Skip to main content

Advertisement

SpringerLink
Log in

Macrophages in multiple myeloma: key roles and therapeutic strategies

  • Non-Thematic Review
  • Published:
Cancer and Metastasis Reviews Aims and scope Submit manuscript

Abstract

Macrophages are a vital component of the tumour microenvironment and crucial mediators of tumour progression. In the last decade, significant strides have been made in understanding the crucial functional roles played by macrophages in the development of the plasma cell (PC) malignancy, multiple myeloma (MM). Whilst the interaction between MM PC and stromal cells within the bone marrow (BM) microenvironment has been extensively studied, we are only just starting to appreciate the multifaceted roles played by macrophages in disease progression. Accumulating evidence demonstrates that macrophage infiltration is associated with poor overall survival in MM. Indeed, macrophages influence numerous pathways critical for the initiation and progression of MM, including homing of malignant cells to BM, tumour cell growth and survival, drug resistance, angiogenesis and immune suppression. As such, therapeutic strategies aimed at targeting macrophages within the BM niche have promise in the clinical setting. This review will discuss the functions elicited by macrophages throughout different stages of MM and provide a comprehensive evaluation of potential macrophage-targeted therapies.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

Data availability

Not applicable.

References

  1. Kumar, S. K., Rajkumar, V., Kyle, R. A., van Duin, M., Sonneveld, P., Mateos, M. V., Gay, F., & Anderson, K. C. (2017). Multiple myeloma. Nature Reviews. Disease Primers, 3, 17046. https://doi.org/10.1038/nrdp.2017.46.

    Article  PubMed  Google Scholar 

  2. Moreau, P., Attal, M., & Facon, T. (2015). Frontline therapy of multiple myeloma. Blood, 125(20), 3076–3084. https://doi.org/10.1182/blood-2014-09-568915.

    Article  CAS  PubMed  Google Scholar 

  3. Cowan, A. J., Allen, C., Barac, A., Basaleem, H., Bensenor, I., Curado, M. P., Foreman, K., Gupta, R., Harvey, J., Hosgood, H. D., Jakovljevic, M., Khader, Y., Linn, S., Lad, D., Mantovani, L., Nong, V. M., Mokdad, A., Naghavi, M., Postma, M., Roshandel, G., Shackelford, K., Sisay, M., Nguyen, C. T., Tran, T. T., Xuan, B. T., Ukwaja, K. N., Vollset, S. E., Weiderpass, E., Libby, E. N., & Fitzmaurice, C. (2018). Global burden of multiple myeloma: A systematic analysis for the global burden of disease study 2016. JAMA Oncology, 4(9), 1221–1227. https://doi.org/10.1001/jamaoncol.2018.2128.

    Article  PubMed  PubMed Central  Google Scholar 

  4. International Myeloma Working, G. (2003). Criteria for the classification of monoclonal gammopathies, multiple myeloma and related disorders: A report of the International Myeloma Working Group. British Journal of Haematology, 121(5), 749–757.

    Article  Google Scholar 

  5. Roodman, G. D. (2009). Pathogenesis of myeloma bone disease. Leukemia, 23(3), 435–441. https://doi.org/10.1038/leu.2008.336.

    Article  CAS  PubMed  Google Scholar 

  6. Landgren, O., Kyle, R. A., Pfeiffer, R. M., Katzmann, J. A., Caporaso, N. E., Hayes, R. B., Dispenzieri, A., Kumar, S., Clark, R. J., Baris, D., Hoover, R., & Rajkumar, S. V. (2009). Monoclonal gammopathy of undetermined significance (MGUS) consistently precedes multiple myeloma: A prospective study. Blood, 113(22), 5412–5417. https://doi.org/10.1182/blood-2008-12-194241.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Weiss, B. M., Abadie, J., Verma, P., Howard, R. S., & Kuehl, W. M. (2009). A monoclonal gammopathy precedes multiple myeloma in most patients. Blood, 113(22), 5418–5422. https://doi.org/10.1182/blood-2008-12-195008.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Alsayed, Y., Ngo, H., Runnels, J., Leleu, X., Singha, U. K., Pitsillides, C. M., Spencer, J. A., Kimlinger, T., Ghobrial, J. M., Jia, X., Lu, G., Timm, M., Kumar, A., Côté, D., Veilleux, I., Hedin, K. E., Roodman, G. D., Witzig, T. E., Kung, A. L., Hideshima, T., Anderson, K. C., Lin, C. P., & Ghobrial, I. M. (2007). Mechanisms of regulation of CXCR4/SDF-1 (CXCL12)-dependent migration and homing in multiple myeloma. Blood, 109(7), 2708–2717. https://doi.org/10.1182/blood-2006-07-035857.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Lawson, M. A., McDonald, M. M., Kovacic, N., Hua Khoo, W., Terry, R. L., Down, J., Kaplan, W., Paton-Hough, J., Fellows, C., Pettitt, J. A., Neil Dear, T., van Valckenborgh, E., Baldock, P. A., Rogers, M. J., Eaton, C. L., Vanderkerken, K., Pettit, A. R., Quinn, J. M. W., Zannettino, A. C. W., Phan, T. G., & Croucher, P. I. (2015). Osteoclasts control reactivation of dormant myeloma cells by remodelling the endosteal niche. Nature Communications, 6, 8983. https://doi.org/10.1038/ncomms9983.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Khoo, W. H., Ledergor, G., Weiner, A., Roden, D. L., Terry, R. L., McDonald, M. M., Chai, R. C., de Veirman, K., Owen, K. L., Opperman, K. S., Vandyke, K., Clark, J. R., Seckinger, A., Kovacic, N., Nguyen, A., Mohanty, S. T., Pettitt, J. A., Xiao, Y., Corr, A. P., Seeliger, C., Novotny, M., Lasken, R. S., Nguyen, T. V., Oyajobi, B. O., Aftab, D., Swarbrick, A., Parker, B., Hewett, D. R., Hose, D., Vanderkerken, K., Zannettino, A. C. W., Amit, I., Phan, T. G., & Croucher, P. I. (2019). A niche-dependent myeloid transcriptome signature defines dormant myeloma cells. Blood, 134(1), 30–43. https://doi.org/10.1182/blood.2018880930.

