Cancer and Metastasis Reviews

, Volume 33, Issue 2–3, pp 545–553 | Cite as

A multi-targeted approach to treating bone metastases

  • Daniel F. Camacho
  • Kenneth J. Pienta


The treatment of bone-metastatic cancer now takes advantage of the unique biology of this clinical state. The complex interplay between the cancer cells and the bone microenvironment leads to a host of therapeutic targets, with agents in various stages of clinical use or study. Targets include interactions between the cancer cells and osteoclasts, osteoblasts, endothelial cells, stromal cells, hematopoietic progenitor cells, cells of the immune system, and the bone matrix. Efforts at understanding specific mechanisms of drug resistance in the bone are also ongoing. Successful clinical outcomes will be the result of co-targeting and interrupting the various tumor-supportive elements and cooperating pathways at the level of the tumor cell, the primary and metastatic microenvironments, and systemic cancer effects, leading to a “scaled network disruption” to undermine the disease state.


Prostate cancer Bone metastasis Microenvironment Targeted therapy Ecotherapy 


  1. 1.
    Li, S., Peng, Y., Weinhandl, E. D., Blaes, A. H., Cetin, K., & Chia, V. M., et al. (2012). Estimated number of prevalent cases of metastatic bone disease in the US adult population. Clin Epidemiol, 4, 87–93.Google Scholar
  2. 2.
    Loberg, R. D., Bradley, D. A., Tomlins, S. A., Chinnaiyan, A. M., & Pienta, K. J. (2007). The lethal phenotype of cancer: the molecular basis of death due to malignancy. CA: A Cancer Journal for Clinicians, 57(4), 225–241.Google Scholar
  3. 3.
    Fidler, I. (2003). The pathogenesis of cancer metastasis: the ‘seed and soil’ hypothesis revisited. Nature Reviews. Cancer, 3, 1–6.CrossRefGoogle Scholar
  4. 4.
    Paget, S. (1889). The distribution of secondary growth in cancer of breast. Lancet, 1, 98–101.Google Scholar
  5. 5.
    Ewing, J. (1919). Metastasis. In Neoplastic diseases (pp. 76–88). Philadelphia: Saunders.Google Scholar
  6. 6.
    Pienta, K. J., & Loberg, R. (2005). The ‘emigration, migration, and immigration’ of prostate cancer. Clinical Prostate Cancer, 4(1), 24–30.PubMedCrossRefGoogle Scholar
  7. 7.
    Norton, L. (1988). A Gompertzian model of human breast cancer growth. Cancer Research, 48, 7067–7071.PubMedGoogle Scholar
  8. 8.
    Zetter, B. (1998). Angiogenesis and tumor metastasis. Annual Review of Medicine, 49, 407–424.PubMedCrossRefGoogle Scholar
  9. 9.
    Wang, J., Loberg, R., & Taichman, R. S. (2006). The pivotal role of CXCL12 (SDF-1)/CXCR4 axis in bone metastasis. Cancer Metastasis Reviews, 25(4), 573–587.PubMedCrossRefGoogle Scholar
  10. 10.
    Kortesidis, A., Zannettino, A., Isenmann, S., Shi, S., Lapidot, T., & Gronthos, S. (2005). Stromal-derived factor-1 promotes the growth, survival, and development of human bone marrow stromal stem cells. Blood, 105(10), 3793–3801.PubMedCrossRefGoogle Scholar
  11. 11.
    Jung, Y., Wang, J., Schneider, A., Sun, Y.-X., Koh-Paige, A. J., Osman, N. I., et al. (2006). Regulation of SDF-1 (CXCL12) production by osteoblasts; a possible mechanism for stem cell homing. Bone, 38(4), 497–508.PubMedCrossRefGoogle Scholar
  12. 12.
    Sun, Y., Fang, M., Wang, J., Cooper, C. R., Pienta, K. J., & Taichman, R. S., et al. (2007). Expression and Activation of a v b 3 Integrins by SDF-1 / CXC12 Increases the Aggressiveness of Prostate Cancer Cells. Prostate, 67(1), 61–73.Google Scholar
  13. 13.
