Skip to main content

Advertisement

Log in

Bone marrow myeloid cells in regulation of multiple myeloma progression

  • Focussed Research Review
  • Published:
Cancer Immunology, Immunotherapy Aims and scope Submit manuscript

Abstract

Survival, growth, and response to chemotherapy of cancer cells depends strongly on the interaction of cancer cells with the tumor microenvironment. In multiple myeloma, a cancer of plasma cells that localizes preferentially in the bone marrow, the microenvironment is highly enriched with myeloid cells. The majority of myeloid cells are represented by mature and immature neutrophils. The contribution of the different myeloid cell populations to tumor progression and chemoresistance in multiple myeloma is discussed.

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

Access this article

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

Instant access to the full article PDF.

Fig. 1

Similar content being viewed by others

Abbreviations

CCL:

Chemokine (C–C motif) ligand

mDCs:

Myeloid dendritic cells

MM:

Multiple myeloma

M-MDSCs:

Monocytic myeloid-derived suppressor cells

NETs:

Neutrophil extracellular traps

OCL:

Osteoclasts

pDCs:

Plasmacytoid dendritic cells

PMN-MDSCs:

Polymorphonuclear myeloid-derived suppressor cells

PSGL-1:

P-selectin glycoprotein ligand

RANK:

Receptor activator of NK-kappaB

RANKL:

Receptor activator of NK-kappaB ligand

TME:

Tumor microenvironment

References

  1. Meads M, Gatenby R, Dalton W (2009) Environment-mediated drug resistance: a major contributor to minimal residual disease. Nat Rev Cancer 9(9):665–674

    Article  CAS  PubMed  Google Scholar 

  2. ACS (2017) Cancer facts and figs. 2017. American Cancer Society. http://www.cancer.org/research/cancer-facts-statistics/all-cancer-facts-figures/cancer-facts-figures-2017.html. Accessed 27 Jan 2017

  3. Bain B, Clark D, Lampert I, Wilkins B (2001) Bone marrow pathology, 3rd edn. Blackwell Science, Oxford

    Book  Google Scholar 

  4. Wong D, Winter O, Hartig C, Siebels S, Szyska M, Tiburzy B, Meng L, Kulkarni U, Fähnrich A, Bommert K, Bargou R, Berek C, Chu V, Bogen B, Jundt F, Manz R (2014) Eosinophils and megakaryocytes support the early growth of murine MOPC315 myeloma cells in their bone marrow niches. PLoS One 9(10):e109018

    Article  PubMed  PubMed Central  Google Scholar 

  5. Chu V, Fröhlich A, Steinhauser G, Scheel T, Roch T, Fillatreau S, Lee J, Löhning M, Berek C (2011) Eosinophils are required for the maintenance of plasma cells in the bone marrow. Nat Immunol 12(2):151–159

    Article  CAS  PubMed  Google Scholar 

  6. Wong T, Kita H, Hanson C, Walters D, Arendt B, Jelinek D (2013) Induction of malignant plasma cell proliferation by eosinophils. PLoS One 8(7):e70554

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Bronte V, Brandau S, Chen S, Colombo M, Frey A, Greten T, Mandruzzato S, Murray P, Ochoa A, Ostrand-Rosenberg S, Rodriguez P, Sica A, Umansky V, Vonderheide R, Gabrilovich D (2016) Recommendations for myeloid-derived suppressor cell nomenclature and characterization standards. Nat Commun 7:12150

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Condamine T, Dominguez GA, Youn JI, Kossenkov AV, Mony S, Alicea-Torres K, Tcyganov E, Hashimoto A, Nefedova Y, Lin C, Partlova S, Garfall A, Vogl DT, Xu X, Knight SC, Malietzis G, Lee GH, Eruslanov E, Albelda SM, Wang X, Mehta JL, Bewtra M, Rustgi A, Hockstein N, Witt R, Masters G, Nam B, Smirnov D, Sepulveda MA, Gabrilovich DI (2016) Lectin-type oxidized LDL receptor-1 distinguishes population of human polymorphonuclear myeloid-derived suppressor cells in cancer patients. Sci Immunol 1(2):aaf8943. doi:10.1126/sciimmunol.aaf8943