    Article  CAS  PubMed  Google Scholar 

  11. Manier, S., Sacco, A., Leleu, X., Ghobrial, I. M., & Roccaro, A. M. (2012). Bone marrow microenvironment in multiple myeloma progression. Journal of Biomedicine & Biotechnology, 2012, 1–5. https://doi.org/10.1155/2012/157496.

    Article  CAS  Google Scholar 

  12. Hideshima, T., Nakamura, N., Chauhan, D., & Anderson, K. C. (2001). Biologic sequelae of interleukin-6 induced PI3-K/Akt signaling in multiple myeloma. Oncogene, 20(42), 5991–6000. https://doi.org/10.1038/sj.onc.1204833.

    Article  CAS  PubMed  Google Scholar 

  13. Vacca, A., & Ribatti, D. (2006). Bone marrow angiogenesis in multiple myeloma. Leukemia, 20(2), 193–199. https://doi.org/10.1038/sj.leu.2404067.

    Article  CAS  PubMed  Google Scholar 

  14. Heider, U., Hofbauer, L. C., Zavrski, I., Kaiser, M., Jakob, C., & Sezer, O. (2005). Novel aspects of osteoclast activation and osteoblast inhibition in myeloma bone disease. Biochemical and Biophysical Research Communications, 338(2), 687–693. https://doi.org/10.1016/j.bbrc.2005.09.146.

    Article  CAS  PubMed  Google Scholar 

  15. Noll, J. E., Williams, S. A., Tong, C. M., Wang, H., Quach, J. M., Purton, L. E., Pilkington, K., To, L. B., Evdokiou, A., Gronthos, S., & Zannettino, A. C. W. (2014). Myeloma plasma cells alter the bone marrow microenvironment by stimulating the proliferation of mesenchymal stromal cells. Haematologica, 99(1), 163–171. https://doi.org/10.3324/haematol.2013.090977.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Singhal, S., & Mehta, J. (2006). Multiple myeloma. Clinical Journal of the American Society of Nephrology, 1(6), 1322–1330. https://doi.org/10.2215/CJN.03060906.

    Article  CAS  PubMed  Google Scholar 

  17. Reagan, M. R., Liaw, L., Rosen, C. J., & Ghobrial, I. M. (2015). Dynamic interplay between bone and multiple myeloma: Emerging roles of the osteoblast. Bone, 75, 161–169. https://doi.org/10.1016/j.bone.2015.02.021.

    Article  PubMed  PubMed Central  Google Scholar 

  18. Franssen, L. E., Mutis, T., Lokhorst, H. M., & van de Donk, N. (2019). Immunotherapy in myeloma: How far have we come? Therapeutic Advances in Hematology, 10, 2040620718822660. https://doi.org/10.1177/2040620718822660.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Beider, K., Bitner, H., Leiba, M., Gutwein, O., Koren-Michowitz, M., Ostrovsky, O., et al. (2014). Multiple myeloma cells recruit tumor-supportive macrophages through the CXCR4/CXCL12 axis and promote their polarization toward the M2 phenotype. Oncotarget, 5(22), 11283–11296. https://doi.org/10.18632/oncotarget.2207.

    Article  PubMed  PubMed Central  Google Scholar 

  20. De Beule, N., De Veirman, K., Maes, K., De Bruyne, E., Menu, E., Breckpot, K., et al. (2017). Tumour-associated macrophage-mediated survival of myeloma cells through STAT3 activation. The Journal of Pathology, 241(4), 534–546. https://doi.org/10.1002/path.4860.

    Article  CAS  PubMed  Google Scholar 

  21. Chen, H., Li, M., Wang, C., Sanchez, E., Soof, C., Udd, K., Director, C., Cao, J., Tang, G., & Berenson, J. (2017). Increase in M2 macrophage polarization in multiple myeloma bone marrow is inhibited with the JAK2 inhibitor ruxolitinib which shows anti-MM effects. Clinical Lymphoma, Myeloma & Leukemia, 17(1), e93. https://doi.org/10.1016/j.clml.2017.03.166.

    Article  Google Scholar 

  22. Wang, Q., Lu, Y., Li, R., Jiang, Y., Zheng, Y., Qian, J., Bi, E., Zheng, C., Hou, J., Wang, S., & Yi, Q. (2018). Therapeutic effects of CSF1R-blocking antibodies in multiple myeloma. Leukemia, 32(1), 176–183. https://doi.org/10.1038/leu.2017.193.

    Article  CAS  PubMed  Google Scholar 

  23. Opperman, K. S., Vandyke, K., Clark, K. C., Coulter, E. A., Hewett, D. R., Mrozik, K. M., Schwarz, N., Evdokiou, A., Croucher, P. I., Psaltis, P. J., Noll, J. E., & Zannettino, A. C. W. (2019). Clodronate-liposome mediated macrophage depletion abrogates multiple myeloma tumor establishment in vivo. Neoplasia, 21(8), 777–787. https://doi.org/10.1016/j.neo.2019.05.006.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Gordon, S., & Pluddemann, A. (2017). Tissue macrophages: Heterogeneity and functions. BMC Biology, 15(1), 53. https://doi.org/10.1186/s12915-017-0392-4.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Jacobsen, R. N., Forristal, C. E., Raggatt, L. J., Nowlan, B., Barbier, V., Kaur, S., van Rooijen, N., Winkler, I. G., Pettit, A. R., & Levesque, J. P. (2014). Mobilization with granulocyte colony-stimulating factor blocks medullar erythropoiesis by depleting F4/80(+)VCAM1(+)CD169(+)ER-HR3(+)Ly6G(+) erythroid island macrophages in the mouse. Experimental Hematology, 42(7), 547–561. https://doi.org/10.1016/j.exphem.2014.03.009.