    Sun, Y.-X., Schneider, A., Jung, Y., Wang, J., Dai, J., Wang, J., et al. (2005). Skeletal localization and neutralization of the SDF-1(CXCL12)/CXCR4 axis blocks prostate cancer metastasis and growth in osseous sites in vivo. Journal of Bone and Mineral Research, 20(2), 318–329.PubMedCrossRefGoogle Scholar
  14. 14.
    Havens, A. M., Jung, Y., Sun, Y. X., Wang, J., Shah, R., Bühring, H., et al. (2006). The role of sialomucin CD164 (MGC-24v or endolyn) in prostate cancer metastasis. BMC cancer, 6, 195.PubMedCentralPubMedCrossRefGoogle Scholar
  15. 15.
    Jung, Y., Wang, J., Song, J., Shiozawa, Y., Wang, J., Havens, A., et al. (2007). Annexin II expressed by osteoblasts and endothelial cells regulates stem cell adhesion, homing, and engraftment following transplantation. Blood, 110(1), 82–90.PubMedCentralPubMedCrossRefGoogle Scholar
  16. 16.
    Sikes, R. A., Nicholson, B. E., Koeneman, K. S., Edlund, N. M., Bissonette, E. A., Bradley, M. J., et al. (2004). Cellular interactions in the tropism of prostate cancer to bone. International Journal of Cancer, 110(4), 497–503.CrossRefGoogle Scholar
  17. 17.
    Chung, L. W. K., Baseman, A., Assikis, V., & Zhau, H. E. (2005). Molecular insights into prostate cancer progression: the missing link of tumor microenvironment. The Journal of Urology, 173, 10–20.PubMedCrossRefGoogle Scholar
  18. 18.
    Lipton, A. (2006). Future treatment of bone metastases. Clinical Cancer Research, 12(20 Pt 2), 6305s–6308s.PubMedCrossRefGoogle Scholar
  19. 19.
    Mundy, G. R. (2002). Metastasis to bone: causes, consequences and therapeutic opportunities. Nature reviews. Cancer, 2(8), 584–593.PubMedCrossRefGoogle Scholar
  20. 20.
    Loberg, R. D., Logothetis, C. J., Keller, E. T., & Pienta, K. J. (2005). Pathogenesis and treatment of prostate cancer bone metastases: targeting the lethal phenotype. Journal of clinical oncology : official journal of the American Society of Clinical Oncology, 23(32), 8232–8241.CrossRefGoogle Scholar
  21. 21.
    Candelaria-Quintana, D., Dayao, Z. R., & Royce, M. E. (2012). The role of antiresorptive therapies in improving patient care in early and metastatic breast cancer. Breast cancer research and treatment, 132(2), 355–363.PubMedCrossRefGoogle Scholar
  22. 22.
    Fornier, M. N. (2010). Denosumab: second chapter in controlling bone metastases or a new book? Journal of Clinical Oncology, 28(35), 5127–5131.PubMedCrossRefGoogle Scholar
  23. 23.
    Ha, T. C., & Li, H. (2007). Meta-analysis of clodronate and breast cancer survival. British Journal of Cancer, 96(12), 1796–1801.PubMedCentralPubMedCrossRefGoogle Scholar
  24. 24.
    Wu, S., Dahut, W. L., & Gulley, J. L. (2007). The use of bisphosphonates in cancer patients. Acta Oncologica, 46(5), 581–591.PubMedCrossRefGoogle Scholar
  25. 25.
    Saad, F., Gleason, D. M., Murray, R., Tchekmedyian, S., Venner, P., Lacombe, L., et al. (2004). Long-term efficacy of zoledronic acid for the prevention of skeletal complications in patients with metastatic hormone-refractory prostate cancer. Journal of the National Cancer Institute, 96(11), 879–882.PubMedCrossRefGoogle Scholar
  26. 26.
    Lüftner, D., Henschke, P., & Possinger, K. (2007). Clinical value of bisphosphonates in cancer therapy. Anticancer research, 27(4A), 1759–1768.PubMedGoogle Scholar
  27. 27.
    Schwarz, E. M., & Ritchlin, C. T. (2007). Clinical development of anti-RANKL therapy. Arthritis Research & Therapy, 9(Suppl 1), S7.CrossRefGoogle Scholar
  28. 28.