    Article  PubMed  PubMed Central  Google Scholar 

  9. Ramachandran I, Condamine T, Lin C, Herlihy S, Garfall A, Vogl D, Gabrilovich D, Nefedova Y (2016) Bone marrow PMN-MDSCs and neutrophils are functionally similar in protection of multiple myeloma from chemotherapy. Cancer Lett 371(1):117–124

    Article  CAS  PubMed  Google Scholar 

  10. Binsfeld M, Muller J, Lamour V, De Veirman K, De Raeve H, Bellahcène A, Van Valckenborgh E, Baron F, Beguin Y, Caers J, Heusschen R (2016) Granulocytic myeloid-derived suppressor cells promote angiogenesis in the context of multiple myeloma. Oncotarget 7(25):37931–37943

    PubMed  PubMed Central  Google Scholar 

  11. Gorgun G, Whitehill G, Anderson J, Hideshima T, Maguire C, Laubach J, Raje N, Munshi N, Richardson P, Anderson K (2013) Tumor-promoting immune-suppressive myeloid-derived suppressor cells in the multiple myeloma microenvironment in humans. Blood 121(15):2975–2987

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Favaloro J, Liyadipitiya T, Brown R, Yang S, Suen H, Woodland N, Nassif N, Hart D, Fromm P, Weatherburn C, Gibson J, Ho P, Joshua D (2014) Myeloid derived suppressor cells are numerically, functionally and phenotypically different in patients with multiple myeloma. Leuk Lymphoma 55(12):2893–2900

    Article  CAS  PubMed  Google Scholar 

  13. Van Valckenborgh E, Schouppe E, Movahedi K, De Bruyne E, Menu E, De Baetselier P, Vanderkerken K, Van Ginderachter J (2012) Multiple myeloma induces the immunosuppressive capacity of distinct myeloid-derived suppressor cell subpopulations in the bone marrow. Leukemia 26(11):2424–2428

    Article  PubMed  Google Scholar 

  14. Ramachandran I, Martner A, Pisklakova A, Condamine T, Chase T, Vogl T, Roth J, Gabrilovich D, Nefedova Y (2013) Myeloid-derived suppressor cells regulate growth of multiple myeloma by inhibiting T cells in bone marrow. J Immunol 190(7):3815–3823

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Serafini P, Meckel K, Kelso M, Noonan K, Califano J, Koch W, Dolcetti L, Bronte V, Borrello I (2006) Phosphodiesterase-5 inhibition augments endogenous antitumor immunity by reducing myeloid-derived suppressor cell function. J Exp Med 203(12):2691–2702

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Ramachandran IR, Martner A, Pisklakova A, Condamine T, Chase T, Vogl T, Roth J, Gabrilovich D, Nefedova Y (2013) Myeloid-derived suppressor cells regulate growth of multiple myeloma by inhibiting T cells in bone marrow. J Immunol 190(7):3815–3823. doi:10.4049/jimmunol.1203373

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. De Veirman K, Van Ginderachter J, Lub S, De Beule N, Thielemans K, Bautmans I, Oyajobi B, De Bruyne E, Menu E, Lemaire M, Van Riet I, Vanderkerken K, Van Valckenborgh E (2015) Multiple myeloma induces Mcl-1 expression and survival of myeloid-derived suppressor cells. Oncotarget 6(12):10532–10547

    Article  PubMed  PubMed Central  Google Scholar 

  18. Urban CF, Ermert D, Schmid M, Abu-Abed U, Goosmann C, Nacken W, Brinkmann V, Jungblut PR, Zychlinsky A (2009) Neutrophil extracellular traps contain calprotectin, a cytosolic protein complex involved in host defense against Candida albicans. PLoS Pathog 5(10):e1000639. doi:10.1371/journal.ppat.1000639

