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.

Pre-metastatic niches: organ-specific homes for metastases

Key Points

  • Organs of future metastasis are selectively and actively modified by the primary tumour before metastatic spread has occurred.

  • Tumours induce the formation of microenvironments in distant organs that are conducive to the survival and outgrowth of tumour cells before their arrival at these sites. These microenvironments are termed pre-metastatic niches (PMNs).

  • PMN formation is a stepwise process resulting from the combined systemic effects of tumour-secreted factors and tumour-shed extracellular vesicles.

  • PMN formation is initiated with local changes such as the induction of vascular leakiness, remodelling of stroma and extracellular matrix, followed by systemic effects on the immune system.

  • The development of new technologies and approaches to identify PMNs in distant organ sites in patients could revolutionize cancer treatment and lead to pre-emptive treatments to hinder metastasis.

  • The PMN is a new paradigm for the initiation of metastasis. Our ability to fight metastasis would benefit greatly from understanding the pathological processes occurring before the development of macrometastases.

Abstract

It is well established that organs of future metastasis are not passive receivers of circulating tumour cells, but are instead selectively and actively modified by the primary tumour before metastatic spread has even occurred. Sowing the 'seeds' of metastasis requires the action of tumour-secreted factors and tumour-shed extracellular vesicles that enable the 'soil' at distant metastatic sites to encourage the outgrowth of incoming cancer cells. In this Review, we summarize the main processes and new mechanisms involved in the formation of the pre-metastatic niche.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Figure 1: Factors involved in PMN formation.
Figure 2: Model of PMN formation.

References

  1. 1

    Paget, S. The distribution of secondary growths in cancer of the breast. Lancet 133, 571–573 (1889). This was the first time the requirement for a suportive microenvironment, or 'fertile soil' in metastatic outgrowth was recognized.

    Article  Google Scholar 

  2. 2

    Ewing, J. Neoplastic Diseases: A Treatise on Tumours (W. B. Saunders Company, 1928).

    Google Scholar 

  3. 3

    Fidler, I. J. & Nicolson, G. L. Organ selectivity for implantation survival and growth of B16 melanoma variant tumor lines. J. Natl Cancer Inst. 57, 1199–1202 (1976). This study was the first to provide experimental evidence for organotropic metastasis.

    Article  CAS  PubMed  Google Scholar 

  4. 4

    Hart, I. R. & Fidler, I. J. Role of organ selectivity in the determination of metastatic patterns of B16 melanoma. Cancer Res. 40, 2281–2287 (1980).

    CAS  Google Scholar 

  5. 5

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

    CAS  Google Scholar 

  6. 6

    Psaila, B. & Lyden, D. The metastatic niche: adapting the foreign soil. Nat. Rev. Cancer 9, 285–293 (2009).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  7. 7

    Kaplan, R. N. et al. VEGFR1-positive haematopoietic bone marrow progenitors initiate the pre-metastatic niche. Nature 438, 820–827 (2005). This was the first proof-of-principle study demonstrating the existence of and stepwise progression of the PMN.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  8. 8

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

    Article  CAS  Google Scholar 

  9. 9

    Chin, A. R. & Wang, S. E. Cancer tills the premetastatic field: mechanistic basis and clinical implications. Clin. Cancer Res. 22, 3725–3733 (2016).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  10. 10

    Ordonez-Moran, P. & Huelsken, J. Complex metastatic niches: already a target for therapy? Curr. Opin. Cell Biol. 31, 29–38 (2014).

    Article  CAS  PubMed  Google Scholar 

  11. 11

    Quail, D. F. & Joyce, J. A. Microenvironmental regulation of tumor progression and metastasis. Nat. Med. 19, 1423–1437 (2013).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  12. 12

    Joyce, J. A. & Pollard, J. W. Microenvironmental regulation of metastasis. Nat. Rev. Cancer 9, 239–252 (2009).

    Article  CAS  PubMed  Google Scholar 

  13. 13

    Shibue, T. & Weinberg, R. A. Metastatic colonization: settlement, adaptation and propagation of tumor cells in a foreign tissue environment. Semin. Cancer Biol. 21, 99–106 (2011).

    Article  CAS  PubMed  Google Scholar 

  14. 14

    Weilbaecher, K. N., Guise, T. A. & McCauley, L. K. Cancer to bone: a fatal attraction. Nat. Rev. Cancer 11, 411–425 (2011).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  15. 15

    Sleeman, J. P. The metastatic niche and stromal progression. Cancer Metastasis Rev. 31, 429–440 (2012).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  16. 16

    Wculek, S. K. & Malanchi, I. Neutrophils fan cancer's flames. EMBO J. 34, 2211–2212 (2015).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  17. 17

    Woodard, P. K., Dehdashti, F. & Putman, C. E. Radiologic diagnosis of extrathoracic metastases to the lung. Oncology (Williston Park) 12, 431–438 (1998).

