Navigating the bone marrow niche: Translational insights and cancer-driven dysfunction

Nature Reviews Rheumatology

Volumn 12, Issue 3, 2016, Pages 154-168

  Reagan, Michaela R ^a   Rosen, Clifford J ^a  

^a Maine Medical Center Research Institute   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

CHEMOKINE RECEPTOR CXCR4; GLUCOSE TRANSPORTER 1; HYPOXIA INDUCIBLE FACTOR 1ALPHA; HYPOXIA INDUCIBLE FACTOR 1BETA; OSTEOCLAST DIFFERENTIATION FACTOR; STROMAL CELL DERIVED FACTOR 1; VASCULOTROPIN A;

BONE DISEASE; BONE MARROW; BONE MARROW DERIVED MACROPHAGE; BONE MARROW METASTASIS; BONE MARROW NICHE; BONE METASTASIS; BONE REMODELING; BREAST CANCER; CANCER INFILTRATION; CANCER STEM CELL; CARCINOGENESIS; CELL DIFFERENTIATION; CELL HOMING; CYTOKINE RELEASE; HEMATOLOGIC DISEASE; HEMATOPOIETIC STEM CELL; HUMAN; HYPOXIA; MALIGNANT TRANSFORMATION; MESENCHYMAL STROMA CELL; MULTIPLE MYELOMA; NONHUMAN; OSTEOBLAST; POSITIVE FEEDBACK; POSTMENOPAUSE OSTEOPOROSIS; PRIORITY JOURNAL; PROSTATE CANCER; REVIEW; STEM CELL MOBILIZATION; STEM CELL SELF-RENEWAL; TUMOR CELL; TUMOR GROWTH; ANIMAL; BONE MARROW CELL; NEOPLASM; PATHOLOGY; PROCEDURES; STEM CELL NICHE; TRANSLATIONAL RESEARCH;

ANIMALS; BONE MARROW CELLS; HUMANS; NEOPLASMS; NEOPLASTIC STEM CELLS; STEM CELL NICHE; TRANSLATIONAL MEDICAL RESEARCH;

EID: 84959253656     PISSN: 17594790     EISSN: 17594804     Source Type: Journal    
DOI: 10.1038/nrrheum.2015.160     Document Type: Review

References (181)

1. Ushio-Fukai M., & Rehman J. Redox and metabolic regulation of stem/progenitor cells and their niche. Antioxid. Redox Signal. 21, 1587-1590 (2014
2. Bianco P. Mesenchymal stem cells. Annu. Rev. Cell Dev. Biol. 30, 677-704 (2014
3. Scadden D. T. The stem-cell niche as an entity of action. Nature 441, 1075-1079 (2006
4. De Miguel M. P., Alcaina Y., De La Maza D. S., & Lopez-Iglesias P. Cell metabolism under microenvironmental low oxygen tension levels in stemness, proliferation and pluripotency. Curr. Mol. Med. 14, 343-359 (2015
5. Gunjal P. M., et al. Evidence for induction of a tumor metastasis-receptive microenvironment for ovarian cancer cells in bone marrow and other organs as an unwanted and underestimated side effect of chemotherapy/radiotherapy. J. Ovarian Res. 8, 20 (2015
6. Meleshina A. V., et al. Influence of mesenchymal stem cells on metastasis development in mice in vivo. Stem Cell Res. Ther. 6, 15 (2015
7. Bianco P., Robey P. G., Saggio I., & Riminucci M. Mesenchymal stem cells in human bone marrow (skeletal stem cells): a critical discussion of their nature, identity, and significance in incurable skeletal disease. Hum. Gene Ther. 21, 1057-1066 (2010
8. Méndez-Ferrer S., et al. Mesenchymal and haematopoietic stem cells form a unique bone marrow niche. Nature 466, 829-834 (2010
9. Köhler A., Geiger H., & Gunzer M. Imaging hematopoietic stem cells in the marrow of long bones in vivo. Methods Mol. Biol. 750, 215-224 (2011
10. Manolagas S. C., & Jilka R. L. Bone marrow, cytokines, and bone remodeling-emerging insights into the pathophysiology of osteoporosis. N. Engl. J. Med. 332, 305-311 (1995
11. Bianco P., et al. The meaning, the sense and the significance: translating the science of mesenchymal stem cells into medicine. Nat. Med. 19, 35-42 (2013
12. Wong R. S. Mesenchymal stem cells: angels or demons? J. Biomed. Biotechnol. 2011, 459510 (2011
13. Calvi L. M., et al. Osteoblastic cells regulate the haematopoietic stem cell niche. Nature 425, 841-846 (2003
14. Bianco P. Minireview: the stem cell next door: skeletal and hematopoietic stem cell niches in bone. Endocrinology 152, 2957-2962 (2011
15. Ellis S. L., & Nilsson S. K. The location and cellular composition of the hemopoietic stem cell niche. Cytotherapy 14, 135-143 (2012
16. Morrison S. J., & Scadden D. T. The bone marrow niche for haematopoietic stem cells. Nature 505, 327-334 (2014