    Article  PubMed  PubMed Central  Google Scholar 

  19. Park J, Wysocki R, Amoozgar Z, Maiorino L, Fein M, Jorns J, Schott A, Kinugasa-Katayama Y, Lee Y, Won N, Nakasone E, Hearn S, Küttner V, Qiu J, Almeida A, Perurena N, Kessenbrock K, Goldberg M, Egeblad M (2016) Cancer cells induce metastasis-supporting neutrophil extracellular DNA traps. Sci Transl Med 8(361):361ra138

    Article  PubMed  Google Scholar 

  20. Tohme S, Yazdani H, Al-Khafaji A, Chidi A, Loughran P, Mowen K, Wang Y, Simmons R, Huang H, Tsung A (2016) Neutrophil extracellular traps promote the development and progression of liver metastases after surgical stress. Cancer Res 76(6):1367–1380

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Demers M, Wong S, Martinod K, Gallant M, Cabral J, Wang Y, Wagner D (2016) Priming of neutrophils toward NETosis promotes tumor growth. Oncoimmunology 5(5):e1134073

    Article  PubMed  PubMed Central  Google Scholar 

  22. Berger-Achituv S, Brinkmann V, Abed UA, Kühn LI, Ben-Ezra J, Elhasid R, Zychlinsky A (2013) A proposed role for neutrophil extracellular traps in cancer immunoediting. Front Immunol 4:48. doi:10.3389/fimmu.2013.00048

    Article  PubMed  PubMed Central  Google Scholar 

  23. Sangaletti S, Tripodo C, Vitali C, Portararo P, Guarnotta C, Casalini P, Cappetti B, Miotti S, Pinciroli P, Fuligni F, Fais F, Piccaluga PP, Colombo M (2014) Defective stromal remodeling and neutrophil extracellular traps in lymphoid tissues favor the transition from autoimmunity to lymphoma. Cancer Discov 4(1):110–129

    Article  CAS  PubMed  Google Scholar 

  24. Cools-Lartigue J, Spicer J, McDonald B, Gowing S, Chow S, Giannias B, Bourdeau F, Kubes P, Ferri L (2013) Neutrophil extracellular traps sequester circulating tumor cells and promote metastasis. J Clin Invest 123(8):3446–3458

    Article  CAS  PubMed Central  Google Scholar 

  25. Cools-Lartigue J, Spicer J, Najmeh S, Ferri L (2014) Neutrophil extracellular traps in cancer progression. Cell Mol Life Sci 71(21):4179–4194

    Article  CAS  PubMed  Google Scholar 

  26. Ericson S, Zhao Y, Gao H, Miller K, Gibson L, Lynch J, Landreth K (1998) Interleukin-6 production by human neutrophils after Fc-receptor cross-linking or exposure to granulocyte colony-stimulating factor. Blood 91(6):2099–2107

    CAS  PubMed  Google Scholar 

  27. Sawant A, Deshane J, Jules J, Lee C, Harris B, Feng X, Ponnazhagan S (2013) Myeloid-derived suppressor cells function as novel osteoclast progenitors enhancing bone loss in breast cancer. Cancer Res 73(2):672–682

    Article  CAS  PubMed  Google Scholar 

  28. Zhuang J, Zhang J, Lwin S, Edwards J, Edwards C, Mundy G, Yang X (2012) Osteoclasts in multiple myeloma are derived from Gr-1+CD11b+myeloid-derived suppressor cells. PLoS One 7(11):e48871

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. 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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Suyanı E, Sucak G, Akyürek N, Sahin S, Baysal N, Yağcı M, Haznedar R (2013) Tumor-associated macrophages as a prognostic parameter in multiple myeloma. Ann Hematol 92(5):669–677

    Article  PubMed  Google Scholar 

  31. 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

    Article  CAS  PubMed  Google Scholar 

  32. 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, 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

    Article  CAS  PubMed  Google Scholar 

  33. Gutiérrez-González A, Martínez-Moreno M, Samaniego R, Arellano-Sánchez N, Salinas-Muñoz L, Relloso M, Valeri A, Martínez-López J, Corbí Á, Hidalgo A, García-Pardo Á, Teixidó J, Sánchez-Mateos P (2016) Evaluation of the potential therapeutic benefits of macrophage reprogramming in multiple myeloma. Blood 128(18):2241–2252