    Tsourdi, E., Rachner, T. D., Rauner, M., Hamann, C., & Hofbauer, L. C. (2011). Denosumab for bone diseases: translating bone biology into targeted therapy. European Journal of Endocrinology, 165(6), 833–840.PubMedCrossRefGoogle Scholar
  29. 29.
    Miyazaki, T., Tanaka, S., Sanjay, A., & Baron, R. (2006). The role of c-Src kinase in the regulation of osteoclast function. Modern Rheumatology, 16(2), 68–74.PubMedCrossRefGoogle Scholar
  30. 30.
    Huang, F., Reeves, K., Han, X., Fairchild, C., Platero, S., Wong, T. W., et al. (2007). Identification of candidate molecular markers predicting sensitivity in solid tumors to dasatinib: rationale for patient selection. Cancer research, 67(5), 2226–2238.PubMedCrossRefGoogle Scholar
  31. 31.
    Vandyke, K., Dewar, A. L., Diamond, P., Fitter, S., Schultz, C. G., Sims, N. A., et al. (2010). The tyrosine kinase inhibitor dasatinib dysregulates bone remodeling through inhibition of osteoclasts in vivo. Journal of Bone and Mineral Research, 25(8), 1759–1770.PubMedCrossRefGoogle Scholar
  32. 32.
    Ritchie, C. K., Andrews, L. R., Thomas, K. G., Tindall, D. J., & Fitzpatrick, L. A. (1997). The effects of growth factors associated with osteoblasts on prostate carcinoma proliferation and chemotaxis : implications for the development of metastatic disease. Endocrinology, 138(3), 1145–1150.PubMedGoogle Scholar
  33. 33.
    Zangari, M., Esseltine, D., Lee, C.-K., Barlogie, B., Elice, F., Burns, M. J., et al. (2005). Response to bortezomib is associated to osteoblastic activation in patients with multiple myeloma. British Journal of Haematology, 131, 71–73.PubMedCrossRefGoogle Scholar
  34. 34.
    Terpos, E., Heath, D. J., Rahemtulla, A., Zervas, K., Chantry, A., Anagnostopoulos, A., et al. (2006). Bortezomib reduces serum dickkopf-1 and receptor activator of nuclear factor-kB ligand concentrations and normalises indices of bone remodelling in patients with relapsed multiple myeloma. British Journal of Haematology, 135(5), 688–692.PubMedCrossRefGoogle Scholar
  35. 35.
    Vessella, R. L., & Corey, E. (2006). Targeting factors involved in bone remodeling as treatment strategies in prostate cancer bone metastasis. Clinical Cancer Research, 12(20 Pt 2), 6285s–6290s.PubMedCrossRefGoogle Scholar
  36. 36.
    Chauhan, D., Hideshima, T., Mitsiades, C., Richardson, P., & Anderson, K. C. (2005). Proteasome inhibitor therapy in multiple myeloma. Molecular Cancer Therapeutics, 4(4), 686–692.PubMedCrossRefGoogle Scholar
  37. 37.
    Kane, R. C., Dagher, R., Farrell, A., Ko, C.-W., Sridhara, R., Justice, R., et al. (2007). Bortezomib for the treatment of mantle cell lymphoma. Clinical Cancer Research, 13(18 Pt 1), 5291–5294.PubMedCrossRefGoogle Scholar
  38. 38.
    Sartor, O. (2004). Overview of samarium Sm 153 lexidronam in the treatment of painful metastatic bone disease. Reviews in Urology, 6(Suppl 10), S3–S12.PubMedCentralPubMedGoogle Scholar
  39. 39.
    Porter, A. T., McEwan, A. J., Powe, J. E., Reid, R., McGowan, D. G., Lukka, H., et al. (1993). Results of a randomized phase-III trial to evaluate the efficacy of strontium-89 adjuvant to local field external beam irradiation in the management of endocrine resistant metastatic prostate cancer. Int. J. Radiation Oncology Biol. Phys., 25, 805–813.CrossRefGoogle Scholar
  40. 40.
    Baczyk, M., Czepczyński, R., Milecki, P., Pisarek, M., Oleksa, R., & Sowiński, J. (2007). 89Sr versus 153Sm-EDTMP: comparison of treatment efficacy of painful bone metastases in prostate and breast carcinoma. Nuclear Medicine Communications, 28(4), 245–250.PubMedCrossRefGoogle Scholar
  41. 41.