17. Bianco P., Sacchetti B., & Riminucci M. Osteoprogenitors and the hematopoietic microenvironment. Best Pract. Res. Clin. Haematol. 24, 37-47 (2011
18. Sacchetti B., et al. Self-renewing osteoprogenitors in bone marrow sinusoids can organize a hematopoietic microenvironment. Cell 131, 324-336 (2007
19. Morikawa S., et al. Prospective identification, isolation, and systemic transplantation of multipotent mesenchymal stem cells in murine bone marrow. J. Exp. Med. 206, 2483-2496 (2009
20. Liu Y., et al. Osterix-Cre labeled progenitor cells contribute to the formation and maintenance of the bone marrow stroma. PLoS ONE 8, e71318 (2013
21. Kim S. W., et al. Intermittent parathyroid hormone administration converts quiescent lining cells to active osteoblasts. J. Bone Miner. Res. 27, 2075-2084 (2012
22. Asada N., & Katayama Y. Regulation of hematopoiesis in endosteal microenvironments. Int. J. Hematol. 99, 679-684 (2014
23. Huber B. C., Grabmaier U., & Brunner S. Impact of parathyroid hormone on bone marrow-derived stem cell mobilization and migration. World J. Stem Cells 6, 637-643 (2014
24. Kuznetsov S. A., et al. The interplay of osteogenesis and hematopoiesis: expression of a constitutively active PTH/PTHrP receptor in osteogenic cells perturbs the establishment of hematopoiesis in bone and of skeletal stem cells in the bone marrow. J. Cell Biol. 167, 1113-1122 (2004
25. Coskun S., et al. Development of the fetal bone marrow niche and regulation of HSC quiescence and homing ability by emerging osteolineage cells. Cell Rep. 9, 581-590 (2014
26. Omatsu Y., Seike M., Sugiyama T., Kume T., & Nagasawa T. Foxc1 is a critical regulator of haematopoietic stem/progenitor cell niche formation. Nature 508, 536-540 (2014
27. Rosen C. J., Ackert-Bicknell C., Rodriguez J. P., & Pino A. M. Marrow fat and the bone microenvironment: developmental, functional, and pathological implications. Crit. Rev. Eukaryot. Gene Expr. 19, 109-124 (2009
28. Rosen C. J., & Bouxsein M. L. Mechanisms of disease: is osteoporosis the obesity of bone? Nat. Clin. Pract. Rheumatol. 2, 35-43 (2006
29. Gordon M. Y. Stem cells and the microenvironment in aplastic anaemia. Br. J. Haematol. 86, 190-192 (1994
30. Fazeli P. K., et al. Marrow fat and bone - new perspectives. J. Clin. Endocrinol. Metab. 98, 935-945 (2013
31. Scheller E. L., & Rosen C. J. Whats the matter with MAT? Marrow adipose tissue, metabolism, and skeletal health. Ann. NY Acad. Sci. 1311, 14-30 (2014
32. Naveiras O., et al. Bone-marrow adipocytes as negative regulators of the haematopoietic microenvironment. Nature 460, 259-263 (2009
33. Scheller E. L., et al. Use of osmium tetroxide staining with microcomputerized tomography to visualize and quantify bone marrow adipose tissue in vivo. Methods Enzymol. 537, 123-139 (2014
34. Bredella M. A., et al. Determinants of bone microarchitecture and mechanical properties in obese men. J. Clin. Endocrinol. Metab. 97, 4115-4122 (2012
35. Cawthorn W. P., et al. Bone marrow adipose tissue is an endocrine organ that contributes to increased circulating adiponectin during caloric restriction. Cell Metab. 20, 368-375 (2014
36. Bornstein S., et al. FGF 21 and skeletal remodeling during and after lactation in C57BL6 mice. Endocrinology 155, 3516-3526 (2014
37. Ackert-Bicknell C. L., et al. Strain-specific effects of rosiglitazone on bone mass, body composition, and serum insulin-like growth factor I. Endocrinology 150, 1330-1340 (2009
38. Chang M. K., et al. Osteal tissue macrophages are intercalated throughout human and mouse bone lining tissues and regulate osteoblast function in vitro and in vivo. J. Immunol. 181, 1232-1244 (2008
39. Winkler I. G., et al. Bone marrow macrophages maintain hematopoietic stem cell (HSC) niches and their depletion mobilizes HSCs. Blood 116, 4815-4828 (2010