    Article  PubMed  Google Scholar 

  34. Beyar-Katz O, Magidey K, Ben-Tsedek N, Alishekevitz D, Timaner M, Miller V, Lindzen M, Yarden Y, Avivi I, Shaked Y (2016) Bortezomib-induced pro-inflammatory macrophages as a potential factor limiting anti-tumour efficacy. J Pathol 239(3):262–273

    Article  CAS  PubMed  Google Scholar 

  35. Li Y, Zheng Y, Li T, Wang Q, Qian J, Lu Y, Zhang M, Bi E, Yang M, Reu F, Yi Q, Cai Z (2015) Chemokines CCL2, 3, 14 stimulate macrophage bone marrow homing, proliferation, and polarization in multiple myeloma. Oncotarget 6(27):24218–24229

    Article  PubMed  PubMed Central  Google Scholar 

  36. Lee C, Oh J, Park J, Choi J, Bae E, Lee H, Jung W, Lee D, Ahn K, Yoon S (2013) TNF α mediated IL-6 secretion is regulated by JAK/STAT pathway but not by MEK phosphorylation and AKT phosphorylation in U266 multiple myeloma cells. Biomed Res Int 2013:580135

    PubMed  PubMed Central  Google Scholar 

  37. Alexandrakis M, Goulidaki N, Pappa C, Boula A, Psarakis F, Neonakis I, Tsirakis G (2015) Interleukin-10 induces both plasma cell proliferation and angiogenesis in multiple myeloma. Pathol Oncol Res 21(4):929–934

    Article  CAS  PubMed  Google Scholar 

  38. Colonna M, Trinchieri G, Liu Y (2004) Plasmacytoid dendritic cells in immunity. Nat Immunol 5(12):1219–1226

    Article  CAS  PubMed  Google Scholar 

  39. O’Doherty U, Peng M, Gezelter S, Swiggard W, Betjes M, Bhardwaj N, Steinman R (1994) Human blood contains two subsets of dendritic cells, one immunologically mature and the other immature. Immunology 82(3):487–493

    PubMed  PubMed Central  Google Scholar 

  40. Chauhan D, Singh A, Brahmandam M, Carrasco R, Bandi M, Hideshima T, Bianchi G, Podar K, Tai Y, Mitsiades C, Raje N, Jaye D, Kumar S, Richardson P, Munshi N, Anderson K (2009) Functional interaction of plasmacytoid dendritic cells with multiple myeloma cells: a therapeutic target. Cancer Cell 16(4):309–323

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Ratta M, Fagnoni F, Curti A, Vescovini R, Sansoni P, Oliviero B, Fogli M, Ferri E, Della Cuna G, Tura S, Baccarani M, Lemoli R (2002) Dendritic cells are functionally defective in multiple myeloma: the role of interleukin-6. Blood 100(1):230–237

    Article  CAS  PubMed  Google Scholar 

  42. Ray A, Tian Z, Das D, Coffman R, Richardson P, Chauhan D, Anderson K (2014) A novel TLR-9 agonist C792 inhibits plasmacytoid dendritic cell-induced myeloma cell growth and enhance cytotoxicity of bortezomib. Leukemia 28(8):1716–1724

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Brimnes M, Svane I, Johnsen H (2006) Impaired functionality and phenotypic profile of dendritic cells from patients with multiple myeloma. Clin Exp Immunol 144(1):76–84

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Bahlis N, King A, Kolonias D, Carlson L, Liu H, Hussein M, Terebelo H, Byrne GJ, Levine B, Boise L, Lee K (2007) CD28-mediated regulation of multiple myeloma cell proliferation and survival. Blood 109(11):5002–5010

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Murray M, Gavile C, Nair J, Koorella C, Carlson L, Buac D, Utley A, Chesi M, Bergsagel P, Boise L, Lee K (2014) CD28-mediated pro-survival signaling induces chemotherapeutic resistance in multiple myeloma. Blood 123(24):3770–3779

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Walker R, Lawson M, Buckle, CH, Snowden J, Chantry A (2014) Myeloma bone disease: pathogenesis, current treatments and future targets. Br Med Bull 111(1):117–138