    CAS  Google Scholar 

  18. 18

    Francia, G., Cruz-Munoz, W., Man, S., Xu, P. & Kerbel, R. S. Mouse models of advanced spontaneous metastasis for experimental therapeutics. Nat. Rev. Cancer 11, 135–141 (2011).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  19. 19

    Karaca, Z. et al. VEGFR1 expression is related to lymph node metastasis and serum VEGF may be a marker of progression in the follow-up of patients with differentiated thyroid carcinoma. Eur. J. Endocrinol. 164, 277–284 (2011).

    Article  CAS  PubMed  Google Scholar 

  20. 20

    Hirakawa, S. et al. VEGF-C-induced lymphangiogenesis in sentinel lymph nodes promotes tumor metastasis to distant sites. Blood 109, 1010–1017 (2007).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  21. 21

    Hirakawa, S. et al. VEGF-A induces tumor and sentinel lymph node lymphangiogenesis and promotes lymphatic metastasis. J. Exp. Med. 201, 1089–1099 (2005).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  22. 22

    Jung, T. et al. CD44v6 dependence of premetastatic niche preparation by exosomes. Neoplasia 11, 1093–1105 (2009).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  23. 23

    Payen, D., Dupuy, P., Schurando, P. & Laborde, F. Postoperative enoximone in coronary surgery. Systemic and coronary hemodynamics and regional systolic function. Arch. Mal. Coeur Vaiss. 83, 13–17 (in French) (1990

    PubMed  Google Scholar 

  24. 24

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

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  25. 25

    Zhang, C. et al. Human CD133-positive hematopoietic progenitor cells initiate growth and metastasis of colorectal cancer cells. Carcinogenesis 35, 2771–2777 (2014).

    Article  CAS  PubMed  Google Scholar 

  26. 26

    Zhang, Y., Davis, C., Ryan, J., Janney, C. & Pena, M. M. Development and characterization of a reliable mouse model of colorectal cancer metastasis to the liver. Clin. Exp. Metastasis 30, 903–918 (2013).

    Article  CAS  PubMed  Google Scholar 

  27. 27

    Yang, Z. H., Yang, M., Xiong, H. Z. & Li, X. N. Role of vascular endothelial growth factor receptor 1-positive hematopoietic progenitor cell clusters in human colorectal carcinoma metastasis. Nan Fang Yi Ke Da Xue Xue Bao 28, 696–699 (in Chinese) (2008).

    CAS  PubMed  Google Scholar 

  28. 28

    Seubert, B. et al. Tissue inhibitor of metalloproteinases (TIMP)-1 creates a premetastatic niche in the liver through SDF-1/CXCR4-dependent neutrophil recruitment in mice. Hepatology 61, 238–248 (2015).

    Article  CAS  PubMed  Google Scholar 

  29. 29

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

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  30. 30

    Melo, S. A. et al. Glypican-1 identifies cancer exosomes and detects early pancreatic cancer. Nature 523, 177–182 (2015).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  31. 31

    Mundy, G. R. Metastasis to bone: causes, consequences and therapeutic opportunities. Nat. Rev. Cancer 2, 584–593 (2002).

    Article  CAS  Google Scholar 

  32. 32

    Cox, T. R. et al. LOX-mediated collagen crosslinking is responsible for fibrosis-enhanced metastasis. Cancer Res. 73, 1721–1732 (2013).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  33. 33

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

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  34. 34

    Guise, T. A. et al. Evidence for a causal role of parathyroid hormone-related protein in the pathogenesis of human breast cancer-mediated osteolysis. J. Clin. Invest. 98, 1544–1549 (1996).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  35. 35

    Ara, T. et al. Interleukin-6 in the bone marrow microenvironment promotes the growth and survival of neuroblastoma cells. Cancer Res. 69, 329–337 (2009).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  36. 36

    Paule, B. et al. Enhanced expression of interleukin-6 in bone and serum of metastatic renal cell carcinoma. Hum. Pathol. 29, 421–424 (1998).

    Article  CAS  PubMed  Google Scholar 

  37. 37

    Thomas, R. J. et al. Breast cancer cells interact with osteoblasts to support osteoclast formation. Endocrinology 140, 4451–4458 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. 38

    Kang, Y. et al. A multigenic program mediating breast cancer metastasis to bone. Cancer Cell 3, 537–549 (2003). This landmark study defined the breast cancer cell-intrinsic determinants of bone metastasis.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. 39

    Lynch, C. C. et al. MMP-7 promotes prostate cancer-induced osteolysis via the solubilization of RANKL. Cancer Cell 7, 485–496 (2005).

    Article  CAS  PubMed  Google Scholar 

  40. 40

    Lu, X. et al. ADAMTS1 and MMP1 proteolytically engage EGF-like ligands in an osteolytic signaling cascade for bone metastasis. Genes Dev. 23, 1882–1894 (2009).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  41. 41

    Guise, T. Examining the metastatic niche: targeting the microenvironment. Semin. Oncol. 37 (Suppl. 2), S2–S14 (2010).