    Article  CAS  PubMed  Google Scholar 

  26. Chow, A., Huggins, M., Ahmed, J., Hashimoto, D., Lucas, D., Kunisaki, Y., Pinho, S., Leboeuf, M., Noizat, C., van Rooijen, N., Tanaka, M., Zhao, Z. J., Bergman, A., Merad, M., & Frenette, P. S. (2013). CD169(+) macrophages provide a niche promoting erythropoiesis under homeostasis and stress. Nature Medicine, 19(4), 429–436. https://doi.org/10.1038/nm.3057.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Kaur, S., Raggatt, L. J., Batoon, L., Hume, D. A., Levesque, J. P., & Pettit, A. R. (2017). Role of bone marrow macrophages in controlling homeostasis and repair in bone and bone marrow niches. Seminars in Cell & Developmental Biology, 61, 12–21. https://doi.org/10.1016/j.semcdb.2016.08.009.

    Article  CAS  Google Scholar 

  28. Pettit, A. R., Chang, M. K., Hume, D. A., & Raggatt, L. J. (2008). Osteal macrophages: A new twist on coupling during bone dynamics. Bone, 43(6), 976–982. https://doi.org/10.1016/j.bone.2008.08.128.

    Article  PubMed  Google Scholar 

  29. McCabe, A., Zhang, Y., Thai, V., Jones, M., Jordan, M. B., & MacNamara, K. C. (2015). Macrophage-lineage cells negatively regulate the hematopoietic stem cell pool in response to interferon gamma at steady state and during infection. Stem Cells, 33(7), 2294–2305. https://doi.org/10.1002/stem.2040.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Batoon, L., Millard, S. M., Wullschleger, M. E., Preda, C., Wu, A. C., Kaur, S., et al. (2017). CD169(+) macrophages are critical for osteoblast maintenance and promote intramembranous and endochondral ossification during bone repair. Biomaterials, 196, 51–66. https://doi.org/10.1016/j.biomaterials.2017.10.033.

    Article  CAS  PubMed  Google Scholar 

  31. Chow, A., Lucas, D., Hidalgo, A., Mendez-Ferrer, S., Hashimoto, D., Scheiermann, C., et al. (2011). Bone marrow CD169+ macrophages promote the retention of hematopoietic stem and progenitor cells in the mesenchymal stem cell niche. The Journal of Experimental Medicine, 208(2), 261–271. https://doi.org/10.1084/jem.20101688.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Winkler, I. G., Sims, N. A., Pettit, A. R., Barbier, V., Nowlan, B., Helwani, F., Poulton, I. J., van Rooijen, N., Alexander, K. A., Raggatt, L. J., & Lévesque, J. P. (2010). Bone marrow macrophages maintain hematopoietic stem cell (HSC) niches and their depletion mobilizes HSCs. Blood, 116(23), 4815–4828. https://doi.org/10.1182/blood-2009-11-253534.

    Article  CAS  PubMed  Google Scholar 

  33. Martinez, F. O., & Gordon, S. (2014). The M1 and M2 paradigm of macrophage activation: Time for reassessment. F1000Prime Rep, 6, 13. https://doi.org/10.12703/P6-13.

    Article  PubMed  PubMed Central  Google Scholar 

  34. Mantovani, A., Sica, A., Sozzani, S., Allavena, P., Vecchi, A., & Locati, M. (2004). The chemokine system in diverse forms of macrophage activation and polarization. Trends in Immunology, 25(12), 677–686. https://doi.org/10.1016/j.it.2004.09.015.

    Article  CAS  PubMed  Google Scholar 

  35. Mills, C. D., Kincaid, K., Alt, J. M., Heilman, M. J., & Hill, A. M. (2000). M-1/M-2 macrophages and the Th1/Th2 paradigm. Journal of Immunology, 164(12), 6166–6173. https://doi.org/10.4049/jimmunol.164.12.6166.

    Article  CAS  Google Scholar 

  36. Mackaness, G. B. (1962). Cellular resistance to infection. The Journal of Experimental Medicine, 116, 381–406. https://doi.org/10.1084/jem.116.3.381.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Mosser, D. M., & Edwards, J. P. (2008). Exploring the full spectrum of macrophage activation. Nature Reviews. Immunology, 8(12), 958–969. https://doi.org/10.1038/nri2448.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Xue, J., Schmidt, S. V., Sander, J., Draffehn, A., Krebs, W., Quester, I., de Nardo, D., Gohel, T. D., Emde, M., Schmidleithner, L., Ganesan, H., Nino-Castro, A., Mallmann, M. R., Labzin, L., Theis, H., Kraut, M., Beyer, M., Latz, E., Freeman, T. C., Ulas, T., & Schultze, J. L. (2014). Transcriptome-based network analysis reveals a spectrum model of human macrophage activation. Immunity, 40(2), 274–288. https://doi.org/10.1016/j.immuni.2014.01.006.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Aras, S., & Zaidi, M. R. (2017). TAMeless traitors: Macrophages in cancer progression and metastasis. British Journal of Cancer, 117(11), 1583–1591. https://doi.org/10.1038/bjc.2017.356.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Caux, C., Ramos, R. N., Prendergast, G. C., Bendriss-Vermare, N., & Menetrier-Caux, C. (2016). A milestone review on how macrophages affect tumor growth. Cancer Research, 76(22), 6439–6442. https://doi.org/10.1158/0008-5472.CAN-16-2631.

    Article  CAS  PubMed  Google Scholar 

  41. Poh, A. R., & Ernst, M. (2018). Targeting macrophages in Cancer: From bench to bedside. Frontiers in Oncology, 8, 49. https://doi.org/10.3389/fonc.2018.00049.

    Article  PubMed  PubMed Central  Google Scholar 

  42. Suyani, E., Sucak, G. T., Akyurek, N., Sahin, S., Baysal, N. A., Yagci, M., et al. (2013). Tumor-associated macrophages as a prognostic parameter in multiple myeloma. Annals of Hematology, 92(5), 669–677. https://doi.org/10.1007/s00277-012-1652-6.