    Article  CAS  PubMed  Google Scholar 

  47. Abe M, Hiura K, Wilde J, Shioyasono A, Moriyama K, Hashimoto T, Kido S, Oshima T, Shibata H, Ozaki S, Inoue D, Matsumoto T (2004) Osteoclasts enhance myeloma cell growth and survival via cell–cell contact: a vicious cycle between bone destruction and myeloma expansion. Blood 104(8):2484–2491

    Article  CAS  PubMed  Google Scholar 

  48. Yaccoby S, Wezeman MJ, Henderson A, Cottler-Fox M, Yi Q, Barlogie B, Epstein J (2004) Cancer and the microenvironment: myeloma-osteoclast interactions as a model. Cancer Res 64(6):2016–2023

    Article  CAS  PubMed  Google Scholar 

  49. Lawson M, McDonald M, Kovacic N, Hua Khoo W, Terry R, Down J, Kaplan W, Paton-Hough J, Fellows C, Pettitt J, Neil Dear T, Van Valckenborgh E, Baldock P, Rogers M, Eaton C, Vanderkerken K, Pettit A, Quinn J, Zannettino A, Phan T, Croucher P (2015) Osteoclasts control reactivation of dormant myeloma cells by remodelling the endosteal niche. Nat Commun 6:8983

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Terpos E, Szydlo R, Apperley J, Hatjiharissi E, Politou M, Meletis J, Viniou N, Yataganas X, Goldman J, Rahemtulla A (2003) Soluble receptor activator of nuclear factor kappaB ligand-osteoprotegerin ratio predicts survival in multiple myeloma: proposal for a novel prognostic index. Blood 102(3):1064–1069

    Article  CAS  PubMed  Google Scholar 

  51. Farrugia A, Atkins G, To L, Pan B, Horvath N, Kostakis P, Findlay D, Bardy P, Zannettino A (2003) Receptor activator of nuclear factor-kappaB ligand expression by human myeloma cells mediates osteoclast formation in vitro and correlates with bone destruction in vivo. Cancer Res 63(17):5438–5445

    CAS  PubMed  Google Scholar 

  52. Standal T, Seidel C, Hjertner Ø, Plesner T, Sanderson R, Waage A, Borset M, Sundan A (2002) Osteoprotegerin is bound, internalized, and degraded by multiple myeloma cells. Blood 100(8):3002–3007

    Article  CAS  PubMed  Google Scholar 

  53. Schmiedel B, Scheible C, Nuebling T, Kopp H, Wirths S, Azuma M, Schneider P, Jung G, Grosse-Hovest L, Salih H (2013) RANKL expression, function, and therapeutic targeting in multiple myeloma and chronic lymphocytic leukemia. Cancer Res 73(2):683–694

    Article  CAS  PubMed  Google Scholar 

  54. Tsubaki M, Takeda T, Yoshizumi M, Ueda E, Itoh T, Imano M, Satou T, Nishida S (2016) RANK-RANKL interactions are involved in cell adhesion-mediated drug resistance in multiple myeloma cell lines. Tumour Biol 37(7):9099–9110

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

This work was supported by the National Institute of Health grants CA195020 and CA196788 (to Yulia Nefedova) and T32CA009171 (to Sarah E. Herlihy). The authors would like to thank Rachel E. Locke, PhD, for helping with the preparation of the manuscript.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Yulia Nefedova.

Ethics declarations

Conflict of interest

The authors declare no financial interests relevant to the subject of this paper.

Additional information

This paper is a Focussed Research Review based on a presentation given at the conference Regulatory Myeloid Suppressor Cells: From Basic Discovery to Therapeutic Application which was hosted by the Wistar Institute in Philadelphia, PA, USA, 16th–19th June, 2016. It is part of a Cancer Immunology, Immunotherapy series of Focussed Research Reviews.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Herlihy, S.E., Lin, C. & Nefedova, Y. Bone marrow myeloid cells in regulation of multiple myeloma progression. Cancer Immunol Immunother 66, 1007–1014 (2017). https://doi.org/10.1007/s00262-017-1992-0

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00262-017-1992-0

Keywords

Navigation