Engineering the pre-metastatic niche

Abstract

The pre-metastatic niche — the accumulation of aberrant immune cells and extracellular-matrix proteins in target organs — primes the initially healthy organ microenvironment and renders it amenable for subsequent colonization by metastatic cancer cells. By attracting metastatic cells, mimics of the pre-metastatic niche offer both diagnostic and therapeutic potential. However, deconstructing the complexity of the niche by identifying the interactions between cell populations as well as the mediatory roles of the immune system, soluble factors, extracellular-matrix proteins and stromal cells has proved challenging. Experimental models are needed to recapitulate niche-population biology in situ and to mediate in vivo tumour-cell homing, colonization and proliferation. In this Review, we outline the biology of the pre-metastatic niche and discuss advances in the engineering of niche-mimicking biomaterials that regulate the behaviour of tumour cells at an implant site. Such ‘oncomaterials’ offer strategies for the early detection of metastatic events, the inhibition of the formation of the pre-metastatic niche and the attenuation of metastatic progression.

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Figure 1: Formation of the pre-metastatic niche.
Figure 2: MDSC and metastatic-cell trafficking in a breast-tumour-bearing mouse implanted with a biomaterial scaffold.
Figure 3: Biomaterials loaded with soluble factors and exosomes mediate tumour-cell homing.
Figure 4: Modelling organotropism by using ECM- or BMSC-functionalized scaffolds.
Figure 5: Proposed use of engineered mimics as oncomaterials.

References

  1. 1

    Paget, S. The distribution of secondary growths in cancer of the breast. 1889. Cancer Metastasis Rev. 8, 98–101 (1989).

    CAS  PubMed  Google Scholar 

  2. 2

    Maru, Y. The lung metastatic niche. J. Mol. Med. 93, 1185–1192 (2015).

    CAS  PubMed  Article  Google Scholar 

  3. 3

    Azizidoost, S. et al. Hepatic metastatic niche: from normal to pre-metastatic and metastatic niche. Tumour Biol. 37, 1493–1503 (2015).

    PubMed  Article  CAS  Google Scholar 

  4. 4

    Winkler, F. The brain metastatic niche. J. Mol. Med. 93, 1213–1220 (2015).

    CAS  PubMed  Article  Google Scholar 

  5. 5

    Kaplan, R. N., Rafii, S. & Lyden, D. Preparing the “soil”: the premetastatic niche. Cancer Res. 66, 11089–11093 (2006).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  6. 6

    Sleeman, J. P. The lymph node pre-metastatic niche. J. Mol. Med. 93, 1173–1184 (2015).

    CAS  PubMed  Article  Google Scholar 

  7. 7

    Nguyen, D. X., Bos, P. D. & Massague, J. Metastasis: from dissemination to organ-specific colonization. Nat. Rev. Cancer 9, 274–284 (2009).

    CAS  PubMed  Article  Google Scholar 

  8. 8

    Minn, A. J. et al. Genes that mediate breast cancer metastasis to lung. Nature 436, 518–524 (2005).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  9. 9

    Peinado, H. et al. Pre-metastatic niches: organ-specific homes for metastases. Nat. Rev. Cancer 17, 302–317 (2017).

    CAS  PubMed  Article  Google Scholar 

  10. 10

    Bos, P. D. et al. Genes that mediate breast cancer metastasis to the brain. Nature 459, 1005–1009 (2009).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  11. 11

    Ranklin, E. B. & Giaccia, A. J. Hypoxic control of metastasis. Science 352, 175–180 (2016).

    Article  CAS  Google Scholar 

  12. 12

    Peinado, H. et al. Melanoma exosomes educate bone marrow progenitor cells toward a pro-metastatic phenotype through MET. Nat. Med. 18, 883–891 (2012).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  13. 13

    Kaplan, R. N. et al. VEGFR1-positive haematopoietic bone marrow progenitors initiate the pre-metastatic niche. Nature 438, 820–827 (2005).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  14. 14

    Chafe, S. C. et al. Carbonic anhydrase IX promotes myeloid-derived suppressor cell mobilization and establishment of a metastatic niche by stimulating G-CSF production. Cancer Res. 75, 996–1008 (2015).