    Article  PubMed  Google Scholar 

  43. Chen, X., Chen, J., Zhang, W., Sun, R., Liu, T., Zheng, Y., et al. (2017). Prognostic value of diametrically polarized tumor-associated macrophages in multiple myeloma. Oncotarget, 8(68), 112685–112696. https://doi.org/10.18632/oncotarget.22340.

    Article  PubMed  PubMed Central  Google Scholar 

  44. Panchabhai, S., Kelemen, K., Ahmann, G., Sebastian, S., Mantei, J., & Fonseca, R. (2016). Tumor-associated macrophages and extracellular matrix metalloproteinase inducer in prognosis of multiple myeloma. Leukemia, 30(4), 951–954. https://doi.org/10.1038/leu.2015.191.

    Article  CAS  PubMed  Google Scholar 

  45. Wang, H., Hu, W. M., Xia, Z. J., Liang, Y., Lu, Y., Lin, S. X., & Tang, H. (2019). High numbers of CD163+ tumor-associated macrophages correlate with poor prognosis in multiple myeloma patients receiving bortezomib-based regimens. Journal of Cancer, 10(14), 3239–3245. https://doi.org/10.7150/jca.30102.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Vacca, A., Ribatti, D., Presta, M., Minischetti, M., Iurlaro, M., Ria, R., Albini, A., Bussolino, F., & Dammacco, F. (1999). Bone marrow neovascularization, plasma cell angiogenic potential, and matrix metalloproteinase-2 secretion parallel progression of human multiple myeloma. Blood, 93(9), 3064–3073.

    Article  CAS  Google Scholar 

  47. Li, Y., Zheng, Y., Li, T., Wang, Q., Qian, J., Lu, Y., et al. (2015). Chemokines CCL2, 3, 14 stimulate macrophage bone marrow homing, proliferation, and polarization in multiple myeloma. Oncotarget, 6(27), 24218–24229. https://doi.org/10.18632/oncotarget.4523.

    Article  PubMed  PubMed Central  Google Scholar 

  48. Calcinotto, A., Ponzoni, M., Ria, R., Grioni, M., Cattaneo, E., Villa, I., Sabrina Bertilaccio, M. T., Chesi, M., Rubinacci, A., Tonon, G., Bergsagel, P. L., Vacca, A., & Bellone, M. (2015). Modifications of the mouse bone marrow microenvironment favor angiogenesis and correlate with disease progression from asymptomatic to symptomatic multiple myeloma. Oncoimmunology, 4(6), e1008850. https://doi.org/10.1080/2162402X.2015.1008850.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Scavelli, C., Nico, B., Cirulli, T., Ria, R., Di Pietro, G., Mangieri, D., et al. (2008). Vasculogenic mimicry by bone marrow macrophages in patients with multiple myeloma. Oncogene, 27(5), 663–674. https://doi.org/10.1038/sj.onc.1210691.

    Article  CAS  PubMed  Google Scholar 

  50. Andersen, M. N., Abildgaard, N., Maniecki, M. B., Moller, H. J., & Andersen, N. F. (2014). Monocyte/macrophage-derived soluble CD163: A novel biomarker in multiple myeloma. European Journal of Haematology, 93(1), 41–47. https://doi.org/10.1111/ejh.12296.

    Article  CAS  PubMed  Google Scholar 

  51. Andersen, M. N., Andersen, N. F., Rodgaard-Hansen, S., Hokland, M., Abildgaard, N., & Moller, H. J. (2015). The novel biomarker of alternative macrophage activation, soluble mannose receptor (sMR/sCD206): Implications in multiple myeloma. Leukemia Research, 39(9), 971–975. https://doi.org/10.1016/j.leukres.2015.06.003.

    Article  CAS  PubMed  Google Scholar 

  52. Durie, B. G., Vela, E. E., & Frutiger, Y. (1990). Macrophages as an important source of paracrine IL6 in myeloma bone marrow. Current Topics in Microbiology and Immunology, 166, 33–36. https://doi.org/10.1007/978-3-642-75889-8_4.

    Article  CAS  PubMed  Google Scholar 

  53. Kim, J., Denu, R. A., Dollar, B. A., Escalante, L. E., Kuether, J. P., Callander, N. S., Asimakopoulos, F., & Hematti, P. (2012). Macrophages and mesenchymal stromal cells support survival and proliferation of multiple myeloma cells. British Journal of Haematology, 158(3), 336–346. https://doi.org/10.1111/j.1365-2141.2012.09154.x.

    Article  PubMed  PubMed Central  Google Scholar 

  54. Tai, Y. T., Acharya, C., An, G., Moschetta, M., Zhong, M. Y., Feng, X., Cea, M., Cagnetta, A., Wen, K., van Eenennaam, H., van Elsas, A., Qiu, L., Richardson, P., Munshi, N., & Anderson, K. C. (2016). APRIL and BCMA promote human multiple myeloma growth and immunosuppression in the bone marrow microenvironment. Blood, 127(25), 3225–3236. https://doi.org/10.1182/blood-2016-01-691162.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Zheng, Y., Cai, Z., Wang, S., Zhang, X., Qian, J., Hong, S., Li, H., Wang, M., Yang, J., & Yi, Q. (2009). Macrophages are an abundant component of myeloma microenvironment and protect myeloma cells from chemotherapy drug-induced apoptosis. Blood, 114(17), 3625–3628. https://doi.org/10.1182/blood-2009-05-220285.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Wolpe, S. D., Davatelis, G., Sherry, B., Beutler, B., Hesse, D. G., Nguyen, H. T., Moldawer, L. L., Nathan, C. F., Lowry, S. F., & Cerami, A. (1988). Macrophages secrete a novel heparin-binding protein with inflammatory and neutrophil chemokinetic properties. The Journal of Experimental Medicine, 167(2), 570–581. https://doi.org/10.1084/jem.167.2.570.

    Article  CAS  PubMed  Google Scholar 

  57. Sunderkotter, C., Goebeler, M., Schulze-Osthoff, K., Bhardwaj, R., & Sorg, C. (1991). Macrophage-derived angiogenesis factors. Pharmacology & Therapeutics, 51(2), 195–216. https://doi.org/10.1016/0163-7258(91)90077-y.