    Article  CAS  PubMed  Google Scholar 

  42. 42

    Dai, J. et al. Bone morphogenetic protein-6 promotes osteoblastic prostate cancer bone metastases through a dual mechanism. Cancer Res. 65, 8274–8285 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. 43

    Logothetis, C. J. & Lin, S. H. Osteoblasts in prostate cancer metastasis to bone. Nat. Rev. Cancer 5, 21–28 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. 44

    Gaur, T. et al. Canonical WNT signaling promotes osteogenesis by directly stimulating Runx2 gene expression. J. Biol. Chem. 280, 33132–33140 (2005).

    Article  CAS  PubMed  Google Scholar 

  45. 45

    Bennett, C. N. et al. Regulation of osteoblastogenesis and bone mass by Wnt10b. Proc. Natl Acad. Sci. USA 102, 3324–3329 (2005).

    Article  CAS  PubMed  Google Scholar 

  46. 46

    Steeg, P. S., Camphausen, K. A. & Smith, Q. R. Brain metastases as preventive and therapeutic targets. Nat. Rev. Cancer 11, 352–363 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. 47

    Lyle, L. T. et al. Alterations in pericyte subpopulations are associated with elevated blood–tumor barrier permeability in experimental brain metastasis of breast cancer. Clin. Cancer Res. 22, 5287–5299 (2016).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  48. 48

    Percy, D. B. et al. In vivo characterization of changing blood-tumor barrier permeability in a mouse model of breast cancer metastasis: a complementary magnetic resonance imaging approach. Invest. Radiol. 46, 718–725 (2011).

    Article  PubMed  Google Scholar 

  49. 49

    Steeg, P. S. Targeting metastasis. Nat. Rev. Cancer 16, 201–218 (2016).

    Article  CAS  Google Scholar 

  50. 50

    Fong, M. Y. et al. Breast-cancer-secreted miR-122 reprograms glucose metabolism in premetastatic niche to promote metastasis. Nat. Cell Biol. 17, 183–194 (2015). This study was the first to provide evidence of metabolic reprogramming of stromal cells in PMNs through miRNA cargo shuttled by tumour-derived microvesicles.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  51. 51

    Hoshino, A. et al. Tumour exosome integrins determine organotropic metastasis. Nature 527, 329–335 (2015). This landmark study demonstrated that organotropic metastasis can be orchestrated in a tumour cell-autonomous manner through exosome-expressed integrins.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  52. 52

    Hiratsuka, S. et al. MMP9 induction by vascular endothelial growth factor receptor-1 is involved in lung-specific metastasis. Cancer Cell 2, 289–300 (2002).

    Article  CAS  Google Scholar 

  53. 53

    Hiratsuka, S. et al. The S100A8-serum amyloid A3–TLR4 paracrine cascade establishes a pre-metastatic phase. Nat. Cell Biol. 10, 1349–1355 (2008). This study demonstrated that chemokines induced in PMNs facilitate metastasis in a TLR4-dependent manner, through effects on local innate immune cells.

    Article  CAS  PubMed  Google Scholar 

  54. 54

    Shojaei, F. et al. G-CSF-initiated myeloid cell mobilization and angiogenesis mediate tumor refractoriness to anti-VEGF therapy in mouse models. Proc. Natl Acad. Sci. USA 106, 6742–6747 (2009).

    Article  PubMed  Google Scholar 

  55. 55

    Melgarejo, E., Medina, M. A., Sanchez-Jimenez, F. & Urdiales, J. L. Monocyte chemoattractant protein-1: a key mediator in inflammatory processes. Int. J. Biochem. Cell Biol. 41, 998–1001 (2009).

    Article  CAS  PubMed  Google Scholar 

  56. 56

    Lu, Y. et al. Monocyte chemotactic protein-1 (MCP-1) acts as a paracrine and autocrine factor for prostate cancer growth and invasion. Prostate 66, 1311–1318 (2006).

    Article  CAS  PubMed  Google Scholar 

  57. 57

    Cai, Z. et al. Monocyte chemotactic protein 1 promotes lung cancer-induced bone resorptive lesions in vivo. Neoplasia 11, 228–236 (2009).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  58. 58

    Loberg, R. D. et al. Targeting CCL2 with systemic delivery of neutralizing antibodies induces prostate cancer tumor regression in vivo. Cancer Res. 67, 9417–9424 (2007).

    Article  CAS  PubMed  Google Scholar 

  59. 59

    Saji, H. et al. Significant correlation of monocyte chemoattractant protein-1 expression with neovascularization and progression of breast carcinoma. Cancer 92, 1085–1091 (2001).

    Article  CAS  PubMed  Google Scholar 

  60. 60

    Lebrecht, A. et al. Monocyte chemoattractant protein-1 serum levels in patients with breast cancer. Tumour Biol. 25, 14–17 (2004).