    Bauman, G., Charette, M., Reid, R., & Sathya, J. (2005). Radiopharmaceuticals for the palliation of painful bone metastases—a systematic review. Radiotherapy and Oncology, 75(3), 258. E1–258.E13.PubMedCrossRefGoogle Scholar
  42. 42.
    Akerley, W., Butera, J., Wehbe, T., Noto, R., Stein, B., Safran, H., et al. (2002). A multiinstitutional, concurrent chemoradiation trial of strontium-89, estramustine, and vinblastine for hormone refractory prostate carcinoma involving bone. Cancer, 94(6), 1654–1660.PubMedCrossRefGoogle Scholar
  43. 43.
    Tu, S. M., Millikan, R. E., Mengistu, B., Delpassand, E. S., Amato, R. J., Pagliaro, L. C., et al. (2001). Bone-targeted therapy for advanced androgen-independent carcinoma of the prostate: a randomised phase II trial. Lancet, 357, 336–341.PubMedCrossRefGoogle Scholar
  44. 44.
    Harrison, M. R., Wong, T. Z., Armstrong, A. J., & George, D. J. (2013). Radium-223 chloride: a potential new treatment for castration-resistant prostate cancer patients with metastatic bone disease. Cancer Management and Research, 5, 1–14.PubMedCentralPubMedCrossRefGoogle Scholar
  45. 45.
    Rao, K. V. (2007). Lenalidomide in the treatment of multiple myeloma. American Journal of Health-System Pharmacy, 64(17), 1799–1807.PubMedCrossRefGoogle Scholar
  46. 46.
    Murakami, H., Handa, H., Abe, M., Iida, S., Ishii, A., Ishikawa, T., et al. (2007). Low-dose thalidomide plus low-dose dexamethasone therapy in patients with refractory multiple myeloma. European Journal of Haematology, 79(3), 234–239.PubMedCrossRefGoogle Scholar
  47. 47.
    Hicklin, D. J., & Ellis, L. M. (2005). Role of the vascular endothelial growth factor pathway in tumor growth and angiogenesis. Journal of Clinical Oncology, 23(5), 1011–1027.PubMedCrossRefGoogle Scholar
  48. 48.
    Chinot, O. L. (2012). Bevacizumab-based therapy in relapsed glioblastoma: rationale and clinical experience to date. Expert Review of Anticancer Therapy, 12(11), 1413–1427.PubMedCrossRefGoogle Scholar
  49. 49.
    Flaherty, K. T. (2007). Sorafenib: delivering a targeted drug to the right targets. Expert Review of Anticancer Therapy, 7(5), 617–626.PubMedCrossRefGoogle Scholar
  50. 50.
    Pantuck, A. J., Zomorodian, N., & Belldegrun, A. S. (2006). Phase I, open-label, single-center, multiple-dose, dose-escalation clinical study of SUO11248 (sunitinib) in subjects with high-risk prostate cancer who have elected to undergo radical prostatectomy. Clinical Cancer Research, 12, 4018–4026.PubMedCrossRefGoogle Scholar
  51. 51.
    Drevs, J., Zirrgiebel, U., Schmidt-Gersbach, C. I. M., Mross, K., Medinger, M., Lee, L., et al. (2005). Soluble markers for the assessment of biological activity with PTK787/ZK 222584 (PTK/ZK), a vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitor in patients with advanced colorectal cancer from two phase I trials. Annals of Oncology, 16(4), 558–565.PubMedCrossRefGoogle Scholar
  52. 52.
    Smith, D. C., Smith, M. R., Sweeney, C., Elfiky, A. A., Logothetis, C., Corn, P. G., et al. (2013). Cabozantinib in patients with advanced prostate cancer: results of a phase II randomized discontinuation trial. Journal of Clinical Oncology, 31(4), 412–419.PubMedCrossRefGoogle Scholar
  53. 53.
    Eskens, F. A. L. M., Dumez, H., Hoekstra, R., Perschl, A., Brindley, C., Böttcher, S., et al. (2003). Phase I and pharmacokinetic study of continuous twice weekly intravenous administration of cilengitide (EMD 121974), a novel inhibitor of the integrins αvβ3 and αvβ5 in patients with advanced solid tumours. European Journal of Cancer, 39(7), 917–926.PubMedCrossRefGoogle Scholar
  54. 54.
