Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Engineering the pre-metastatic niche

Nature Biomedical Engineering volume 1, Article number: 0077 (2017) Cite this article

Subjects

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.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

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.

Similar content being viewed by others

References

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

    Article  CAS  PubMed  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  Google Scholar 

  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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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).

    Article  PubMed  CAS  Google Scholar 

  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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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).

    Article  CAS  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  Google Scholar 

  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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  Google Scholar 

  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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  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).

    Article  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

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

    Article  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  PubMed Central  CAS  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  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).

    Article  CAS  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  PubMed  PubMed Central  Google Scholar 

  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).

    Article  PubMed  PubMed Central  Google Scholar 

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

    Article  PubMed  PubMed Central  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  PubMed  PubMed Central  Google Scholar 

  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. 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).

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

Download references

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).

Author information

Author notes

  1. Brian A. Aguado and Grace G. Bushnell: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Biomedical Engineering, Northwestern University, Evanston, 60208, Illinois, USA

    Brian A. Aguado

  2. Simpson Querrey Institute for BioNanotechnology, Northwestern University, Chicago, 60611, Illinois, USA

    Brian A. Aguado

  3. Department of Biomedical Engineering, University of Michigan, 1119 Carl A. Gerstacker Building, 2200 Bonisteel Boulevard, Ann Arbor, 48109-2099, Michigan, USA

    Grace G. Bushnell & Lonnie D. Shea

  4. Department of Chemical and Biological Engineering, University of Alabama, Tuscaloosa, 35487, Alabama, USA

    Shreyas S. Rao

  5. Departments of Surgery, Division of Surgical Oncology, Pathology and Biomedical Engineering, University of Michigan, 3303 Cancer Center, 1500 East Medical Center Drive, Ann Arbor, 48105, Michigan, USA

    Jacqueline S. Jeruss

Authors
  1. Brian A. Aguado
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Grace G. Bushnell
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Shreyas S. Rao
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Jacqueline S. Jeruss
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Lonnie D. Shea
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

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.

Corresponding authors

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

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Information

Supplementary tables (PDF 163 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

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

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1038/s41551-017-0077

This article is cited by

Search

Advanced search

Quick links

Nature Briefing: Cancer

Sign up for the Nature Briefing: Cancer newsletter — what matters in cancer research, free to your inbox weekly.

Get what matters in cancer research, free to your inbox weekly. Sign up for Nature Briefing: Cancer