    Article  CAS  PubMed  Google Scholar 

  61. 61

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

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  62. 62

    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  PubMed Central  Google Scholar 

  63. 63

    Lu, X. & Kang, Y. Chemokine (C-C motif) ligand 2 engages CCR2+ stromal cells of monocytic origin to promote breast cancer metastasis to lung and bone. J. Biol. Chem. 284, 29087–29096 (2009).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  64. 64

    Lu, X. & Kang, Y. Organotropism of breast cancer metastasis. J. Mammary Gland Biol. Neoplasia 12, 153–162 (2007).

    Article  PubMed  Google Scholar 

  65. 65

    Granot, Z. et al. Tumor entrained neutrophils inhibit seeding in the premetastatic lung. Cancer Cell 20, 300–314 (2011).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  66. 66

    Bresnick, A. R., Weber, D. J. & Zimmer, D. B. S100 proteins in cancer. Nat. Rev. Cancer 15, 96–109 (2015).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  67. 67

    Lukanidin, E. & Sleeman, J. P. Building the niche: the role of the S100 proteins in metastatic growth. Semin. Cancer Biol. 22, 216–225 (2012).

    Article  CAS  PubMed  Google Scholar 

  68. 68

    Donato, R. et al. Functions of S100 proteins. Curr. Mol. Med. 13, 24–57 (2013).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  69. 69

    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  PubMed Central  Google Scholar 

  70. 70

    Wong, C. C. et al. Hypoxia-inducible factor 1 is a master regulator of breast cancer metastatic niche formation. Proc. Natl Acad. Sci. USA 108, 16369–16374 (2011).

    Article  PubMed  Google Scholar 

  71. 71

    Wong, C. C. et al. Inhibitors of hypoxia-inducible factor 1 block breast cancer metastatic niche formation and lung metastasis. J. Mol. Med. (Berl.) 90, 803–815 (2012).

    Article  CAS  Google Scholar 

  72. 72

    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).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  73. 73

    Erler, J. T. et al. Lysyl oxidase is essential for hypoxia-induced metastasis. Nature 440, 1222–1226 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. 74

    King, H. W., Michael, M. Z. & Gleadle, J. M. Hypoxic enhancement of exosome release by breast cancer cells. BMC Cancer 12, 421 (2012).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  75. 75

    Wang, T. et al. Hypoxia-inducible factors and RAB22A mediate formation of microvesicles that stimulate breast cancer invasion and metastasis. Proc. Natl Acad. Sci. USA 111, E3234–E3242 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. 76

    Gould, S. J. & Raposo, G. As we wait: coping with an imperfect nomenclature for extracellular vesicles. J. Extracell. Vesicles http://dx.doi.org/10.3402/jev.v2i0.20389 (2013).

  77. 77

    Colombo, M., Raposo, G. & Thery, C. Biogenesis, secretion, and intercellular interactions of exosomes and other extracellular vesicles. Annu. Rev. Cell Dev. Biol. 30, 255–289 (2014).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  78. 78

    Raposo, G. & Stoorvogel, W. Extracellular vesicles: exosomes, microvesicles, and friends. J. Cell Biol. 200, 373–383 (2013).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  79. 79

    Peinado, H. et al. Melanoma exosomes educate bone marrow progenitor cells toward a pro-metastatic phenotype through MET. Nat. Med. 18, 883–891 (2012). This was the first study to demonstrate that exosomes secreted by highly metastatic tumours promote metastasis by permanently educating bone marrow progenitors and recruiting them to PMNs.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  80. 80

    Ostenfeld, M. S. et al. Cellular disposal of miR23b by RAB27-dependent exosome release is linked to acquisition of metastatic properties. Cancer Res. 74, 5758–5771 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. 81

    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 

  82. 82

    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  Google Scholar 

  83. 83

    Balaj, L. et al. Tumour microvesicles contain retrotransposon elements and amplified oncogene sequences. Nat. Commun. 2, 180 (2011).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  84. 84

    Skog, J. et al. Glioblastoma microvesicles transport RNA and proteins that promote tumour growth and provide diagnostic biomarkers. Nat. Cell Biol. 10, 1470–1476 (2008).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  85. 85

    Al-Nedawi, K. et al. Intercellular transfer of the oncogenic receptor EGFRvIII by microvesicles derived from tumour cells. Nat. Cell Biol. 10, 619–624 (2008).

    Article  CAS  PubMed  Google Scholar 

  86. 86

    Ratajczak, J. et al. Embryonic stem cell-derived microvesicles reprogram hematopoietic progenitors: evidence for horizontal transfer of mRNA and protein delivery. Leukemia 20, 847–856 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. 87

    Janowska-Wieczorek, A. et al. Microvesicles derived from activated platelets induce metastasis and angiogenesis in lung cancer. Int. J. Cancer 113, 752–760 (2005).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  88. 88

    Janowska-Wieczorek, A., Marquez-Curtis, L. A., Wysoczynski, M. & Ratajczak, M. Z. Enhancing effect of platelet-derived microvesicles on the invasive potential of breast cancer cells. Transfusion 46, 1199–1209 (2006).