    Mullamitha, S. A., Ton, N. C., Parker, G. J. M., Jackson, A., Julyan, P. J., Roberts, C., et al. (2007). Phase I evaluation of a fully human anti-alphav integrin monoclonal antibody (CNTO 95) in patients with advanced solid tumors. Clinical Cancer Research, 13(7), 2128–2135.PubMedCrossRefGoogle Scholar
  55. 55.
    Tucker, G. C. (2006). Integrins: molecular targets in cancer therapy. Current Oncology Reports, 8(2), 96–103.PubMedCrossRefGoogle Scholar
  56. 56.
    Gramoun, A., Shorey, S., Bashutski, J. D., Dixon, S. J., Sims, S. M., Heersche, J. N. M., et al. (2007). Effects of vitaxin, a novel therapeutic in trial for metastatic bone tumors, on osteoclast functions in vitro. Journal of Cellular Biochemistry, 102(2), 341–352.PubMedCrossRefGoogle Scholar
  57. 57.
    Mulgrew, K., Kinneer, K., Yao, X.-T., Ward, B. K., Damschroder, M. M., Walsh, B., et al. (2006). Direct targeting of alphavbeta3 integrin on tumor cells with a monoclonal antibody, Abegrin. Molecular Cancer Therapeutics, 5(12), 3122–3129.PubMedCrossRefGoogle Scholar
  58. 58.
    Cheever, M. A., & Higano, C. S. (2011). PROVENGE (sipuleucel-T) in prostate cancer: the first FDA-approved therapeutic cancer vaccine. Clinical Cancer Research, 17(11), 3520–3526.PubMedCrossRefGoogle Scholar
  59. 59.
    Kantoff, P. W., Higano, C. S., Shore, N. D., Berger, E. R., Small, E. J., Penson, D. F., et al. (2010). Sipuleucel-T immunotherapy for castration-resistant prostate cancer. New England Journal of Medicine, 363(5), 411–422.PubMedCrossRefGoogle Scholar
  60. 60.
    So-Rosillo, R., & Small, E. J. (2006). Sipuleucel-T (APC8015) for prostate cancer. Expert Review of Anticancer Therapy, 6(9), 1163–1167.PubMedCrossRefGoogle Scholar
  61. 61.
    Park, J. W., Melisko, M. E., Esserman, L. J., Jones, L. A., Wollan, J. B., & Sims, R. (2007). Treatment with autologous antigen-presenting cells activated with the HER-2-based antigen lapuleucel-T: results of a phase I study in immunologic and clinical activity in HER-2 overexpressing breast cancer. Journal of Clinical Oncology, 25(24), 3680–3687.PubMedCrossRefGoogle Scholar
  62. 62.
    de Gruijl, T. D., van den Eertwegh, A. J. M., Pinedo, H. M., & Scheper, R. J. (2008). Whole-cell cancer vaccination: from autologous to allogeneic tumor- and dendritic cell-based vaccines. Cancer Immunology, Immunotherapy, 57(10), 1569–1577.PubMedCentralPubMedCrossRefGoogle Scholar
  63. 63.
    Kantoff, P. W., Schuetz, T. J., Blumenstein, B. A., Glode, L. M., Bilhartz, D. L., Wyand, M., et al. (2010). Overall survival analysis of a phase II randomized controlled trial of a poxviral-based PSA-targeted immunotherapy in metastatic castration-resistant prostate cancer. Journal of Clinical Oncology, 28(7), 1099–1105.PubMedCentralPubMedCrossRefGoogle Scholar
  64. 64.
    Dayyani, F., Gallick, G. E., Logothetis, C. J., & Corn, P. G. (2011). Novel therapies for metastatic castrate-resistant prostate cancer. Journal of the National Cancer Institute, 103(22), 1665–1675.PubMedCrossRefGoogle Scholar
  65. 65.
    Reck, M., Bondarenko, I., Luft, A., Serwatowski, P., Barlesi, F., Chacko, R., et al. (2013). Ipilimumab in combination with paclitaxel and carboplatin as first-line therapy in extensive-disease-small-cell lung cancer: results from a randomized, double-blind, multicenter phase 2 trial. Annals of Oncology, 24(1), 75–83.PubMedCrossRefGoogle Scholar
  66. 66.