    CAS  PubMed  Article  Google Scholar 

  15. 15

    Erler, J. T. et al. Hypoxia-induced lysyl oxidase is a critical mediator of bone marrow cell recruitment to form the premetastatic niche. Cancer Cell 15, 35–44 (2009).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  16. 16

    Giles, A. J. et al. Activation of hematopoietic stem/progenitor cells promotes immunosuppression within the pre-metastatic niche. Cancer Res. 76, 1335–1347 (2016).

    CAS  PubMed  Article  Google Scholar 

  17. 17

    Kowanetz, M. et al. Granulocyte-colony stimulating factor promotes lung metastasis through mobilization of Ly6G+Ly6C+ granulocytes. Proc. Natl Acad. Sci. USA 107, 21248–21255 (2010).

    CAS  PubMed  Article  Google Scholar 

  18. 18

    Liu, Y. et al. Tumor exosomal RNAs promote lung pre-metastatic niche formation by activating alveolar epithelial TLR3 to recruit neutrophils. Cancer Cell 30, 243–256 (2016).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  19. 19

    Olkhanud, P. B. et al. Breast cancer lung metastasis requires expression of chemokine receptor CCR4 and regulatory T cells. Cancer Res. 69, 5996–6004 (2009).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  20. 20

    Qian, B. Z. et al. CCL2 recruits inflammatory monocytes to facilitate breast-tumour metastasis. Nature 475, 222–225 (2011).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  21. 21

    Sceneay, J. et al. Primary tumor hypoxia recruits CD11b+/Ly6Cmed/Ly6G+ immune suppressor cells and compromises NK cell cytotoxicity in the premetastatic niche. Cancer Res. 72, 3906–3911 (2012).

    CAS  PubMed  Article  Google Scholar 

  22. 22

    Costa-Silva, B. et al. Pancreatic cancer exosomes initiate pre-metastatic niche formation in the liver. Nat. Cell Biol. 17, 816–826 (2015).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  23. 23

    Hoshino, A. et al. Tumour exosome integrins determine organotropic metastasis. Nature 527, 329–335 (2015).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  24. 24

    Hiratsuka, S., Watanabe, A., Aburatani, H. & Maru, Y. Tumour-mediated upregulation of chemoattractants and recruitment of myeloid cells predetermines lung metastasis. Nat. Cell Biol. 8, 1369–1375 (2006).

    CAS  PubMed  Article  Google Scholar 

  25. 25

    Gill, B. J. & West, J. L. Modeling the tumor extracellular matrix: tissue engineering tools repurposed towards new frontiers in cancer biology. J. Biomech. 47, 1969–1978 (2014).

    PubMed  Article  Google Scholar 

  26. 26

    Infanger, D. W., Lynch, M. E. & Fischbach, C. Engineered culture models for studies of tumor-microenvironment interactions. Annu. Rev. Biomed. Eng. 15, 29–53 (2013).

    CAS  PubMed  Article  Google Scholar 

  27. 27

    Gu, L. & Mooney, D. J. Biomaterials and emerging anticancer therapeutics: engineering the microenvironment. Nat. Rev. Cancer 16, 56–66 (2016).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  28. 28

    Ehsan, S. M., Welch-Reardon, K. M., Waterman, M. L., Hughes, C. C. & George, S. C. A three-dimensional in vitro model of tumor cell intravasation. Integr. Biol. 6, 603–610 (2014).

    CAS  Article  Google Scholar 

  29. 29

    Jeon, J. S. et al. Human 3D vascularized organotypic microfluidic assays to study breast cancer cell extravasation. Proc. Natl Acad. Sci. USA 112, 214–219 (2015).

    CAS  PubMed  Article  Google Scholar 

  30. 30

    Jeon, J. S., Zervantonakis, I. K., Chung, S., Kamm, R. D. & Charest, J. L. In vitro model of tumor cell extravasation. PLoS ONE 8, e56910 (2013).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  31. 31

    Ko, C. Y. et al. The use of chemokine-releasing tissue engineering scaffolds in a model of inflammatory response-mediated melanoma cancer metastasis. Biomaterials 33, 876–885 (2012).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  32. 32

    Bersani, F. et al. Bioengineered implantable scaffolds as a tool to study stromal-derived factors in metastatic cancer models. Cancer Res. 74, 7229–7238 (2014).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  33. 33

