M., Berry, K. K., Bucana, C. D., et al. (1994). Expression of the JE/MCP-1 gene suppresses metastatic potential in murine colon carcinoma cells. Cancer Immunology Immunotherapy, 39(4), 231–238.
Huang, S., Xie, K., Singh, R. K., Gutman, M., & Bar-Eli, M. (1995). Suppression of tumor growth and metastasis of murine renal adenocarcinoma by syngeneic fibroblasts genetically engineered to secrete the JE/MCP-1 cytokine. Journal of Interferon Cytokine Research, 15(7), 655–665.
Monti, P., Leone, B. E., Marchesi, F., Balzano, G., Zerbi, A., Scaltrini, F., et al. (2003). The CC chemokine MCP-1/CCL2 in pancreatic cancer progression: Regulation of expression and potential mechanisms of antimalignant activity. Cancer Research, 63(21), 7451–7461.
Kozlow, W., & Guise, T. A. (2005). Breast cancer metastasis to bone: Mechanisms of osteolysis and implications for therapy. Journal of Mammary Gland Biology Neoplasia, 10(2), 169–180.
Ishikawa, M., Toki, H., Fujii, M., Yamamoto, H., Yumoto, Y., Awazu, R., et al. (1983). Clinical significance of the bone marrow examination in small cell carcinoma of the lung. Gan No Rinsho, 29(5), 399–402.
Iguchi, H., Yasuda, M., Matsuo, T., Sumii, T., & Funakoshi, A. (2004). Clinical features and management of pancreatic cancer with bone metastases. Nippon Shokakibyo Gakkai Zasshi, 101(8):872–878.
Rowland, G. N., Capen, C. C., Black, H. E., & Young, D. M. (1971). Microradiographic evaluation of bone and ultrastructure of C-cells and parathyroid glands of cows receiving parathyroid extract. Beitrage zur Pathologie, 144(4), 360–376.
Junker, K., Romics, I., Szendroi, A., Riesz, P., Moravek, P., Hindermann, W., et al. (2004). Genetic profile of bone metastases in renal cell carcinoma. European Urology, 45(3), 320–324.
Natsuizaka, M., Omura, T., Akaike, T., Kuwata, Y., Yamazaki, K., Sato, T., et al. (2005). Clinical features of hepatocellular carcinoma with extrahepatic metastases. Journal of Gastroenterology and Hepatology, 20(11), 1781–1787.
Mado, K., Ishii, Y., Mazaki, T., Ushio, M., Masuda, H., & Takayama, T. (2006). A case of bone metastasis of colon cancer that markedly responded to S-1/CPT-11 combination chemotherapy and became curable by resection. World Journal of Surgical Oncology, 4, 3.
Berge, T., & Lundberg, S. (1977). Cancer in Malmo 1958–1969. An autopsy study. Acta Pathologica et Microbiologica Scandinavica, Supplementum, 260, 1–235.
Drury, A. B., Palmer, P. H., & Highman, W. J. (1964). Carcinomatous metastasis to the vertebral bodies. Journal of Clinical Pathology, 17, 448–457.
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Craig, M.J., Loberg, R.D. CCL2 (Monocyte Chemoattractant Protein-1) in cancer bone metastases. Cancer Metastasis Rev 25, 611–619 (2006). https://doi.org/10.1007/s10555-006-9027-x
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DOI: https://doi.org/10.1007/s10555-006-9027-x