    Margolin, K., Ernstoff, M. S., Hamid, O., Lawrence, D., McDermott, D., Puzanov, I., et al. (2012). Ipilimumab in patients with melanoma and brain metastases: an open-label, phase 2 trial. The Lancet Oncology, 13(5), 459–465.PubMedCrossRefGoogle Scholar
  67. 67.
    Sun, J., Schiffman, J., Raghunath, A., Ng Tang, D., Chen, H., & Sharma, P. (2008). Concurrent decrease in IL-10 with development of immune-related adverse events in a patient treated with anti-CTLA-4 therapy. Cancer Immunity, 8, 9–15.PubMedCentralPubMedGoogle Scholar
  68. 68.
    Fulton, A., Miller, F., Weise, A., & Wei, W.-Z. (2007). Prospects of controlling breast cancer metastasis by immune intervention. Breast Disease, 26, 115–127.Google Scholar
  69. 69.
    Melero, I., Grimaldi, A. M., Perez-Gracia, J. L., & Ascierto, P. A. (2013). Clinical development of immunostimulatory monoclonal antibodies and opportunities for combination. Clinical cancer research : an official journal of the American Association for Cancer Research, 19(5), 997–1008.CrossRefGoogle Scholar
  70. 70.
    Fishelson, Z., Donin, N., Zell, S., Schultz, S., & Kirschfink, M. (2003). Obstacles to cancer immunotherapy: expression of membrane complement regulatory proteins (mCRPs) in tumors. Molecular Immunology, 40, 109–123.PubMedCrossRefGoogle Scholar
  71. 71.
    Pritchard-Jones, K., Spendlove, I., Wilton, C., Whelan, J., Weeden, S., Lewis, I., et al. (2005). Immune responses to the 105 AD7 human anti-idiotypic vaccine after intensive chemotherapy, for osteosarcoma. British Journal of Cancer, 92(8), 1358–1365.PubMedCentralPubMedCrossRefGoogle Scholar
  72. 72.
    Liao, Y., Schaue, D., & McBride, W. (2007). Modification of the tumor microenvironment to enhance immunity. Frontiers in Bioscience, 12, 3576–3600.PubMedCrossRefGoogle Scholar
  73. 73.
    Dirkx, A. E. M., Oude Egbrink, M. G. A., Wagstaff, J., & Griffioen, A. W. (2006). Monocyte/macrophage infiltration in tumors: modulators of angiogenesis. Journal of Leukocyte Biology, 80(6), 1183–1196.PubMedCrossRefGoogle Scholar
  74. 74.
    Lewis, C. E., & Pollard, J. W. (2006). Distinct role of macrophages in different tumor microenvironments. Cancer Research, 66(2), 605–612.PubMedCrossRefGoogle Scholar
  75. 75.
    Bingle, L., Brown, N. J., & Lewis, C. E. (2002). The role of tumour-associated macrophages in tumour progression: implications for new anticancer therapies. Journal of Pathology, 196, 254–265.PubMedCrossRefGoogle Scholar
  76. 76.
    Sica, A., Schioppa, T., Mantovani, A., & Allavena, P. (2006). Tumour-associated macrophages are a distinct M2 polarised population promoting tumour progression: potential targets of anti-cancer therapy. European Journal of Cancer, 42(6), 717–727.PubMedCrossRefGoogle Scholar
  77. 77.
    Mantovani, A., Schioppa, T., Porta, C., Allavena, P., & Sica, A. (2006). Role of tumor-associated macrophages in tumor progression and invasion. Cancer Metastasis Reviews, 25(3), 315–322.PubMedCrossRefGoogle Scholar
  78. 78.
    Porta, C., Kumar, B. S., Larghi, P., Rubino, L., Mancino, A., & Sica, A. (2007). Tumor promotion by tumor-associated macrophages. Advances in Experimental Medicine and Biology, 604, 67–86.PubMedCrossRefGoogle Scholar
  79. 79.
    Loberg, R. D., Ying, C., Craig, M., Yan, L., Snyder, L. A., & Pienta, K. J. (2007). CCL2 as an important mediator of prostate cancer growth in vivo through the regulation of macrophage infiltration. Neoplasia, 9(7), 556–562.PubMedCentralPubMedCrossRefGoogle Scholar
  80. 80.