    Article  PubMed  Google Scholar 

  89. 89

    Cocucci, E., Racchetti, G. & Meldolesi, J. Shedding microvesicles: artefacts no more. Trends Cell Biol. 19, 43–51 (2009).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  90. 90

    Iero, M. et al. Tumour-released exosomes and their implications in cancer immunity. Cell Death Differ. 15, 80–88 (2008).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  91. 91

    Ratajczak, J., Wysoczynski, M., Hayek, F., Janowska-Wieczorek, A. & Ratajczak, M. Z. Membrane-derived microvesicles: important and underappreciated mediators of cell-to-cell communication. Leukemia 20, 1487–1495 (2006).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  92. 92

    Grange, C. et al. Microvesicles released from human renal cancer stem cells stimulate angiogenesis and formation of lung premetastatic niche. Cancer Res. 71, 5346–5356 (2011).

    Article  CAS  PubMed  Google Scholar 

  93. 93

    Hood, J. L., San, R. S. & Wickline, S. A. Exosomes released by melanoma cells prepare sentinel lymph nodes for tumor metastasis. Cancer Res. 71, 3792–3801 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. 94

    Villarroya-Beltri, C., Baixauli, F., Gutierrez-Vazquez, C., Sanchez-Madrid, F. & Mittelbrunn, M. Sorting it out: regulation of exosome loading. Semin. Cancer Biol. 28, 3–13 (2014).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  95. 95

    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  CAS  PubMed  Google Scholar 

  96. 96

    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 

  97. 97

    Jian, J. et al. Platelet factor 4 is produced by subsets of myeloid cells in premetastatic lung and inhibits tumor metastasis. Oncotarget http://dx.doi.org/10.18632/oncotarget.9486 (2016).

  98. 98

    Huang, Y. et al. Pulmonary vascular destabilization in the premetastatic phase facilitates lung metastasis. Cancer Res. 69, 7529–7537 (2009). This landmark study demonstrated that ANGPT2-, MMP3- and MMP10-dependent pulmonary vascular destabilization is an early event occurring during the pre-metastatic phase, which promotes the extravasation of tumour cells and facilitates lung metastasis.

    Article  CAS  PubMed  Google Scholar 

  99. 99

    Hiratsuka, S. et al. Primary tumours modulate innate immune signalling to create pre-metastatic vascular hyperpermeability foci. Nat. Commun. 4, 1853 (2013).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  100. 100

    Hiratsuka, S. et al. Endothelial focal adhesion kinase mediates cancer cell homing to discrete regions of the lungs via E-selectin up-regulation. Proc. Natl Acad. Sci. USA 108, 3725–3730 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  101. 101

    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).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  102. 102

    Gupta, G. P. et al. Mediators of vascular remodelling co-opted for sequential steps in lung metastasis. Nature 446, 765–770 (2007).

    Article  CAS  PubMed  Google Scholar 

  103. 103

    Padua, D. et al. TGFβ primes breast tumors for lung metastasis seeding through angiopoietin-like 4. Cell 133, 66–77 (2008).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  104. 104

    Jean, C. et al. Inhibition of endothelial FAK activity prevents tumor metastasis by enhancing barrier function. J. Cell Biol. 204, 247–263 (2014).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  105. 105

    Kim, S. et al. Carcinoma-produced factors activate myeloid cells through TLR2 to stimulate metastasis. Nature 457, 102–106 (2009).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  106. 106

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

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  107. 107

    Sevenich, L. et al. Analysis of tumour- and stroma-supplied proteolytic networks reveals a brain-metastasis-promoting role for cathepsin S. Nat. Cell Biol. 16, 876–888 (2014).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  108. 108

    Gay, L. J. & Felding-Habermann, B. Contribution of platelets to tumour metastasis. Nat. Rev. Cancer 11, 123–134 (2011).

    Article  CAS  Google Scholar 

  109. 109

    Kuderer, N. M., Ortel, T. L. & Francis, C. W. Impact of venous thromboembolism and anticoagulation on cancer and cancer survival. J. Clin. Oncol. 27, 4902–4911 (2009).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  110. 110

    Im, J. H. et al. Coagulation facilitates tumor cell spreading in the pulmonary vasculature during early metastatic colony formation. Cancer Res. 64, 8613–8619 (2004).

    Article  CAS  PubMed  Google Scholar 

  111. 111

    Gil-Bernabe, A. M. et al. Recruitment of monocytes/macrophages by tissue factor-mediated coagulation is essential for metastatic cell survival and premetastatic niche establishment in mice. Blood 119, 3164–3175 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. 112

    Labelle, M., Begum, S. & Hynes, R. O. Platelets guide the formation of early metastatic niches. Proc. Natl Acad. Sci. USA 111, E3053–E3061 (2014).

    Article  CAS  PubMed  Google Scholar 

  113. 113

    Hansen, M. T. et al. A link between inflammation and metastasis: serum amyloid A1 and A3 induce metastasis, and are targets of metastasis-inducing S100A4. Oncogene 34, 424–435 (2015).