    Barkan, D. et al. Inhibition of metastatic outgrowth from single dormant tumor cells by targeting the cytoskeleton. Cancer Res. 68, 6241–6250 (2008).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  34. 34

    de la Fuente, A. et al. M-Trap: exosome-based capture of tumor cells as a new technology in peritoneal metastasis. J. Natl Cancer Inst. 107, djv184 (2015).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  35. 35

    Rao, S. S. et al. Enhanced survival with implantable scaffolds that capture metastatic breast cancer cells in vivo. Cancer Res. 76, 5209–5218 (2016).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  36. 36

    Azarin, S. M. et al. In vivo capture and label-free detection of early metastatic cells. Nat. Commun. 6, 8094 (2015).

    PubMed  PubMed Central  Article  Google Scholar 

  37. 37

    Fidler, I. J. The pathogenesis of cancer metastasis: the ‘seed and soil’ hypothesis revisited. Nat. Rev. Cancer 3, 453–458 (2003).

    CAS  PubMed  Article  Google Scholar 

  38. 38

    Gupta, G. P. & Massague, J. Cancer metastasis: building a framework. Cell 127, 679–695 (2006).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  39. 39

    Chambers, A. F., Groom, A. C. & MacDonald, I. C. Dissemination and growth of cancer cells in metastatic sites. Nat. Rev. Cancer 2, 563–572 (2002).

    CAS  PubMed  Article  Google Scholar 

  40. 40

    Krebs, M. G. et al. Molecular analysis of circulating tumour cells-biology and biomarkers. Nat. Rev. Clin. Oncol. 11, 129–144 (2014).

    CAS  PubMed  Article  Google Scholar 

  41. 41

    Holzapfel, B. M. et al. How smart do biomaterials need to be? A translational science and clinical point of view. Adv. Drug Delivery Rev. 65, 581–603 (2013).

    CAS  Article  Google Scholar 

  42. 42

    Thibaudeau, L. et al. A tissue-engineered humanized xenograft model of human breast cancer metastasis to bone. Dis. Model. Mech. 7, 299–309 (2014).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  43. 43

    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, 10304–10308 (2007).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  44. 44

    Aguado, B. A. et al. Secretome identification of immune cell factors mediating metastatic cell homing. Sci. Rep. 5, 17566 (2015).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  45. 45

    Yang, L., Edwards, C. M. & Mundy, G. R. Gr-1+CD11b+ myeloid-derived suppressor cells: formidable partners in tumor metastasis. J. Bone Miner. Res. 25, 1701–1706 (2010).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  46. 46

    Gabrilovich, D. I. & Nagaraj, S. Myeloid-derived suppressor cells as regulators of the immune system. Nat. Rev. Immunol. 9, 162–174 (2009).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  47. 47

    Sharma, S. K. et al. Pulmonary alveolar macrophages contribute to the premetastatic niche by suppressing antitumor T cell responses in the lungs. J. Immunol. 194, 5529–5538 (2015).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  48. 48

    Monteiro, A. C. et al. T cells induce pre-metastatic osteolytic disease and help bone metastases establishment in a mouse model of metastatic breast cancer. PLoS ONE 8, e68171 (2013).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  49. 49

    Tan, W. et al. Tumour-infiltrating regulatory T cells stimulate mammary cancer metastasis through RANKL-RANK signalling. Nature 470, 548–553 (2011).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  50. 50

    Cox, T. R. et al. The hypoxic cancer secretome induces pre-metastatic bone lesions through lysyl oxidase. Nature 522, 106–110 (2015).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  51. 51

    Peinado, H., Lavotshkin, S. & Lyden, D. The secreted factors responsible for pre-metastatic niche formation: old sayings and new thoughts. Semin. Cancer Biol. 21, 139–146 (2011).

    CAS  PubMed  Article  Google Scholar 

  52. 52

    Smith, H. A. & Kang, Y. The metastasis-promoting roles of tumor-associated immune cells. J. Mol. Med. 91, 411–429 (2013).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  53. 53

    Headley, M. B. et al. Visualization of immediate immune responses to pioneer metastatic cells in the lung. Nature 531, 513–517 (2016).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  54. 54

    Boehler, R. M., Graham, J. G. & Shea, L. D. Tissue engineering tools for modulation of the immune response. Biotechniques 51, 239–254 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  55. 55

    Anderson, J. M., Rodriguez, A. & Chang, D. T. Foreign body reaction to biomaterials. Semin. Immunol. 20, 86–100 (2008).