40. Alexander K. A., et al. Osteal macrophages promote in vivo intramembranous bone healing in a mouse tibial injury model. J. Bone Miner. Res. 26, 1517-1532 (2011
41. Pettit A. R., Chang M. K., Hume D. A., & Raggatt L. J. Osteal macrophages: a new twist on coupling during bone dynamics. Bone 43, 976-982 (2008
42. Casanova-Acebes M., A González N., Weiss L. A., & Hidalgo A. Innate immune cells as homeostatic regulators of the hematopoietic niche. Int. J. Hematol. 99, 685-694 (2014
43. Baschuk N., Rautela J., & Parker B. S. Bone specific immunity and its impact on metastasis. BoneKEy Rep. 4, 665 (2015
44. Garhyan J., et al. Preclinical and clinical evidence of mycobacterium tuberculosis persistence in the hypoxic niche of bone marrow mesenchymal stem cells after therapy. Am. J. Pathol. 185, 1924-1934 (2015
45. Wesseling-Perry K. The BRC canopy: an important player in bone remodeling. Am. J. Pathol. 184, 924-926 (2014
46. Jensen P. R., Andersen T. L., Hauge E. M., Bollerslev J., & Delaissé J. M. A joined role of canopy and reversal cells in bone remodeling-lessons from glucocorticoid-induced osteoporosis. Bone 73, 16-23 (2015
47. Zhao M., et al. Megakaryocytes maintain homeostatic quiescence and promote post-injury regeneration of hematopoietic stem cells. Nat. Med. 20, 1321-1326 (2014
48. Bruns I., et al. Megakaryocytes regulate hematopoietic stem cell quiescence through CXCL4 secretion. Nat. Med. 20, 1315-1320 (2014
49. Winkler I. G., et al. Vascular niche E selectin regulates hematopoietic stem cell dormancy, self renewal and chemoresistance. Nat. Med. 18, 1651-1657 (2012
50. Greenbaum A., et al. CXCL12 in early mesenchymal progenitors is required for haematopoietic stem-cell maintenance. Nature 495, 227-230 (2013
51. Hooper A. T., et al. Engraftment and reconstitution of hematopoiesis is dependent on VEGFR2 mediated regeneration of sinusoidal endothelial cells. Cell Stem Cell 4, 263-274 (2009
52. Ding L., Saunders T. L., Enikolopov G., & Morrison S. J. Endothelial and perivascular cells maintain haematopoietic stem cells. Nature 481, 457-462 (2012
53. Méndez-Ferrer S., Lucas D., Battista M., & Frenette P. S. Haematopoietic stem cell release is regulated by circadian oscillations. Nature 452, 442-427 (2008
54. Kotova P. D., et al. Functional expression of adrenoreceptors in mesenchymal stromal cells derived from the human adipose tissue. Biochim. Biophys. Acta 1843, 1899-1908 (2014
55. Xie Y., et al. Detection of functional haematopoietic stem cell niche using real-time imaging. Nature 457, 97-101 (2009
56. Hu X., et al. Severe hypoxia exerts parallel and cell-specific regulation of gene expression and alternative splicing in human mesenchymal stem cells. BMC Genomics 15, 303 (2014
57. Krock B. L., et al. The aryl hydrocarbon receptor nuclear translocator is an essential regulator of murine hematopoietic stem cell viability. Blood 125, 3263-3272 (2015
58. Forristal C. E., & Levesque J. P. Targeting the hypoxia-sensing pathway in clinical hematology. Stem Cells Transl. Med. 3, 135-140 (2014
59. Winkler I. G., et al. Positioning of bone marrow hematopoietic and stromal cells relative to blood flow in vivo: serially reconstituting hematopoietic stem cells reside in distinct nonperfused niches. Blood 116, 375-385 (2010
60. Imanirad P., & Dzierzak E. Hypoxia and HIFs in regulating the development of the hematopoietic system. Blood Cells. Mol. Dis. 51, 256-263 (2013
61. Miharada K., et al. Hematopoietic stem cells are regulated by Cripto, as an intermediary of HIF 1α in the hypoxic bone marrow niche. Ann. NY Acad. Sci. 1266, 55-62 (2012
62. DAngelo G., Duplan E., Boyer N., Vigne P., & Frelin C. Hypoxia up-regulates prolyl hydroxylase activity: a feedback mechanism that limits HIF 1 responses during reoxygenation. J. Biol. Chem. 278, 38183-38187 (2003