    Article  CAS  Google Scholar 

  58. Ribatti, D., Nico, B., & Vacca, A. (2006). Importance of the bone marrow microenvironment in inducing the angiogenic response in multiple myeloma. Oncogene, 25(31), 4257–4266. https://doi.org/10.1038/sj.onc.1209456.

    Article  CAS  PubMed  Google Scholar 

  59. Aggarwal, R., Ghobrial, I. M., & Roodman, G. D. (2006). Chemokines in multiple myeloma. Experimental Hematology, 34(10), 1289–1295. https://doi.org/10.1016/j.exphem.2006.06.017.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Lentzsch, S., Gries, M., Janz, M., Bargou, R., Dorken, B., & Mapara, M. Y. (2003). Macrophage inflammatory protein 1-alpha (MIP-1 alpha ) triggers migration and signaling cascades mediating survival and proliferation in multiple myeloma (MM) cells. Blood, 101(9), 3568–3573. https://doi.org/10.1182/blood-2002-08-2383.

    Article  CAS  PubMed  Google Scholar 

  61. Tai, Y. T., Podar, K., Catley, L., Tseng, Y. H., Akiyama, M., Shringarpure, R., Burger, R., Hideshima, T., Chauhan, D., Mitsiades, N., Richardson, P., Munshi, N. C., Kahn, C. R., Mitsiades, C., & Anderson, K. C. (2003). Insulin-like growth factor-1 induces adhesion and migration in human multiple myeloma cells via activation of beta1-integrin and phosphatidylinositol 3′-kinase/AKT signaling. Cancer Research, 63(18), 5850–5858.

    CAS  PubMed  Google Scholar 

  62. 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. https://doi.org/10.1038/sj.bjc.6600833.

    Article  CAS  PubMed  Google Scholar 

  63. Condeelis, J., & Pollard, J. W. (2006). Macrophages: Obligate partners for tumor cell migration, invasion, and metastasis. Cell, 124(2), 263–266. https://doi.org/10.1016/j.cell.2006.01.007.

    Article  CAS  PubMed  Google Scholar 

  64. Sousa, S., & Maatta, J. (2016). The role of tumour-associated macrophages in bone metastasis. Journal of Bone Oncology, 5(3), 135–138. https://doi.org/10.1016/j.jbo.2016.03.004.

    Article  PubMed  PubMed Central  Google Scholar 

  65. Vasiliadou, I., & Holen, I. (2013). The role of macrophages in bone metastasis. Journal of Bone Oncology, 2(4), 158–166. https://doi.org/10.1016/j.jbo.2013.07.002.

    Article  PubMed  PubMed Central  Google Scholar 

  66. Lim, S. Y., Yuzhalin, A. E., Gordon-Weeks, A. N., & Muschel, R. J. (2016). Tumor-infiltrating monocytes/macrophages promote tumor invasion and migration by upregulating S100A8 and S100A9 expression in cancer cells. Oncogene, 35(44), 5735–5745. https://doi.org/10.1038/onc.2016.107.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Green, C. E., Liu, T., Montel, V., Hsiao, G., Lester, R. D., Subramaniam, S., Gonias, S. L., & Klemke, R. L. (2009). Chemoattractant signaling between tumor cells and macrophages regulates cancer cell migration, metastasis and neovascularization. PLoS One, 4(8), e6713. https://doi.org/10.1371/journal.pone.0006713.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Roh-Johnson, M., Bravo-Cordero, J. J., Patsialou, A., Sharma, V. P., Guo, P., Liu, H., Hodgson, L., & Condeelis, J. (2014). Macrophage contact induces RhoA GTPase signaling to trigger tumor cell intravasation. Oncogene, 33(33), 4203–4212. https://doi.org/10.1038/onc.2013.377.

    Article  CAS  PubMed  Google Scholar 

  69. Little, A. C., Pathanjeli, P., Wu, Z., Bao, L., Goo, L. E., Yates, J. A., Oliver, C. R., Soellner, M. B., & Merajver, S. D. (2019). IL-4/IL-13 stimulated macrophages enhance breast cancer invasion via Rho-GTPase regulation of synergistic VEGF/CCL-18 signaling. Frontiers in Oncology, 9, 456. https://doi.org/10.3389/fonc.2019.00456.

    Article  PubMed  PubMed Central  Google Scholar 

  70. Harney, A. S., Arwert, E. N., Entenberg, D., Wang, Y., Guo, P., Qian, B. Z., Oktay, M. H., Pollard, J. W., Jones, J. G., & Condeelis, J. S. (2015). Real-time imaging reveals local, transient vascular permeability, and tumor cell intravasation stimulated by TIE2hi macrophage-derived VEGFA. Cancer Discovery, 5(9), 932–943. https://doi.org/10.1158/2159-8290.CD-15-0012.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Qian, B., Deng, Y., Im, J. H., Muschel, R. J., Zou, Y., Li, J., Lang, R. A., & Pollard, J. W. (2009). A distinct macrophage population mediates metastatic breast cancer cell extravasation, establishment and growth. PLoS One, 4(8), e6562. https://doi.org/10.1371/journal.pone.0006562.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Lin, E. Y., Nguyen, A. V., Russell, R. G., & Pollard, J. W. (2001). Colony-stimulating factor 1 promotes progression of mammary tumors to malignancy. The Journal of Experimental Medicine, 193(6), 727–740. https://doi.org/10.1084/jem.193.6.727.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Chen, J., He, D., Chen, Q., Guo, X., Yang, L., Lin, X., Li, Y., Wu, W., Yang, Y., He, J., Zhang, E., Yi, Q., & Cai, Z. (2017). BAFF is involved in macrophage-induced bortezomib resistance in myeloma. Cell Death & Disease, 8(11), e3161. https://doi.org/10.1038/cddis.2017.533.

    Article  CAS  Google Scholar 

  74. Zheng, Y., Yang, J., Qian, J., Qiu, P., Hanabuchi, S., Lu, Y., Wang, Z., Liu, Z., Li, H., He, J., Lin, P., Weber, D., Davis, R. E., Kwak, L., Cai, Z., & Yi, Q. (2013). PSGL-1/selectin and ICAM-1/CD18 interactions are involved in macrophage-induced drug resistance in myeloma. Leukemia, 27(3), 702–710. https://doi.org/10.1038/leu.2012.272.