    CAS  PubMed  Article  Google Scholar 

  56. 56

    Franz, S., Rammelt, S., Scharnweber, D. & Simon, J. C. Immune responses to implants — a review of the implications for the design of immunomodulatory biomaterials. Biomaterials 32, 6692–6709 (2011).

    CAS  PubMed  Article  Google Scholar 

  57. 57

    Mikos, A. G., McIntire, L. V., Anderson, J. M. & Babensee, J. E. Host response to tissue engineered devices. Adv. Drug Delivery Rev. 33, 111–139 (1998).

    CAS  Article  Google Scholar 

  58. 58

    Liu, Y. & Cao, X. Characteristics and significance of the pre-metastatic niche. Cancer Cell 30, 668–681 (2016).

    CAS  PubMed  Article  Google Scholar 

  59. 59

    Rutkowski, M. R. et al. Microbially driven TLR5-dependent signaling governs distal malignant progression through tumor-promoting inflammation. Cancer Cell 27, 27–40 (2015).

    CAS  PubMed  Article  Google Scholar 

  60. 60

    Hiratsuka, S. et al. The S100A8-serum amyloid A3-TLR4 paracrine cascade establishes a pre-metastatic phase. Nat. Cell Biol. 10, 1349–1355 (2008).

    CAS  PubMed  Article  Google Scholar 

  61. 61

    Tomita, T., Sakurai, Y., Ishibashi, S. & Maru, Y. Imbalance of Clara cell-mediated homeostatic inflammation is involved in lung metastasis. Oncogene 30, 3429–3439 (2011).

    CAS  PubMed  Article  Google Scholar 

  62. 62

    Rafii, S. & Lyden, D. S100 chemokines mediate bookmarking of premetastatic niches. Nat. Cell Biol. 8, 1321–1323 (2006).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  63. 63

    Yan, H. H. et al. Gr-1+CD11b+ myeloid cells tip the balance of immune protection to tumor promotion in the premetastatic lung. Cancer Res. 70, 6139–6149 (2010).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  64. 64

    Krishnan, V., Vogler, E. A., Sosnoski, D. M. & Mastro, A. M. In vitro mimics of bone remodeling and the vicious cycle of cancer in bone. J. Cell Physiol. 229, 453–462 (2014).

    CAS  PubMed  Article  Google Scholar 

  65. 65

    Pathi, S. P., Lin, D. D., Dorvee, J. R., Estroff, L. A. & Fischbach, C. Hydroxyapatite nanoparticle-containing scaffolds for the study of breast cancer bone metastasis. Biomaterials 32, 5112–5122 (2011).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  66. 66

    Kang, Y. et al. A multigenic program mediating breast cancer metastasis to bone. Cancer Cell 3, 537–549 (2003).

    CAS  Article  Google Scholar 

  67. 67

    Gower, R. M. et al. Modulation of leukocyte infiltration and phenotype in microporous tissue engineering scaffolds via vector induced IL-10 expression. Biomaterials 35, 2024–2031 (2014).

    CAS  PubMed  Article  Google Scholar 

  68. 68

    Gabrilovich, D. I. & Nagaraj, S. Myeloid-derived suppressor cells as regulators of the immune system. Nat. Rev. Immunol. 9, 162–174 (2009).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  69. 69

    Kwon, H. et al. Development of an in vitro model to study the impact of BMP-2 on metastasis to bone. J. Tissue Eng. Regen. Med. 4, 590–599 (2010).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  70. 70

    Katsuno, Y. et al. Bone morphogenetic protein signaling enhances invasion and bone metastasis of breast cancer cells through Smad pathway. Oncogene 27, 6322–6333 (2008).

    CAS  PubMed  Article  Google Scholar 

  71. 71

    Feeley, B. T. et al. Overexpression of noggin inhibits BMP-mediated growth of osteolytic prostate cancer lesions. Bone 38, 154–166 (2006).

    CAS  PubMed  Article  Google Scholar 

  72. 72

    Andersen, C. B. et al. Structure of the haptoglobin–haemoglobin complex. Nature 489, 456–459 (2012).