63. Palomδki S., et al. HIF 1α is upregulated in human mesenchymal stem cells. Stem Cells 31, 1902-1909 (2013
64. Andrade P. Z., et al. Ex vivo expansion of cord blood haematopoietic stem/progenitor cells under physiological oxygen tensions: clear-cut effects on cell proliferation, differentiation and metabolism. J. Tissue Eng. Regen. Med. http://dx.doi.org/10.1002/term.1731 (2013
65. Liu X., et al. Maintenance of mouse hematopoietic stem cells ex vivo by reprogramming cellular metabolism. Blood 125, 1562-1565 (2015
66. Kocabas F., Zheng J., Zhang C., & Sadek H. A. Metabolic characterization of hematopoietic stem cells. Methods Mol. Biol. 1185, 155-164 (2014
67. Wagegg M., et al. Hypoxia promotes osteogenesis but suppresses adipogenesis of human mesenchymal stromal cells in a hypoxia-inducible factor 1 dependent manner. PLoS ONE 7, e46483 (2012
68. Duan X., et al. Vegfa regulates perichondrial vascularity and osteoblast differentiation in bone development. Development 142, 1984-1991 (2015
69. Regan J. N., et al. Up-regulation of glycolytic metabolism is required for HIF1α driven bone formation. Proc. Natl. Acad. Sci. USA 111, 8673-8678 (2014
70. Chang S. H., et al. Association between metformin use and transformation of monoclonal gammopathy of undetermined significance to multiple myeloma in U.S. veterans with diabetes mellitus: a population-based cohort study. Lancet Haematol. 2, e30-e36 (2015
71. Jang W. G., Kim E. J., Lee K. N., Son H. J., & Koh J. T. AMP-activated protein kinase (AMPK) positively regulates osteoblast differentiation via induction of Dlx5 dependent Runx2 expression in MC3T3E1 cells. Biochem. Biophys. Res. Commun. 404, 1004-1009 (2011
72. Guntur A. R., Le P. T., Farber C. R., & Rosen C. J. Bioenergetics during calvarial osteoblast differentiation reflect strain differences in bone mass. Endocrinology 155, 1589-1595 (2014
73. Esen E., & Long F. Aerobic glycolysis in osteoblasts. Curr. Osteoporos. Rep. 12, 433-438 (2014
74. Esen E., Lee S. Y., Wice B. M., & Long F. PTH promotes bone anabolism by stimulating aerobic glycolysis via IGF signaling. J. Bone Miner. Res. http://dx.doi.org/10.1002/jbmr.2556 (2015
75. Nagasawa T. CXC chemokine ligand 12 (CXCL12) and its receptor CXCR4. J. Mol. Med. (Berl.) 92, 433-439 (2014
76. Nervi B., Link D. C., & DiPersio J. F. Cytokines and hematopoietic stem cell mobilization. J. Cell. Biochem. 99, 690-705 (2006
77. Nguyen T. M., et al. EphB4 expressing stromal cells exhibit an enhanced capacity for hematopoietic stem cell maintenance. Stem Cells 33, 2838-2849 (2015
78. Krevvata M., et al. Inhibition of leukemia cell engraftment and disease progression in mice by osteoblasts. Blood 124, 2834-2846 (2014
79. Kode A., et al. FoxO1 dependent induction of acute myeloid leukemia by osteoblasts in mice. Leukemia http://dx.doi.org/10.1038/leu.2015.161 (2015
80. Guise T. A., et al. Basic mechanisms responsible for osteolytic and osteoblastic bone metastases. Clin. Cancer Res. 12, 6213s-6216s (2006
81. Weilbaecher K. N., Guise T. A., & McCauley L. K. Cancer to bone: a fatal attraction. Nat. Rev. Cancer 11, 411-425 (2011
82. Cui Q., et al. Targeting myeloma-osteoclast interaction with Vγ9Vδ2 T cells. Int. J. Hematol. 94, 63-70 (2011
83. Le Gall C., et al. A cathepsin K inhibitor reduces breast cancer induced osteolysis and skeletal tumor burden. Cancer Res. 67, 9894-9902 (2007
84. Jones D. H., et al. Regulation of cancer cell migration and bone metastasis by RANKL. Nature 440, 692-696 (2006
85. Roodman G. D. Genes associate with abnormal bone cell activity in bone metastasis. Cancer Metastasis Rev. 31, 569-578 (2012
86. Medyouf H., et al. Myelodysplastic cells in patients reprogram mesenchymal stromal cells to establish a transplantable stem cell niche disease unit. Cell Stem Cell 14, 824-837 (2014
87. Reagan M. R., & Ghobrial I. M. Multiple myeloma mesenchymal stem cells: characterization, origin, and tumor-promoting effects. Clin. Cancer Res. 18, 342-349 (2012