    Article  CAS  PubMed  Google Scholar 

  75. Gutierrez-Gonzalez, A., Martinez-Moreno, M., Samaniego, R., Arellano-Sanchez, N., Salinas-Munoz, L., Relloso, M., et al. (2016). Evaluation of the potential therapeutic benefits of macrophage reprogramming in multiple myeloma. Blood, 128(18), 2241–2252. https://doi.org/10.1182/blood-2016-01-695395.

    Article  CAS  PubMed  Google Scholar 

  76. Kumar, S., Witzig, T. E., Timm, M., Haug, J., Wellik, L., Kimlinger, T. K., Greipp, P. R., & Rajkumar, S. V. (2004). Bone marrow angiogenic ability and expression of angiogenic cytokines in myeloma: Evidence favoring loss of marrow angiogenesis inhibitory activity with disease progression. Blood, 104(4), 1159–1165. https://doi.org/10.1182/blood-2003-11-3811.

    Article  CAS  PubMed  Google Scholar 

  77. Vacca, A., & Ribatti, D. (2011). Angiogenesis and vasculogenesis in multiple myeloma: Role of inflammatory cells. Recent Results in Cancer Research, 183, 87–95. https://doi.org/10.1007/978-3-540-85772-3_4.

    Article  PubMed  Google Scholar 

  78. Ria, R., Reale, A., De Luisi, A., Ferrucci, A., Moschetta, M., & Vacca, A. (2011). Bone marrow angiogenesis and progression in multiple myeloma. American Journal of Blood Research, 1(1), 76–89.

    CAS  PubMed  PubMed Central  Google Scholar 

  79. Ribatti, D., & Vacca, A. (2009). The role of monocytes-macrophages in vasculogenesis in multiple myeloma. Leukemia, 23(9), 1535–1536. https://doi.org/10.1038/leu.2009.55.

    Article  CAS  PubMed  Google Scholar 

  80. Martin, S. K., To, L. B., Horvath, N., & Zannettino, A. C. W. (2004). Angiogenesis in multiple myeloma: Implications in myeloma therapy. Cancer Reviews: Asia-Pacific, 02(02), 119–129. https://doi.org/10.1142/s0219836304000470.

    Article  Google Scholar 

  81. De Luisi, A., Binetti, L., Ria, R., Ruggieri, S., Berardi, S., Catacchio, I., et al. (2013). Erythropoietin is involved in the angiogenic potential of bone marrow macrophages in multiple myeloma. Angiogenesis, 16(4), 963–973. https://doi.org/10.1007/s10456-013-9369-2.

    Article  CAS  PubMed  Google Scholar 

  82. Chen, H., Campbell, R. A., Chang, Y., Li, M., Wang, C. S., Li, J., Sanchez, E., Share, M., Steinberg, J., Berenson, A., Shalitin, D., Zeng, Z., Gui, D., Perez-Pinera, P., Berenson, R. J., Said, J., Bonavida, B., Deuel, T. F., & Berenson, J. R. (2009). Pleiotrophin produced by multiple myeloma induces transdifferentiation of monocytes into vascular endothelial cells: A novel mechanism of tumor-induced vasculogenesis. Blood, 113(9), 1992–2002. https://doi.org/10.1182/blood-2008-02-133751.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Kim, J., & Hematti, P. (2009). Mesenchymal stem cell-educated macrophages: A novel type of alternatively activated macrophages. Experimental Hematology, 37(12), 1445–1453. https://doi.org/10.1016/j.exphem.2009.09.004.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Anghelina, M., Krishnan, P., Moldovan, L., & Moldovan, N. I. (2004). Monocytes and macrophages form branched cell columns in matrigel: Implications for a role in neovascularization. Stem Cells and Development, 13(6), 665–676. https://doi.org/10.1089/scd.2004.13.665.

    Article  CAS  PubMed  Google Scholar 

  85. Kim, D., Wang, J., Willingham, S. B., Martin, R., Wernig, G., & Weissman, I. L. (2012). Anti-CD47 antibodies promote phagocytosis and inhibit the growth of human myeloma cells. Leukemia, 26(12), 2538–2545. https://doi.org/10.1038/leu.2012.141.

    Article  CAS  PubMed  Google Scholar 

  86. Sun, J., Muz, B., Alhallak, K., Markovic, M., Gurley, S., Wang, Z., Guenthner, N., Wasden, K., Fiala, M., King, J., Kohnen, D., Salama, N. N., Vij, R., & Azab, A. K. (2020). Targeting CD47 as a novel immunotherapy for multiple myeloma. Cancers (Basel), 12(2). https://doi.org/10.3390/cancers12020305.

  87. Ruffell, B., Chang-Strachan, D., Chan, V., Rosenbusch, A., Ho, C. M., Pryer, N., et al. (2014). Macrophage IL-10 blocks CD8+ T cell-dependent responses to chemotherapy by suppressing IL-12 expression in intratumoral dendritic cells. Cancer Cell, 26(5), 623–637. https://doi.org/10.1016/j.ccell.2014.09.006.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Fonseca, R., Abouzaid, S., Bonafede, M., Cai, Q., Parikh, K., Cosler, L., & Richardson, P. (2017). Trends in overall survival and costs of multiple myeloma, 2000-2014. Leukemia, 31(9), 1915–1921. https://doi.org/10.1038/leu.2016.380.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Global Burden of Disease Cancer, C, Fitzmaurice, C., Akinyemiju, T. F., Al Lami, F. H., Alam, T., Alizadeh-Navaei, R., et al. (2018). Global, regional, and national cancer incidence, mortality, years of life lost, years lived with disability, and disability-adjusted life-years for 29 cancer groups, 1990 to 2016: A systematic analysis for the global burden of disease study. JAMA Oncology, 4(11), 1553–1568. https://doi.org/10.1001/jamaoncol.2018.2706.