    CAS  PubMed  Article  Google Scholar 

  73. 73

    Fujita, K. et al. Serum fucosylated haptoglobin as a novel prognostic biomarker predicting high-Gleason prostate cancer. Prostate 74, 1052–1058 (2014).

    CAS  PubMed  Article  Google Scholar 

  74. 74

    Pompach, P. et al. Site-specific glycoforms of haptoglobin in liver cirrhosis and hepatocellular carcinoma. Mol. Cell. Proteomics 12, 1281–1293 (2013).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  75. 75

    Sun, L. et al. Combination of haptoglobin and osteopontin could predict colorectal cancer hepatic metastasis. Ann. Surg. Oncol. 19, 2411–2419 (2012).

    PubMed  Article  Google Scholar 

  76. 76

    Takeda, Y. et al. Fucosylated haptoglobin is a novel type of cancer biomarker linked to the prognosis after an operation in colorectal cancer. Cancer 118, 3036–3043 (2012).

    CAS  PubMed  Article  Google Scholar 

  77. 77

    Azmi, A. S., Bao, B. & Sarkar, F. H. Exosomes in cancer development, metastasis, and drug resistance: a comprehensive review. Cancer Metastasis Rev. 32, 623–642 (2013).

    CAS  PubMed  Article  Google Scholar 

  78. 78

    Thakur, B. K. et al. Double-stranded DNA in exosomes: a novel biomarker in cancer detection. Cell Res. 24, 766–769 (2014).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  79. 79

    Abels, E. R. & Breakefield, X. O. Introduction to extracellular vesicles: biogenesis, RNA cargo selection, content, release, and uptake. Cell. Mol. Neurobiol. 36, 301–312 (2016).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  80. 80

    Wendler, F. et al. Extracellular vesicles swarm the cancer microenvironment: from tumor-stroma communication to drug intervention. Oncogene 36, 877–884 (2017).

    CAS  PubMed  Article  Google Scholar 

  81. 81

    Valadi, H. et al. Exosome-mediated transfer of mRNAs and microRNAs is a novel mechanism of genetic exchange between cells. Nat. Cell Biol. 9, 654–659 (2007).

    CAS  PubMed  Article  Google Scholar 

  82. 82

    Becker, A. et al. Extracellular vesicles in cancer: cell-to-cell mediators of metastasis. Cancer Cell 30, 836–848 (2016).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  83. 83

    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 (2015).

    CAS  PubMed  Article  Google Scholar 

  84. 84

    Barkan, D., Green, J. E. & Chambers, A. F. Extracellular matrix: a gatekeeper in the transition from dormancy to metastatic growth. Eur. J. Cancer 46, 1181–1188 (2010).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  85. 85

    Oskarsson, T. Extracellular matrix components in breast cancer progression and metastasis. Breast 22 (Suppl. 2), S66–S72 (2013).

    PubMed  Article  Google Scholar 

  86. 86

    Desgrosellier, J. S. & Cheresh, D. A. Integrins in cancer: biological implications and therapeutic opportunities. Nat. Rev. Cancer 10, 9–22 (2010).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  87. 87

    Barney, L. E. et al. A cell-ECM screening method to predict breast cancer metastasis. Integr. Biol. 7, 198–212 (2015).

    CAS  Article  Google Scholar 

  88. 88

    Aguado, B. A. et al. Extracellular matrix mediators of metastatic cell colonization characterized using scaffold mimics of the pre-metastatic niche. Acta Biomater. 33, 13–24 (2016).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  89. 89

    Crapo, P. M., Gilbert, T. W. & Badylak, S. F. An overview of tissue and whole organ decellularization processes. Biomaterials 32, 3233–3243 (2011).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  90. 90

    Lu, W. D. et al. Development of an acellular tumor extracellular matrix as a three-dimensional scaffold for tumor engineering. PLoS ONE 9, e103672 (2014).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  91. 91

    Mishra, D. K. et al. Human lung cancer cells grown on acellular rat lung matrix create perfusable tumor nodules. Ann. Thorac. Surg. 93, 1075–1081 (2012).