88. Reagan M. R., Liaw L., Rosen C. J., & Ghobrial I. M. Dynamic interplay between bone and multiple myeloma: emerging roles of the osteoblast. Bone 75, 161-169 (2015
89. Schepers K., et al. Myeloproliferative neoplasia remodels the endosteal bone marrow niche into a self-reinforcing leukemic niche. Cell Stem Cell 13, 285-299 (2013
90. Raaijmakers M. H. Myelodysplastic syndromes: revisiting the role of the bone marrow microenvironment in disease pathogenesis. Int. J. Hematol. 95, 17-25 (2012
91. Shiozawa Y., & Taichman R. S. Cancer stem cells and the bone marrow microenvironment. BoneKEy Rep. 1, 48 (2012
92. Kang Y., & Pantel K. Tumor cell dissemination: emerging biological insights from animal models and cancer patients. Cancer Cell 23, 573-581 (2013
93. Chantry A. D., et al. Inhibiting activin A signaling stimulates bone formation and prevents cancer-induced bone destruction in vivo. J. Bone Miner. Res. 25, 2633-2646 (2010
94. Kingsley L. A., Fournier P. G., Chirgwin J. M., & Guise T. A. Molecular biology of bone metastasis. Mol. Cancer Ther. 6, 2609-2617 (2007
95. Kimura T., et al. Targeting of bone-derived insulin-like growth factor-II by a human neutralizing antibody suppresses the growth of prostate cancer cells in a human bone environment. Clin. Cancer Res. 16, 121-129 (2010
96. Kovacic N., Croucher P. I., & McDonald M. M. Signaling between tumor cells and the host bone marrow microenvironment. Calcif. Tissue Int. 94, 125-139 (2013
97. Ottewell P. D., ODonnell L., & Holen I. Molecular alterations that drive breast cancer metastasis to bone. BoneKEy Rep. 4, 643 (2015
98. Suva L. J., Washam C., Nicholas R. W., & Griffin R. J. Bone metastasis: mechanisms and therapeutic opportunities. Nat. Rev. Endocrinol. 7, 208-218 (2011
99. Martinez-Outschoorn U., Sotgia F., & Lisanti M. P. Tumor microenvironment and metabolic synergy in breast cancers: critical importance of mitochondrial fuels and function. Semin. Oncol. 41, 195-216 (2014
100. Olechnowicz S. W., & Edwards C. M. Contributions of the host microenvironment to cancer-induced bone disease. Cancer Res. 74, 1625-1631 (2014
101. Raaijmakers M. H. Niche contributions to oncogenesis: emerging concepts and implications for the hematopoietic system. Haematologica 96, 1041-1048 (2011
102. Dawson M. R., Chae S. S., Jain R. K., & Duda D. G. Direct evidence for lineage-dependent effects of bone marrow stromal cells on tumor progression. Am. J. Cancer Res. 1, 144-154 (2011
103. Asimakopoulos F., et al. Macrophages in multiple myeloma: emerging concepts and therapeutic implications. Leuk. Lymphoma 54, 2112-2121 (2013
104. Logothetis C. J., & Lin S. H. Osteoblasts in prostate cancer metastasis to bone. Nat. Rev. Cancer 5, 21-28 (2005
105. Hardaway A. L., Herroon M. K., Rajagurubandara E., & Podgorski I. Bone marrow fat: linking adipocyte-induced inflammation with skeletal metastases. Cancer Metastasis Rev. 33, 527-543 (2014
106. Compton J. T., & Lee F. Y. A review of osteocyte function and the emerging importance of sclerostin. J. Bone Joint Surg. Am. 96, 1659-1668 (2014
107. McMillin D. W., et al. Tumor cell-specific bioluminescence platform to identify stroma-induced changes to anticancer drug activity. Nat. Med. 16, 483 (2010
108. Liu S., et al. Breast cancer stem cells are regulated by mesenchymal stem cells through cytokine networks. Cancer Res. 71, 614-624 (2011
109. Reagan M. R., & Ghobrial I. M. Multiple myeloma-mesenchymal stem cells: characterization, origin, and tumor-promoting effects. Clin. Cancer Res. 18, 342-349 (2012
110. Reagan M. R., et al. Investigating osteogenic differentiation in multiple myeloma using a novel 3D bone marrow niche model. Blood 124, 3250-3259 (2014