    Article  CAS  PubMed  Google Scholar 

  114. 114

    Mauti, L. A. et al. Myeloid-derived suppressor cells are implicated in regulating permissiveness for tumor metastasis during mouse gestation. J. Clin. Invest. 121, 2794–2807 (2011).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  115. 115

    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  Google Scholar 

  116. 116

    Malanchi, I. et al. Interactions between cancer stem cells and their niche govern metastatic colonization. Nature 481, 85–89 (2012). This landmark study demonstrated that a subpopulation of cancer stem cells is responsible for metastatic colonization and that this process depends on signals provided by the stromal niche.

    Article  CAS  Google Scholar 

  117. 117

    Kudo, A. Periostin in fibrillogenesis for tissue regeneration: periostin actions inside and outside the cell. Cell. Mol. Life Sci. 68, 3201–3207 (2011).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  118. 118

    Fukuda, K. et al. Periostin is a key niche component for wound metastasis of melanoma. PLoS ONE 10, e0129704 (2015).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  119. 119

    Wang, Z. et al. Periostin promotes immunosuppressive premetastatic niche formation to facilitate breast tumour metastasis. J. Pathol. 239, 484–495 (2016).

    Article  CAS  PubMed  Google Scholar 

  120. 120

    Gao, D. et al. Myeloid progenitor cells in the premetastatic lung promote metastases by inducing mesenchymal to epithelial transition. Cancer Res. 72, 1384–1394 (2012).

    Article  CAS  PubMed  Google Scholar 

  121. 121

    Egeblad, M. & Werb, Z. New functions for the matrix metalloproteinases in cancer progression. Nat. Rev. Cancer 2, 161–174 (2002).

    Article  CAS  PubMed  Google Scholar 

  122. 122

    Cameron, J. D., Skubitz, A. P. & Furcht, L. T. Type IV collagen and corneal epithelial adhesion and migration. Effects of type IV collagen fragments and synthetic peptides on rabbit corneal epithelial cell adhesion and migration in vitro. Invest. Ophthalmol. Vis. Sci. 32, 2766–2773 (1991).

    CAS  PubMed  Google Scholar 

  123. 123

    Shahan, T. A., Fawzi, A., Bellon, G., Monboisse, J. C. & Kefalides, N. A. Regulation of tumor cell chemotaxis by type IV collagen is mediated by a Ca2+-dependent mechanism requiring CD47 and the integrin αVβ3 . J. Biol. Chem. 275, 4796–4802 (2000).

    Article  CAS  PubMed  Google Scholar 

  124. 124

    Kessenbrock, K., Plaks, V. & Werb, Z. Matrix metalloproteinases: regulators of the tumor microenvironment. Cell 141, 52–67 (2010).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  125. 125

    van Deventer, H. W. et al. C-C chemokine receptor 5 on stromal cells promotes pulmonary metastasis. Cancer Res. 65, 3374–3379 (2005).

    Article  CAS  PubMed  Google Scholar 

  126. 126

    van Deventer, H. W. et al. C-C chemokine receptor 5 on pulmonary fibrocytes facilitates migration and promotes metastasis via matrix metalloproteinase 9. Am. J. Pathol. 173, 253–264 (2008).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  127. 127

    Canesin, G. et al. Lysyl oxidase-like 2 (LOXL2) and E47 EMT factor: novel partners in E-cadherin repression and early metastasis colonization. Oncogene 34, 951–964 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  128. 128

    Engler, A. J., Humbert, P. O., Wehrle-Haller, B. & Weaver, V. M. Multiscale modeling of form and function. Science 324, 208–212 (2009).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  129. 129

    Krieg, M. et al. Tensile forces govern germ-layer organization in zebrafish. Nat. Cell Biol. 10, 429–436 (2008).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  130. 130

    Ronnov-Jessen, L. & Bissell, M. J. Breast cancer by proxy: can the microenvironment be both the cause and consequence? Trends Mol. Med. 15, 5–13 (2009).

    Article  CAS  PubMed  Google Scholar 

  131. 131

    Levental, K. R. et al. Matrix crosslinking forces tumor progression by enhancing integrin signaling. Cell 139, 891–906 (2009).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  132. 132

    Goetz, J. G. et al. Biomechanical remodeling of the microenvironment by stromal caveolin-1 favors tumor invasion and metastasis. Cell 146, 148–163 (2011).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  133. 133

    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).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  134. 134

    White, E. S. & Muro, A. F. Fibronectin splice variants: understanding their multiple roles in health and disease using engineered mouse models. IUBMB Life 63, 538–546 (2011).

    Article  CAS  PubMed  Google Scholar 

  135. 135

    Papaspyridonos, M. et al. Id1 suppresses anti-tumour immune responses and promotes tumour progression by impairing myeloid cell maturation. Nat. Commun. 6, 6840 (2015).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  136. 136

    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  PubMed  Google Scholar 

  137. 137

    Casbon, A. J. et al. Invasive breast cancer reprograms early myeloid differentiation in the bone marrow to generate immunosuppressive neutrophils. Proc. Natl Acad. Sci. USA 112, E566–E575 (2015).