    PubMed  PubMed Central  Article  Google Scholar 

  92. 92

    Villasante, A., Marturano-Kruik, A. & Vunjak-Novakovic, G. Bioengineered human tumor within a bone niche. Biomaterials 35, 5785–5794 (2014).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  93. 93

    Kubala, L. et al. The potentiation of myeloperoxidase activity by the glycosaminoglycan-dependent binding of myeloperoxidase to proteins of the extracellular matrix. Biochim. Biophys. Acta 1830, 4524–4536 (2013).

    CAS  PubMed  Article  Google Scholar 

  94. 94

    van der Veen, B. S., de Winther, M. P. & Heeringa, P. Myeloperoxidase: molecular mechanisms of action and their relevance to human health and disease. Antioxid. Redox Signal. 11, 2899–2937 (2009).

    CAS  PubMed  Article  Google Scholar 

  95. 95

    Taubenberger, A. V., Quent, V. M., Thibaudeau, L., Clements, J. A. & Hutmacher, D. W. Delineating breast cancer cell interactions with engineered bone microenvironments. J. Bone Miner. Res. 28, 1399–1411 (2013).

    CAS  PubMed  Article  Google Scholar 

  96. 96

    Lee, J. et al. Implantable microenvironments to attract hematopoietic stem/cancer cells. Proc. Natl Acad. Sci. USA 109, 19638–19643 (2012).

    CAS  PubMed  Article  Google Scholar 

  97. 97

    Vaiselbuh, S. R., Edelman, M., Lipton, J. M. & Liu, J. M. Ectopic human mesenchymal stem cell-coated scaffolds in NOD/SCID mice: an in vivo model of the leukemia niche. Tissue Eng. Part C Methods 16, 1523–1531 (2010).

    CAS  PubMed  Article  Google Scholar 

  98. 98

    Seib, F. P., Berry, J. E., Shiozawa, Y., Taichman, R. S. & Kaplan, D. L. Tissue engineering a surrogate niche for metastatic cancer cells. Biomaterials 51, 313–319 (2015).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  99. 99

    Holzapfel, B. M. et al. Species-specific homing mechanisms of human prostate cancer metastasis in tissue engineered bone. Biomaterials 35, 4108–4115 (2014).

    CAS  PubMed  Article  Google Scholar 

  100. 100

    Lee, E. et al. Breast cancer cells condition lymphatic endothelial cells within pre-metastatic niches to promote metastasis. Nat. Commun. 5, 4715 (2014).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  101. 101

    Wculek, S. K. & Malanchi, I. Neutrophils support lung colonization of metastasis-initiating breast cancer cells. Nature 528, 413–417 (2015).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  102. 102

    Kalluri, R. & Zeisberg, M. Fibroblasts in cancer. Nat. Rev. Cancer 6, 392–401 (2006).

    CAS  PubMed  Article  Google Scholar 

  103. 103

    De Boeck, A. et al. Differential secretome analysis of cancer-associated fibroblasts and bone marrow-derived precursors to identify microenvironmental regulators of colon cancer progression. Proteomics 13, 379–388 (2013).

    CAS  PubMed  Article  Google Scholar 

  104. 104

    De Vlieghere, E. et al. Tumor-environment biomimetics delay peritoneal metastasis formation by deceiving and redirecting disseminated cancer cells. Biomaterials 54, 148–157 (2015).

    CAS  PubMed  Article  Google Scholar 

  105. 105

    Yoneda, T., Williams, P. J., Hiraga, T., Niewolna, M. & Nishimura, R. A bone-seeking clone exhibits different biological properties from the MDA-MB-231 parental human breast cancer cells and a brain-seeking clone in vivo and in vitro. J. Bone Miner. Res. 16, 1486–1495 (2001).

    CAS  PubMed  Article  Google Scholar 

  106. 106

    Martine, L. C. et al. Engineering a humanized bone organ model in mice to study bone metastases. Nat. Protoc. 12, 639–663 (2017).

    CAS  PubMed  Article  Google Scholar 

  107. 107

    Hugo, H. et al. Epithelial–mesenchymal and mesenchymal–epithelial transitions in carcinoma progression. J. Cell. Physiol. 213, 374–383 (2007).

    CAS  PubMed  Article  Google Scholar 

  108. 108

    Ell, B. & Kang, Y. Transcriptional control of cancer metastasis. Trends Cell Biol. 23, 603–611 (2013).