    Article  Google Scholar 

  90. Shen, L., Li, H., Shi, Y., Wang, D., Gong, J., Xun, J., Zhou, S., Xiang, R., & Tan, X. (2016). M2 tumour-associated macrophages contribute to tumour progression via legumain remodelling the extracellular matrix in diffuse large B cell lymphoma. Scientific Reports, 6, 30347. https://doi.org/10.1038/srep30347.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Wu, X., Schulte, B. C., Zhou, Y., Haribhai, D., Mackinnon, A. C., Plaza, J. A., Williams, C. B., & Hwang, S. T. (2014). Depletion of M2-like tumor-associated macrophages delays cutaneous T-cell lymphoma development in vivo. Journal of Investigative Dermatology, 134(11), 2814–2822. https://doi.org/10.1038/jid.2014.206.

    Article  CAS  Google Scholar 

  92. Piaggio, F., Kondylis, V., Pastorino, F., Di Paolo, D., Perri, P., Cossu, I., et al. (2016). A novel liposomal Clodronate depletes tumor-associated macrophages in primary and metastatic melanoma: Anti-angiogenic and anti-tumor effects. Journal of Controlled Release, 223, 165–177. https://doi.org/10.1016/j.jconrel.2015.12.037.

    Article  CAS  PubMed  Google Scholar 

  93. Fritz, J. M., Tennis, M. A., Orlicky, D. J., Lin, H., Ju, C., Redente, E. F., Choo, K. S., Staab, T. A., Bouchard, R. J., Merrick, D. T., Malkinson, A. M., & Dwyer-Nield, L. D. (2014). Depletion of tumor-associated macrophages slows the growth of chemically induced mouse lung adenocarcinomas. Frontiers in Immunology, 5, 587. https://doi.org/10.3389/fimmu.2014.00587.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Reusser, N. M., Dalton, H. J., Pradeep, S., Gonzalez-Villasana, V., Jennings, N. B., Vasquez, H. G., Wen, Y., Rupaimoole, R., Nagaraja, A. S., Gharpure, K., Miyake, T., Huang, J., Hu, W., Lopez-Berestein, G., & Sood, A. K. (2014). Clodronate inhibits tumor angiogenesis in mouse models of ovarian cancer. Cancer Biology & Therapy, 15(8), 1061–1067. https://doi.org/10.4161/cbt.29184.

    Article  CAS  Google Scholar 

  95. Cannarile, M. A., Weisser, M., Jacob, W., Jegg, A. M., Ries, C. H., & Ruttinger, D. (2017). Colony-stimulating factor 1 receptor (CSF1R) inhibitors in cancer therapy. Journal for Immunotherapy of Cancer, 5(1), 53. https://doi.org/10.1186/s40425-017-0257-y.

    Article  PubMed  PubMed Central  Google Scholar 

  96. Ries, C. H., Cannarile, M. A., Hoves, S., Benz, J., Wartha, K., Runza, V., Rey-Giraud, F., Pradel, L. P., Feuerhake, F., Klaman, I., Jones, T., Jucknischke, U., Scheiblich, S., Kaluza, K., Gorr, I. H., Walz, A., Abiraj, K., Cassier, P. A., Sica, A., Gomez-Roca, C., de Visser, K. E., Italiano, A., le Tourneau, C., Delord, J. P., Levitsky, H., Blay, J. Y., & Rüttinger, D. (2014). Targeting tumor-associated macrophages with anti-CSF-1R antibody reveals a strategy for cancer therapy. Cancer Cell, 25(6), 846–859. https://doi.org/10.1016/j.ccr.2014.05.016.

    Article  CAS  PubMed  Google Scholar 

  97. Gomez-Roca, C. A., Italiano, A., Le Tourneau, C., Cassier, P. A., Toulmonde, M., D'Angelo, S. P., et al. (2019). Phase I study of emactuzumab single agent or in combination with paclitaxel in patients with advanced/metastatic solid tumors reveals depletion of immunosuppressive M2-like macrophages. Annals of Oncology, 30(8), 1381–1392. https://doi.org/10.1093/annonc/mdz163.

    Article  CAS  PubMed  Google Scholar 

  98. von Tresckow, B., Morschhauser, F., Ribrag, V., Topp, M. S., Chien, C., Seetharam, S., Aquino, R., Kotoulek, S., de Boer, C. J., & Engert, A. (2015). An open-label, multicenter, phase I/II study of JNJ-40346527, a CSF-1R inhibitor, in patients with relapsed or refractory Hodgkin lymphoma. Clinical Cancer Research, 21(8), 1843–1850. https://doi.org/10.1158/1078-0432.CCR-14-1845.

    Article  CAS  Google Scholar 

  99. Cassier, P. A., Italiano, A., Gomez-Roca, C. A., Le Tourneau, C., Toulmonde, M., Cannarile, M. A., et al. (2015). CSF1R inhibition with emactuzumab in locally advanced diffuse-type tenosynovial giant cell tumours of the soft tissue: A dose-escalation and dose-expansion phase 1 study. The Lancet Oncology, 16(8), 949–956. https://doi.org/10.1016/S1470-2045(15)00132-1.

    Article  CAS  PubMed  Google Scholar 

  100. Chen, H., Li, M., Sanchez, E., Soof, C. M., Bujarski, S., Ng, N., Cao, J., Hekmati, T., Zahab, B., Nosrati, J. D., Wen, M., Wang, C. S., Tang, G., Xu, N., Spektor, T. M., & Berenson, J. R. (2019). JAK1/2 pathway inhibition suppresses M2 polarization and overcomes resistance of myeloma to lenalidomide by reducing TRIB1, MUC1, CD44, CXCL12, and CXCR4 expression. British Journal of Haematology, 188, 283–294. https://doi.org/10.1111/bjh.16158.

    Article  CAS  PubMed  Google Scholar 

  101. Li, Y. (2019). CD47 blockade and rituximab in non-Hodgkin’s lymphoma. The New England Journal of Medicine, 380(5), 497–498. https://doi.org/10.1056/NEJMc1816156.