    Article  CAS  Google Scholar 

  138. 138

    Bergers, G. et al. Matrix metalloproteinase-9 triggers the angiogenic switch during carcinogenesis. Nat. Cell Biol. 2, 737–744 (2000).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  139. 139

    Ahn, G. O. & Brown, J. M. Matrix metalloproteinase-9 is required for tumor vasculogenesis but not for angiogenesis: role of bone marrow-derived myelomonocytic cells. Cancer Cell 13, 193–205 (2008).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  140. 140

    Wu, C. F. et al. The lack of type I interferon induces neutrophil-mediated pre-metastatic niche formation in the mouse lung. Int. J. Cancer 137, 837–847 (2015).

    Article  CAS  PubMed  Google Scholar 

  141. 141

    Zaidi, M. R. & Merlino, G. The two faces of interferon-γ in cancer. Clin. Cancer Res. 17, 6118–6124 (2011).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  142. 142

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

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  143. 143

    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).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  144. 144

    Moses, W. W. Fundamental limits of spatial resolution in PET. Nucl. Instrum. Methods Phys. Res. A 648 (Suppl. 1), S236–S240 (2011).

    Article  CAS  PubMed  Google Scholar 

  145. 145

    Marom, E. M., Sarvis, S., Herndon, J. E. II & Patz, E. F. Jr. T1 lung cancers: sensitivity of diagnosis with fluorodeoxyglucose PET. Radiology 223, 453–459 (2002).

    Article  PubMed  Google Scholar 

  146. 146

    James, K. et al. Measuring response in solid tumors: unidimensional versus bidimensional measurement. J. Natl Cancer Inst. 91, 523–528 (1999).

    Article  CAS  PubMed  Google Scholar 

  147. 147

    Diaz-Cano, S. J. Tumor heterogeneity: mechanisms and bases for a reliable application of molecular marker design. Int. J. Mol. Sci. 13, 1951–2011 (2012).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  148. 148

    Ieni, A., Giuffre, G., Adamo, V. & Tuccari, G. Prognostic impact of CD133 immunoexpression in node-negative invasive breast carcinomas. Anticancer Res. 31, 1315–1320 (2011).

    CAS  PubMed  Google Scholar 

  149. 149

    Jain, S. et al. Incremental increase in VEGFR1+ hematopoietic progenitor cells and VEGFR2+ endothelial progenitor cells predicts relapse and lack of tumor response in breast cancer patients. Breast Cancer Res. Treat. 132, 235–242 (2012).

    Article  CAS  PubMed  Google Scholar 

  150. 150

    Kosaka, Y. et al. Identification of the high-risk group for metastasis of gastric cancer cases by vascular endothelial growth factor receptor-1 overexpression in peripheral blood. Br. J. Cancer 96, 1723–1728 (2007).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  151. 151

    Xu, W. W. et al. Targeting VEGFR1- and VEGFR2-expressing non-tumor cells is essential for esophageal cancer therapy. Oncotarget 6, 1790–1805 (2015).

    PubMed  Google Scholar 

  152. 152

    Zhang, W. et al. Myeloid clusters are associated with a pro-metastatic environment and poor prognosis in smoking-related early stage non-small cell lung cancer. PLoS ONE 8, e65121 (2013).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  153. 153

    Zhang, W. et al. CD8+ T-cell immunosurveillance constrains lymphoid premetastatic myeloid cell accumulation. Eur. J. Immunol. 45, 71–81 (2015).

    Article  CAS  PubMed  Google Scholar 

  154. 154

    Deng, J. et al. S1PR1-STAT3 signaling is crucial for myeloid cell colonization at future metastatic sites. Cancer Cell 21, 642–654 (2012). This study demonstrated that myeloid cells depend on S1PR1–STAT3 signalling to participate in PMN formation.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  155. 155

    Pala, S. et al. Prognostic significance of neutrophilic infiltration in benign lymph nodes in patients with muscle-invasive bladder cancer. Eur. Urol. http://dx.doi.org/10.1016/j.euf.2016.03.003 (2016).

  156. 156

    Cicatiello, V. et al. Powerful anti-tumor and anti-angiogenic activity of a new anti-vascular endothelial growth factor receptor 1 peptide in colorectal cancer models. Oncotarget 6, 10563–10576 (2015).

    PubMed  PubMed Central  Article  Google Scholar 

  157. 157

    Fraga, C. A. et al. A high HIF-1α expression genotype is associated with poor prognosis of upper aerodigestive tract carcinoma patients. Oral Oncol. 48, 130–135 (2012).

    Article  CAS  PubMed  Google Scholar 

  158. 158

    Otto, B. et al. Molecular changes in pre-metastatic lymph nodes of esophageal cancer patients. PLoS ONE 9, e102552 (2014).