    CAS  PubMed  Article  Google Scholar 

  109. 109

    Ocana, O. H. et al. Metastatic colonization requires the repression of the epithelial-mesenchymal transition inducer Prrx1. Cancer Cell 22, 709–724 (2012).

    CAS  PubMed  Article  Google Scholar 

  110. 110

    Ghajar, C. M. et al. The perivascular niche regulates breast tumour dormancy. Nat. Cell Biol. 15, 807–817 (2013).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  111. 111

    Holmgren, L., O’Reilly, M. S. & Folkman, J. Dormancy of micrometastases: balanced proliferation and apoptosis in the presence of angiogenesis suppression. Nat. Med. 1, 149–153 (1995).

    CAS  PubMed  Article  Google Scholar 

  112. 112

    Meng, S. et al. Circulating tumor cells in patients with breast cancer dormancy. Clin. Cancer Res. 10, 8152–8162 (2004).

    PubMed  Article  Google Scholar 

  113. 113

    Naumov, G. N. et al. Persistence of solitary mammary carcinoma cells in a secondary site: a possible contributor to dormancy. Cancer Res. 62, 2162–2168 (2002).

    CAS  PubMed  Google Scholar 

  114. 114

    Giancotti, F. G. Mechanisms governing metastatic dormancy and reactivation. Cell 155, 750–764 (2013).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  115. 115

    Luzzi, K. J. et al. Multistep nature of metastatic inefficiency. Am. J. Pathol. 153, 865–873 (1998).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  116. 116

    Weiss, L. Metastatic inefficiency. Adv. Cancer Res. 54, 159–211 (1990).

    CAS  PubMed  Article  Google Scholar 

  117. 117

    Weiss, L. Metastatic inefficiency: intravascular and intraperitoneal implantation of cancer cells. Cancer Treat. Res. 82, 1–11 (1996).

    CAS  PubMed  Article  Google Scholar 

  118. 118

    Arrigoni, C., Bersini, S., Gilardi, M. & Moretti, M. In vitro co-culture models of breast cancer metastatic progression towards bone. Int. J. Mol. Sci. 17, 1405 (2016).

    PubMed Central  Article  CAS  PubMed  Google Scholar 

  119. 119

    Bersini, S. et al. A microfluidic 3D in vitro model for specificity of breast cancer metastasis to bone. Biomaterials 35, 2454–2461 (2014).

    CAS  PubMed  Article  Google Scholar 

  120. 120

    Liu, X. Q., Kiefl, R., Roskopf, C., Tian, F. & Huber, R. M. Interactions among lung cancer cells, fibroblasts, and macrophages in 3D co-cultures and the impact on MMP-1 and VEGF expression. PLoS ONE 11, e0156268 (2016).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  121. 121

    Talukdar, S. & Kundu, S. C. Engineered 3D silk-based metastasis models: interactions between human breast adenocarcinoma, mesenchymal stem cells and osteoblast-like cells. Adv. Funct. Mater. 23, 5249–5260 (2013).

    CAS  Article  Google Scholar 

  122. 122

    Sieh, S. et al. Paracrine interactions between LNCaP prostate cancer cells and bioengineered bone in 3D in vitro culture reflect molecular changes during bone metastasis. Bone 63, 121–131 (2014).

    CAS  PubMed  Article  Google Scholar 

  123. 123

    Weigelt, B., Peterse, J. L. & van‘t Veer, L. J. Breast cancer metastasis: markers and models. Nat. Rev. Cancer 5, 591–602 (2005).

    CAS  PubMed  Article  Google Scholar 

  124. 124

    Klein, C. A. Parallel progression of primary tumours and metastases. Nat. Rev. Cancer 9, 302–312 (2009).

    CAS  PubMed  Article  Google Scholar 

  125. 125

    Esmaeilsabzali, H., Beischlag, T. V., Cox, M. E., Parameswaran, A. M. & Park, E. J. Detection and isolation of circulating tumor cells: principles and methods. Biotechnol. Adv. 31, 1063–1084 (2013).

    CAS  PubMed  Article  Google Scholar 

  126. 126

    Yoon, H. J., Kozminsky, M. & Nagrath, S. Emerging role of nanomaterials in circulating tumor cell isolation and analysis. ACS Nano 8, 1995–2017 (2014).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  127. 127

    Pantel, K., Brakenhoff, R. H. & Brandt, B. Detection, clinical relevance and specific biological properties of disseminating tumour cells. Nat. Rev. Cancer 8, 329–340 (2008).