111. Walenda T., et al. Feedback signals in myelodysplastic syndromes: increased self-renewal of the malignant clone suppresses normal hematopoiesis. PLoS Comput. Biol. 10, e1003599 (2014
112. Kawano Y., et al. Targeting the bone marrow microenvironment in multiple myeloma. Immunol. Rev. 263, 160-172 (2015
113. Moschetta M., et al. Role of endothelial progenitor cells in cancer progression. Biochim. Biophys. Acta 1846, 26-39 (2014
114. Roccaro A. M., et al. BM mesenchymal stromal cell-derived exosomes facilitate multiple myeloma progression. J. Clin. Invest. 123, 1542-1555 (2013
115. Evans A. G., & Calvi L. M. Notch signaling in the malignant bone marrow microenvironment: implications for a niche-based model of oncogenesis. Ann. NY Acad. Sci. 1335, 63-77 (2015
116. Van den Berk L. C. J., et al. Disturbed CXCR4/CXCL12 axis in paediatric precursor B cell acute lymphoblastic leukaemia. Br. J. Haematol. 166, 240-249 (2014
117. Glavey S. V., et al. The sialyltransferase ST3GAL6 influences homing and survival in multiple myeloma. Blood 124, 1765-1776 (2014
118. Glavey S. V., et al. The cancer glycome: carbohydrates as mediators of metastasis. Blood Rev. 29, 269-279 (2015
119. Ellis S. L., et al. The relationship between bone, hemopoietic stem cells, and vasculature. Blood 118, 1516-1524 (2011
120. Ottewell P. D., ODonnell L., & Holen I. Molecular alterations that drive breast cancer metastasis to bone. BoneKEy Rep. 4, 643 (2015
121. Roccaro A. M., et al. SDF 1 inhibition targets the bone marrow niche for cancer therapy. Cell Rep. 9, 118-128 (2014
122. Harms J. F., et al. A small molecule antagonist of the αvβ3 integrin suppresses MDA MB 435 skeletal metastasis. Clin. Exp. Metastasis 21, 119-128 (2004
123. Kaplan R. N., Psaila B., & Lyden D. Niche to niche migration of bone marrow derived cells. Trends Mol. Med. 13, 72-81 (2007
124. Sullivan C., et al. Functional ramifications for the loss of P selectin expression on hematopoietic and leukemic stem cells. PLoS ONE 6, e26246 (2011
125. Croset M., Kan C., & Cl?zardin P. Tumour-derived miRNAs and bone metastasis. BoneKEy Rep. 4, 688 (2015
126. Runnels J. M., et al. Optical techniques for tracking multiple myeloma engraftment, growth, and response to therapy. J. Biomed. Opt. 16, 011006 (2011
127. Azab A. K., et al. Hypoxia promotes dissemination of multiple myeloma through acquisition of epithelial to mesenchymal transition-like features. Blood 119, 5782-5794 (2012
128. Muz B., De La Puente P., Azab F., Luderer M., & Azab A. K. Hypoxia promotes stem cell-like phenotype in multiple myeloma cells. Blood Cancer J. 4, e262 (2014
129. Xiang L., et al. Hypoxia-inducible factor 1 mediates TAZ expression and nuclear localization to induce the breast cancer stem cell phenotype. Oncotarget 5, 12509-12527 (2014
130. Gezer D., Vukovic M., Soga T., Pollard P. J., & Kranc K. R. Concise review: genetic dissection of hypoxia signaling pathways in normal and leukemic stem cells. Stem Cells 32, 1390-1397 (2014
131. Borsi E., et al. Hypoxia inducible factor 1 α as a therapeutic target in multiple myeloma. Oncotarget 5, 1779-1792 (2014
132. Maiso P., et al. Metabolic signature identifies novel targets for drug resistance in multiple myeloma. Cancer Res. 75, 2071-2082 (2015
133. Yu C., et al. Prostate cancer and parasitism of the bone hematopoietic stem cell niche. Crit. Rev. Eukaryot. Gene Expr. 22, 131-148 (2012
134. Kim J. K., et al. TBK1 regulates prostate cancer dormancy through mTOR inhibition. Neoplasia 15, 1064-1074 (2013
135. Pedersen E. A., Shiozawa Y., Pienta K. J., & Taichman R. S. The prostate cancer bone marrow niche: more than just ertile soil. Asian J. Androl. 14, 423-427 (2012
136. Mart?nez-Jaramillo G., Vela-Ojeda J., Flores-Guzmαn P., & Mayani H. In vitro growth of hematopoietic progenitors and stromal bone marrow cells from patients with multiple myeloma. Leuk. Res. 35, 250-255 (2011
