Bone Marrow Niche: Role of Different Cells in Bone Metastasis
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Purpose of Review
This report summarizes current knowledge of bone marrow hematopoietic stem cell (HSC) niche, focusing on the identification of niche cells and molecular mechanisms involved in HSC maintenance and bone metastasis.
Novel imaging techniques are greatly improving our understanding of bone marrow niche and latest studies have revealed several complex multicellular regulatory mechanisms of niche function. Especially, the intriguing role of bone marrow macrophages and osteomacs is an emerging topic in the field. It appears that, e.g., macrophage polarization is important for communication with bone marrow stromal cells (BMSCs). Bone marrow is also a favorable environment for disseminated tumor cells and recent data shows that various niche cell types, including endothelial cells and BMSCs, regulate the progression of bone metastasis.
Bone marrow niche represents a multicellular system with complex interactions. Emerging data is providing us with a deeper understanding of this fascinating tissue and its role in metastasis.
KeywordsBone marrow niche Hematopoietic stem cells Bone marrow stromal cells Myeloid cells Bone metastasis Disseminated tumor cells
Compliance with Ethical Standards
Conflict of Interest
Terhi J. Heino and Jorma A. Määttä declare no conflicts of interest.
Human and Animal Rights and Informed Consent
This article does not contain any studies with human or animal subjects performed by any of the authors.
Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance
- 5.Shiozawa Y, Pedersen EA, Havens AM, Jung Y, Mishra A, Joseph J, et al. Human prostate cancer metastases target the hematopoietic stem cell niche to establish footholds in mouse bone marrow. J Clin Invest. 2011;121(4):1298–312. https://doi.org/10.1172/JCI43414.CrossRefPubMedPubMedCentralGoogle Scholar
- 6.Wang N, Docherty FE, Brown HK, Reeves KJ, Fowles AC, Ottewell PD, et al. Prostate cancer cells preferentially home to osteoblast-rich areas in the early stages of bone metastasis: evidence from in vivo models. J Bone Miner Res. 2014;29(12):2688–96. https://doi.org/10.1002/jbmr.2300.CrossRefPubMedGoogle Scholar
- 15.Nombela-Arrieta C, Pivarnik G, Winkel B, Canty KJ, Harley B, Mahoney JE, et al. Quantitative imaging of haematopoietic stem and progenitor cell localization and hypoxic status in the bone marrow microenvironment. Nat Cell Biol. 2013;15(5):533–43. https://doi.org/10.1038/ncb2730.CrossRefPubMedPubMedCentralGoogle Scholar
- 17.• Shimoto M, Sugiyama T, Nagasawa T. Numerous niches for hematopoietic stem cells remain empty during homeostasis. Blood. 2017;129(15):2124–31. https://doi.org/10.1182/blood-2016-09-740563. This article reveals that in contrast to previous assumptions many of the potential HSC niches in bone marrow are empty at normal conditions. CrossRefPubMedGoogle Scholar
- 18.•• Coutu DL, Kokkaliaris KD, Kunz L, Schroeder T. Three-dimensional map of nonhematopoietic bone and bone-marrow cells and molecules. Nature. Biotech. 2017;35(12):1202–10. https://doi.org/10.1038/nbt.4006. Here, for the first time, the spatial distribution of various cell populations and extracellular structures in bone marrow are presented in detail and the image databank is now available for the scientific community. Google Scholar
- 19.• Greenbaum A, Chan KY, Dobreva T, Brown D, Balani DH, Boyce R, et al. Bone CLARITY: clearing, imaging, and computational analysis of osteoprogenitors within intact bone marrow. Sci Transl Med. 2017;9(387):eaah6518. https://doi.org/10.1126/scitranslmed.aah6518. The methodology presented in this communication significantly improves the possibilities to analyze bone marrow niche composition and structure. CrossRefPubMedGoogle Scholar
- 21.Leisten I, Kramann R, Ventura Ferreira MS, Bovi M, Neuss S, Ziegler P, et al. 3D co-culture of hematopoietic stem and progenitor cells and mesenchymal stem cells in collagen scaffolds as a model of the hematopoietic niche. Biomaterials. 2012;33(6):1736–47. https://doi.org/10.1016/j.biomaterials.2011.11.034.CrossRefPubMedGoogle Scholar
- 26.Chow A, Lucas D, Hidalgo A, Méndez-Ferrer S, Hashimoto D, Scheiermann C, et al. Bone marrow CD169+ macrophages promote the retention of hematopoietic stem and progenitor cells in the mesenchymal stem cell niche. J Exp Med. 2011;208(2):261–71. https://doi.org/10.1084/jem.20101688.CrossRefPubMedPubMedCentralGoogle Scholar
- 43.Rucci N, Teti A. Osteomimicry: how the seed grows in the soil. Calcif Tissue Int. 2017; https://doi.org/10.1007/s00223-017-0365-1.