    Bailey, C., Negus, R., Morris, A., Ziprin, P., Goldin, R., Allavena, P., et al. (2007). Chemokine expression is associated with the accumulation of tumour associated macrophages (TAMs) and progression in human colorectal cancer. Clinical & Experimental Metastasis, 24(2), 121–130.CrossRefGoogle Scholar
  81. 81.
    Craig, M. J., & Loberg, R. D. (2006). CCL2 (monocyte chemoattractant protein-1) in cancer bone metastases. Cancer Metastasis Reviews, 25(4), 611–619.PubMedCrossRefGoogle Scholar
  82. 82.
    Pienta, K. J., Machiels, J.-P., Schrijvers D., Alekseev B., M. Shkolnik, & Crabb, S. J., et al. (2013). Phase 2 study of carlumab (CNTO 888), a human monoclonal antibody against CC-chemokine ligand 2 (CCL2), in metastatic castration-resistant prostate cancer. Invest New Drugs, 31(3), 760–768.Google Scholar
  83. 83.
    Sandhu, S. K., Papadopoulos, K., Fong, P. C., Patnaik, A., Messiou, C., Olmos, D., et al. (2013). A first-in-human, first-in-class, phase I study of carlumab (CNTO 888), a human monoclonal antibody against CC-chemokine ligand 2 in patients with solid tumors. Cancer Chemotherapy and Pharmacology, 71(4), 1041–1050.PubMedCrossRefGoogle Scholar
  84. 84.
    Baay, M., Brouwer, A., Pauwels, P., Peeters, M., & Lardon, F. (2011). Tumor Cells and Tumor-Associated Macrophages: Secreted Proteins as Potential Targets for Therapy. Clinical & Developmental Immunology, p. 565187.Google Scholar
  85. 85.
    Petit, I., Szyper-Kravitz, M., Nagler, A., Lahav, M., Peled, A., Habler, L., et al. (2002). G-CSF induces stem cell mobilization by decreasing bone marrow SDF-1 and up-regulating CXCR4. Nature Immunology, 3(7), 687–694.PubMedCrossRefGoogle Scholar
  86. 86.
    Shiozawa, Y., Pedersen, E. A., Havens, A. M., Jung, Y., Mishra, A., Joseph, J., et al. (2011). Human prostate cancer metastases target the hematopoietic stem cell niche to establish footholds in mouse bone marrow. Journal of Clinical Investigation, 121(4), 1298–1312.PubMedCentralPubMedCrossRefGoogle Scholar
  87. 87.
    Smith, M. C. P., Luker, K. E., Garbow, J. R., Prior, J. L., Jackson, E., Piwnica-Worms, D., et al. (2004). CXCR4 regulates growth of both primary and metastatic breast cancer. Cancer Research, 64(23), 8604–8612.PubMedCrossRefGoogle Scholar
  88. 88.
    Meads, M. B., Hazlehurst, L. A., & Dalton, W. S. (2008). The bone marrow microenvironment as a tumor sanctuary and contributor to drug resistance. Clinical Cancer Research, 14(9), 2519–2526.PubMedCrossRefGoogle Scholar
  89. 89.
    Vincent, T., & Mechti, N. (2005). Extracellular matrix in bone marrow can mediate drug resistance in myeloma. Leukemia & Lymphoma, 46(6), 803–811.CrossRefGoogle Scholar
  90. 90.
    Camacho, D. F., & Pienta, K. J. (2012). Disrupting the networks of cancer. Clinical Cancer Research, 18(10), 2801–2808.PubMedCrossRefGoogle Scholar
  91. 91.
    Chen, K. W., & Pienta, K. J. (2011). Modeling invasion of metastasizing cancer cells to bone marrow utilizing ecological principles. Theoretical Biology and Medical Modeling, 8(36), 1–11.Google Scholar

Copyright information

© Springer Science+Business Media New York 2014

Authors and Affiliations

  1. 1.Department of Internal MedicineUniversity of Michigan Comprehensive Cancer CenterAnn ArborUSA
  2. 2.Brady Urological InstituteBaltimoreUSA

Personalised recommendations