137. Bruns I., et al. Multiple myeloma-related deregulation of bone marrow-derived CD34+ hematopoietic stem and progenitor cells. Blood 120, 2620-2630 (2012
138. Mundy G. R. Mechanisms of osteolytic bone destruction. Bone 12, S1-S6 (1991
139. Swami A., et al. Engineered nanomedicine for myeloma and bone microenvironment targeting. Proc. Natl. Acad. Sci. USA 111, 10287-10292 (2014
140. Jones M. D., et al. A proteasome inhibitor, bortezomib, inhibits breast cancer growth and reduces osteolysis by downregulating metastatic genes. Clin. Cancer Res. 16, 4978-4989 (2010
141. Kaplan R. N., et al. VEGFR1 positive haematopoietic bone marrow progenitors initiate the pre-metastatic niche. Nature 438, 820-827 (2005
142. Cox T. R., et al. The hypoxic cancer secretome induces pre-metastatic bone lesions through lysyl oxidase. Nature 522, 106-110 (2015
143. Martinez L. M., et al. Changes in the peripheral blood and bone marrow from untreated advanced breast cancer patients that are associated with the establishment of bone metastases. Clin. Exp. Metastasis 31, 213-232 (2014
144. Benito-Martin A., Di Giannatale A., Ceder S., & Peinado H. The new deal: a potential role for secreted vesicles in innate immunity and tumor progression. Front. Immunol. 6, 66 (2015
145. Zhang Y., & Wang X. F. A niche role for cancer exosomes in metastasis. Nat. Cell Biol. 17, 709-711 (2015
146. Sceneay J., Smyth M. J., & Mφller A. The pre-metastatic niche: finding common ground. Cancer Metastasis Rev. 32, 449-464 (2013
147. Liu S., et al. Vascular endothelial growth factor plays a critical role in the formation of the pre-metastatic niche via prostaglandin E2. Oncol. Rep. 32, 2477-2484 (2014
148. Kerr B. A., McCabe N. P., Feng W., & Byzova T. V. Platelets govern pre-metastatic tumor communication to bone. Oncogene 32, 4319-4324 (2013
149. Phoenix K. N., Vumbaca F., Fox M. M., Evans R., & Claffey K. P. Dietary energy availability affects primary and metastatic breast cancer and metformin efficacy. Breast Cancer Res. Treat. 123, 333-344 (2010
150. Brinton L. T., Sloane H. S., Kester M., & Kelly K. A. Formation and role of exosomes in cancer. Cell. Mol. Life Sci. 72, 659-671 (2014
151. Raaijmakers M. H., et al. Bone progenitor dysfunction induces myelodysplasia and secondary leukaemia. Nature 464, 852-857 (2010
152. Sasser A. K., et al. Human bone marrow stromal cells enhance breast cancer cell growth rates in a cell line-dependent manner when evaluated in 3D tumor environments. Cancer Lett. 254, 255-264 (2007
153. Mastro A. M., & Vogler E. A. A three-dimensional osteogenic tissue model for the study of metastatic tumor cell interactions with bone. Cancer Res. 69, 4097-4100 (2009
154. Sieh S., Lubik A. A., Clements J. A., Nelson C. C., & Hutmacher D. W. Interactions between human osteoblasts and prostate cancer cells in a novel 3D in vitro model. Organogenesis 6, 181-188
155. Maréchal M., et al. Bone augmentation with autologous periosteal cells and two different calcium phosphate scaffolds under an occlusive titanium barrier: an experimental study in rabbits. J. Periodontol. 79, 896-904 (2008
156. Augst A., et al. Effects of chondrogenic and osteogenic regulatory factors on composite constructs grown using human mesenchymal stem cells, silk scaffolds and bioreactors. J. R. Soc. Interface 5, 929-939 (2008
157. Marolt D., et al. Bone and cartilage tissue constructs grown using human bone marrow stromal cells, silk scaffolds and rotating bioreactors. Biomaterials 27, 6138-6149 (2006
158. Ferrarini M., et al. Ex-vivo dynamic 3D culture of human tissues in the RCCSTM bioreactor allows the study of multiple myeloma biology and response to therapy. PLoS ONE 8, e71613 (2013
159. Meinel L., et al. Engineering bone-like tissue in vitro using human bone marrow stem cells and silk scaffolds. J. Biomed. Mater. Res. A 71, 25-34 (2004