- 47.Ono M, Kosaka N, Tominaga N, Yoshioka Y, Takeshita F, Takahashi RU, et al. Exosomes from bone marrow mesenchymal stem cells contain a microRNA that promotes dormancy in metastatic breast cancer cells. Sci Signal. 2014;7(332):ra63. https://doi.org/10.1126/scisignal.2005231.CrossRefPubMedGoogle Scholar
- 48.Bliss SA, Sinha G, Sandiford OA, Williams LM, Engelberth DJ, Guiro K, et al. Mesenchymal stem cell-derived exosomes stimulate cycling quiescence and early breast cancer dormancy in bone marrow. Cancer Res. 2016;76(19):5832–44. https://doi.org/10.1158/0008-5472.CAN-16-1092.CrossRefPubMedGoogle Scholar
- 51.Butler JM, Nolan DJ, Vertes EL, Varnum-Finney B, Kobayashi H, Hooper AT, et al. Endothelial cells are essential for the self-renewal and repopulation of Notch-dependent hematopoietic stem cells. Cell Stem Cell. 2010;6(3):251–64. https://doi.org/10.1016/j.stem.2010.02.001.CrossRefPubMedPubMedCentralGoogle Scholar
- 57.•• Mohamad SF, Xu L, Ghosh J, Childress PJ, Abeysekera I, Himes ER, et al. Osteomacs interact with megakaryocytes and osteoblasts to regulate murine hematopoietic stem cell function. Blood Adv. 2017;1(26):2520–8. https://doi.org/10.1182/bloodadvances.2017011304. In this study, a crosstalk between osteomacs, osteoblasts, and megakaryocytes in regulation of HSCs is presented for the first time. Further, the phenotype and function of osteomacs were shown to differ from bone marrow macrophages in this context. CrossRefPubMedPubMedCentralGoogle Scholar
- 59.• Alexander KA, Raggatt LJ, Millard S, Batoon L, Chiu-Ku Wu A, Chang MK, et al. Resting and injury-induced inflamed periosteum contain multiple macrophage subsets that are located at sites of bone growth and regeneration. Immunol Cell Biol. 2017;95(1):7–16. https://doi.org/10.1038/icb.2016.74. This study demonstrates the heterogeneity of osteomacs during trauma healing. CrossRefPubMedGoogle Scholar
- 66.•• Hur J, Choi JI, Lee H, Nham P, Kim TW, Chae CW, et al. CD82/KAI1 maintains the dormancy of long-term hematopoietic stem cells through interaction with DARC-expressing macrophages. Cell Stem Cell. 2016;18(4):508–21. https://doi.org/10.1016/j.stem.2016.01.013. This article identifies a novel interaction mechanism, by which a specific subset of macrophages maintains the dormancy of HSCs. It is possible that similar mechanisms could also play a role in DTC dormancy. CrossRefPubMedGoogle Scholar
- 68.•• Espagnolle N, Balguerie A, Arnaud E, Sensebé L, Varin A. CD54-mediated interaction with pro-inflammatory macrophages increases the immunosuppressive function of human mesenchymal stromal cells. Stem Cell Rep. 2017;8(4):961–76. https://doi.org/10.1016/j.stemcr.2017.02.008. In this communication different signaling mechanisms were shown to be active in M1 and M2 polarized macrophages in regulation of the immunosuppressive functions of MSCs. This finding may be critical in MSC-based cell therapies. CrossRefGoogle Scholar
- 70.• Soki FN, Cho SW, Kim YW, Jones JD, Park SI, Koh AJ, et al. Bone marrow macrophages support prostate cancer growth in bone. Oncotarget. 2015;3;6(34):35782–96. https://doi.org/10.18632/oncotarget.6042. This publication demonstrates that cancer cells similarly alter macrophage phenotype in bone marrow microenvironment as has previously been demonstrated for soft tissues. Google Scholar
- 79.•• Zhuang X, Zhang H, Li X, Li X, Cong M, Peng F, et al. Differential effects on lung and bone metastasis of breast cancer by Wnt signalling inhibitor DKK1. Nat Cell Biol. 2017;19(10):1274–85. https://doi.org/10.1038/ncb3613. In this study, Wnt signaling was demonstrated as a central regulatory mechanism for the tropism of breast cancer metastasis. CrossRefPubMedGoogle Scholar
- 80.•• Krzeszinski JY, Schwaid AG, Cheng WY, Jin Z, Gallegos ZR, Saghatelian A, et al. Lipid osteoclastokines regulate breast cancer bone metastasis. Endocrinology. 2017;158(3):477–89. https://doi.org/10.1210/en.2016-1570. A novel, interesting role for osteoclast lipid secretome in bone metastasis formation is described in this article. PubMedGoogle Scholar