    CAS  PubMed  Article  Google Scholar 

  128. 128

    Riethdorf, S. et al. Detection of circulating tumor cells in peripheral blood of patients with metastatic breast cancer: a validation study of the CellSearch system. Clin. Cancer Res. 13, 920–928 (2007).

    CAS  PubMed  Article  Google Scholar 

  129. 129

    Bichsel, C. A. et al. Diagnostic microchip to assay 3D colony-growth potential of captured circulating tumor cells. Lab Chip 12, 2313–2316 (2012).

    CAS  PubMed  Article  Google Scholar 

  130. 130

    Lee, J., Kohl, N., Shanbhang, S. & Parekkadan, B. Scaffold-integrated microchips for end-to-end in vitro tumor cell attachment and xenograft formation. Technology 3, 179–188 (2015).

    PubMed  PubMed Central  Article  Google Scholar 

  131. 131

    Yu, M. et al. Ex vivo culture of circulating breast tumor cells for individualized testing of drug susceptibility. Science 345, 216–220 (2014).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  132. 132

    Bednarz-Knoll, N., Alix-Panabières, C. & Pantel, K. Clinical relevance and biology of circulating tumor cells. Breast Cancer Res. 13, 228 (2011).

    PubMed  PubMed Central  Article  Google Scholar 

  133. 133

    Yi, J. & Backman, V. Imaging a full set of optical scattering properties of biological tissue by inverse spectroscopic optical coherence tomography. Opt. Lett. 37, 4443–4445 (2012).

    PubMed  PubMed Central  Article  Google Scholar 

  134. 134

    Kalluri, R. The biology and function of exosomes in cancer. J. Clin. Invest. 126, 1208–1215 (2016).

    PubMed  PubMed Central  Article  Google Scholar 

  135. 135

    Tauro, B. J. et al. Two distinct populations of exosomes are released from LIM1863 colon carcinoma cell-derived organoids. Mol. Cell. Proteomics 12, 587–598 (2013).

    CAS  PubMed  Article  Google Scholar 

  136. 136

    Sosa, M. S., Bragado, P. & Aguirre-Ghiso, J. A. Mechanisms of disseminated cancer cell dormancy: an awakening field. Nat. Rev. Cancer 14, 611–622 (2014).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  137. 137

    Frangioni, J. V. New technologies for human cancer imaging. J. Clin. Oncol. 26, 4012–4021 (2008).

    PubMed  PubMed Central  Article  Google Scholar 

  138. 138

    Nemeth, J. A. et al. Severe combined immunodeficient-hu model of human prostate cancer metastasis to human bone. Cancer Res. 59, 1987–1993 (1999).

    CAS  PubMed  Google Scholar 

  139. 139

    Xia, T. S. et al. Bone metastasis in a novel breast cancer mouse model containing human breast and human bone. Breast Cancer Res. Treat. 132, 471–486 (2012).

    CAS  PubMed  Article  Google Scholar 

  140. 140

    Kwon, H. et al. Development of an in vitro model to study the impact of BMP-2 on metastasis to bone. J. Tissue Eng. Regen. Med. 4, 590–599 (2010).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  141. 141

    Cristofanilli, M. et al. Circulating tumor cells, disease progression, and survival in metastatic breast cancer. N. Engl. J. Med. 351, 781–791 (2004).

    CAS  PubMed  Article  Google Scholar 

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Acknowledgements

We thank K. Aguado for figure illustrations. B.A.A. and G.G.B. acknowledge the support of a National Science Foundation Graduate Research Fellowship. Financial support for this work was provided by the National Institutes of Health and the National Cancer Institute (R01 CA173745).

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B.A.A., G.G.B. and L.D.S. wrote and edited the manuscript. B.A.A. prepared the figures. B.A.A. and G.G.B. prepared the tables. S.S.R. and J.S.J. edited and advised on the manuscript.

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Correspondence to Jacqueline S. Jeruss or Lonnie D. Shea.

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The authors declare no competing financial interests.

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Aguado, B., Bushnell, G., Rao, S. et al. Engineering the pre-metastatic niche. Nat Biomed Eng 1, 0077 (2017). https://doi.org/10.1038/s41551-017-0077

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