160. Hsiao A. Y., et al. Microfluidic system for formation of PC 3 prostate cancer co-culture spheroids. Biomaterials 30, 3020-3027 (2009
161. Pallotta I., Lovett M., Kaplan D. L., & Balduini A. Three-dimensional system for the in vitro study of megakaryocytes and functional platelet production using silk-based vascular tubes. Tissue Eng. Part C Methods 17, 1223-1232 (2011
162. Wray L. S., et al. A silk-based scaffold platform with tunable architecture for engineering critically-sized tissue constructs. Biomaterials 33, 9214-9224 (2012
163. Di Buduo C. A., et al. Programmable 3D silk bone marrow niche for platelet generation ex vivo and modeling of megakaryopoiesis pathologies. Blood 125, 2254-2264 (2015
164. Roccaro A. M., et al. CXCR4 regulates extra-medullary myeloma through epithelial mesenchymal transition-like transcriptional activation. Cell Rep. 12, 622-635 (2015
165. Hu Z., Zhang Z., Guise T., & Seth P. Systemic delivery of an oncolytic adenovirus expressing soluble transforming growth factor β receptor II Fc fusion protein can inhibit breast cancer bone metastasis in a mouse model. Hum. Gene Ther. 21, 1623-1629 (2010
166. Paton-Hough J., Chantry A. D., & Lawson M. A. A review of current murine models of multiple myeloma used to assess the efficacy of therapeutic agents on tumour growth and bone disease. Bone 77, 57-68 (2015
167. Van Der Horst G., et al. Targeting of αv-integrins in stem/progenitor cells and supportive microenvironment impairs bone metastasis in human prostate cancer. Neoplasia 13, 516-525 (2011
168. Fowler J. A., Mundy G. R., Lwin S. T., Lynch C. C., & Edwards C. M. A murine model of myeloma that allows genetic manipulation of the host microenvironment. Dis. Model. Mech. 2, 604-611 (2009
169. Chesi M., et al. AID-dependent activation of a MYC transgene induces multiple myeloma in a conditional mouse model of post-germinal center malignancies. Cancer Cell 13, 167-180 (2008
170. Schueler J., et al. Intratibial injection of human multiple myeloma cells in NOD/SCID IL 2Rγ(null) mice mimics human myeloma and serves as a valuable tool for the development of anticancer strategies. PLoS ONE 8, e79939 (2013
171. Tassone P., et al. A SCID-hu in vivo model of human Waldenstrφm macroglobulinemia. Blood 106, 1341-1345 (2005
172. Libouban H. The use of animal models in multiple myeloma. Morphologie 99, 63-72 (2015
173. Goldstein R. H., Reagan M. R., Anderson K., Kaplan D. L., & Rosenblatt M. Human bone marrow-derived MSCs can home to orthotopic breast cancer tumors and promote bone metastasis. Cancer Res. 70, 10044 (2010
174. Reagan M. R., et al. Stem cell implants for cancer therapy: TRAIL-expressing mesenchymal stem cells target cancer cells in situ. J. Breast Cancer 15, 273-282 (2012
175. Moreau J. E., et al. Tissue-engineered bone serves as a target for metastasis of human breast cancer in a mouse model. Cancer Res. 67, 10304 (2007
176. Takayanagi H. Osteoimmunology in 2014: Two-faced immunology - from osteogenesis to bone resorption. Nat. Rev. Rheumatol. 11, 74-76 (2015
177. Neer R. M., et al. Effect of parathyroid hormone (1-34) on fractures and bone mineral density in postmenopausal women with osteoporosis. N. Engl. J. Med. 344, 1434-1441 (2001
178. Pennisi A., et al. The proteasome inhibitor, bortezomib suppresses primary myeloma and stimulates bone formation in myelomatous and nonmyelomatous bones in vivo. Am. J. Hematol. 84, 6-14 (2009
179. Lv F. J., Tuan R. S., Cheung K. M., & Leung V. Y. Concise review: the surface markers and identity of human mesenchymal stem cells. Stem Cells 32, 1408-1419 (2014
180. Ratajczak M. Z. Phenotypic and functional characterization of hematopoietic stem cells. Curr. Opin. Hematol. 15, 293-300 (2008
181. Liu Y., et al. Osterix-Cre labeled progenitor cells contribute to the formation and maintenance of the bone marrow stroma. PLoS ONE 8, e71318 (2013