    Article  PubMed  Google Scholar 

  102. Majeti, R., Chao, M. P., Alizadeh, A. A., Pang, W. W., Jaiswal, S., Gibbs Jr., K. D., van Rooijen, N., & Weissman, I. L. (2009). CD47 is an adverse prognostic factor and therapeutic antibody target on human acute myeloid leukemia stem cells. Cell, 138(2), 286–299. https://doi.org/10.1016/j.cell.2009.05.045.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Michaels, A. D., Newhook, T. E., Adair, S. J., Morioka, S., Goudreau, B. J., Nagdas, S., Mullen, M. G., Persily, J. B., Bullock, T. N. J., Slingluff Jr., C. L., Ravichandran, K. S., Parsons, J. T., & Bauer, T. W. (2018). CD47 blockade as an adjuvant immunotherapy for resectable pancreatic cancer. Clinical Cancer Research, 24(6), 1415–1425. https://doi.org/10.1158/1078-0432.CCR-17-2283.

    Article  CAS  PubMed  Google Scholar 

  104. Weiskopf, K., Jahchan, N. S., Schnorr, P. J., Cristea, S., Ring, A. M., Maute, R. L., Volkmer, A. K., Volkmer, J. P., Liu, J., Lim, J. S., Yang, D., Seitz, G., Nguyen, T., Wu, D., Jude, K., Guerston, H., Barkal, A., Trapani, F., George, J., Poirier, J. T., Gardner, E. E., Miles, L. A., de Stanchina, E., Lofgren, S. M., Vogel, H., Winslow, M. M., Dive, C., Thomas, R. K., Rudin, C. M., van de Rijn, M., Majeti, R., Garcia, K. C., Weissman, I. L., & Sage, J. (2016). CD47-blocking immunotherapies stimulate macrophage-mediated destruction of small-cell lung cancer. The Journal of Clinical Investigation, 126(7), 2610–2620. https://doi.org/10.1172/JCI81603.

    Article  PubMed  PubMed Central  Google Scholar 

  105. Advani, R., Flinn, I., Popplewell, L., Forero, A., Bartlett, N. L., Ghosh, N., Kline, J., Roschewski, M., LaCasce, A., Collins, G. P., Tran, T., Lynn, J., Chen, J. Y., Volkmer, J. P., Agoram, B., Huang, J., Majeti, R., Weissman, I. L., Takimoto, C. H., Chao, M. P., & Smith, S. M. (2018). CD47 blockade by Hu5F9-G4 and rituximab in non-Hodgkin’s lymphoma. The New England Journal of Medicine, 379(18), 1711–1721. https://doi.org/10.1056/NEJMoa1807315.

    Article  CAS  PubMed  Google Scholar 

  106. Brierley, C. K., Staves, J., Roberts, C., Johnson, H., Vyas, P., Goodnough, L. T., & Murphy, M. F. (2019). The effects of monoclonal anti-CD47 on RBCs, compatibility testing, and transfusion requirements in refractory acute myeloid leukemia. Transfusion, 59(7), 2248–2254. https://doi.org/10.1111/trf.15397.

    Article  CAS  PubMed  Google Scholar 

  107. Zheng, J., Yang, M., Shao, J., Miao, Y., Han, J., & Du, J. (2013). Chemokine receptor CX3CR1 contributes to macrophage survival in tumor metastasis. Molecular Cancer, 12(1), 141. https://doi.org/10.1186/1476-4598-12-141.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Funding

This work was supported by a National Health and Medical Research Council Project Grant [A.C.W.Z., J.E.N.; APP1140996]. K.V. was supported by an Early Career Cancer Research Fellowship from the Cancer Council SA Beat Cancer Project on behalf of its donors and the State Government of South Australia through the Department of Health. P.J.P. is a recipient of a L2 Future Leader Fellowship from the National Heart Foundation of Australia (FLF102056) and a L2 Career Development Fellowship from the National Health and Medical Research Council of Australia (CDF1161506). J.E.N. was supported by a Veronika Sacco Clinical Cancer Research Fellowship from the Florey Medical Research Foundation, University of Adelaide.

Author information

Authors and Affiliations

  1. Myeloma Research Laboratory, Adelaide Medical School, Faculty of Health and Medical Sciences, University of Adelaide, Adelaide, SA, Australia

    Khatora S. Opperman, Kate Vandyke, Jacqueline E. Noll & Andrew C. W. Zannettino

  2. Cancer Program, Precision Medicine Theme, South Australian Health and Medical Research Institute, Level 5 South, SAHMRI, PO Box 11060, Adelaide, SA, 5001, Australia

    Khatora S. Opperman, Kate Vandyke, Jacqueline E. Noll & Andrew C. W. Zannettino

  3. Vascular Research Centre, Heart and Vascular Program, Lifelong Health Theme, South Australian Health and Medical Research Institute, Adelaide, SA, Australia

    Peter J. Psaltis

  4. Central Adelaide Local Health Network, Adelaide, SA, Australia

    Peter J. Psaltis & Andrew C. W. Zannettino

Authors
  1. Khatora S. Opperman
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Kate Vandyke
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Peter J. Psaltis
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Jacqueline E. Noll
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Andrew C. W. Zannettino
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

All authors contributed to the development of this review article. Critical analysis and review of the literature were performed by Khatora S. Opperman. The manuscript was written by Khatora S. Opperman with revisions provided by Kate Vandyke, Peter J. Psaltis, Jacqueline E. Noll and Andrew C.W. Zannettino.

Corresponding author

Correspondence to Jacqueline E. Noll.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Ethics approval

Not applicable.

Consent to participate

Not applicable.

Consent for publication

All authors have read and approved the final version of the manuscript and consent to publication.

Code availability

Not applicable.

Additional information

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Opperman, K.S., Vandyke, K., Psaltis, P.J. et al. Macrophages in multiple myeloma: key roles and therapeutic strategies. Cancer Metastasis Rev 40, 273–284 (2021). https://doi.org/10.1007/s10555-020-09943-1

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10555-020-09943-1

Keywords

Search

Navigation