    PubMed  PubMed Central  Article  Google Scholar 

  159. 159

    Wakisaka, N. et al. Primary tumor-secreted lymphangiogenic factors induce pre-metastatic lymphvascular niche formation at sentinel lymph nodes in oral squamous cell carcinoma. PLoS ONE 10, e0144056 (2015).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  160. 160

    Vered, M. et al. Factors associated with collagen metabolism in the lymph node pre-metastatic niche in oral cancer. Oral Surg. Oral Med. Oral Pathol. Oral Radiol. 120, e155–e156 (2015).

    Article  Google Scholar 

  161. 161

    Pal, S. K. & Figlin, R. A. Targeted therapies: pazopanib: carving a niche in a crowded therapeutic landscape. Nat. Rev. Clin. Oncol. 7, 362–363 (2010).

    Article  CAS  PubMed  Google Scholar 

  162. 162

    US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT01832259 (2016).

  163. 163

    Torrano, V. et al. Vesicle-MaNiA: extracellular vesicles in liquid biopsy and cancer. Curr. Opin. Pharmacol. 29, 47–53 (2016).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  164. 164

    Gold, B., Cankovic, M., Furtado, L. V., Meier, F. & Gocke, C. D. Do circulating tumor cells, exosomes, and circulating tumor nucleic acids have clinical utility? A report of the association for molecular pathology. J. Mol. Diagn. 17, 209–224 (2015).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  165. 165

    Zhou, W. et al. Cancer-secreted miR-105 destroys vascular endothelial barriers to promote metastasis. Cancer Cell 25, 501–515 (2014).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  166. 166

    Hu, L., Wickline, S. A. & Hood, J. L. Magnetic resonance imaging of melanoma exosomes in lymph nodes. Magn. Reson. Med. http://dx.doi.org/10.1002/mrm.25376 (2014).

  167. 167

    Shokeen, M. et al. Molecular imaging of very late antigen-4 (alpha4beta1 integrin) in the premetastatic niche. J. Nucl. Med. 53, 779–786 (2012).

    Article  PubMed  Google Scholar 

  168. 168

    Soodgupta, D. et al. Very late antigen-4 (α4β1 Integrin) targeted PET imaging of multiple myeloma. PLoS ONE 8, e55841 (2013).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  169. 169

    Zhu, L. et al. Label-free quantitative detection of tumor-derived exosomes through surface plasmon resonance imaging. Anal. Chem. 86, 8857–8864 (2014).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  170. 170

    Joo, Y. N. et al. P2Y2R activation by nucleotides released from the highly metastatic breast cancer cell MDA-MB-231 contributes to pre-metastatic niche formation by mediating lysyl oxidase secretion, collagen crosslinking, and monocyte recruitment. Oncotarget 5, 9322–9334 (2014).

    PubMed  PubMed Central  Article  Google Scholar 

  171. 171

    Liu, Z. et al. Protein tyrosine phosphatase receptor type O expression in the tumor niche correlates with reduced tumor growth, angiogenesis, circulating tumor cells and metastasis of breast cancer. Oncol. Rep. 33, 1908–1914 (2015).

    Article  CAS  PubMed  Google Scholar 

  172. 172

    Ling, X. et al. The CXCR4 antagonist AMD3465 regulates oncogenic signaling and invasiveness in vitro and prevents breast cancer growth and metastasis in vivo. PLoS ONE 8, e58426 (2013).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  173. 173

    Kirsch, M., Schackert, G. & Black, P. M. Angiogenesis, metastasis, and endogenous inhibition. J. Neurooncol. 50, 173–180 (2000).

    Article  CAS  PubMed  Google Scholar 

  174. 174

    Bissell, M. J. & Hines, W. C. Why don't we get more cancer? A proposed role of the microenvironment in restraining cancer progression. Nat. Med. 17, 320–329 (2011).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  175. 175

    Ghajar, C. M. Metastasis prevention by targeting the dormant niche. Nat. Rev. Cancer 15, 238–247 (2015).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  176. 176

    Baillargeon, J. & Rose, D. P. Obesity, adipokines, and prostate cancer (review). Int. J. Oncol. 28, 737–745 (2006).

    CAS  PubMed  Google Scholar 

  177. 177

    Mistry, T., Digby, J. E., Desai, K. M. & Randeva, H. S. Obesity and prostate cancer: a role for adipokines. Eur. Urol. 52, 46–53 (2007).

    Article  CAS  PubMed  Google Scholar 

  178. 178

    Ribeiro, R. J. et al. Tumor cell-educated periprostatic adipose tissue acquires an aggressive cancer-promoting secretory profile. Cell. Physiol. Biochem. 29, 233–240 (2012).

    Article  CAS  PubMed  Google Scholar 

  179. 179

    Nieman, K. M. et al. Adipocytes promote ovarian cancer metastasis and provide energy for rapid tumor growth. Nat. Med. 17, 1498–1503 (2011).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  180. 180

    Thaker, P. H. et al. Chronic stress promotes tumor growth and angiogenesis in a mouse model of ovarian carcinoma. Nat. Med. 12, 939–944 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  181. 181

    Cox, T. R. & Erler, J. T. Remodeling and homeostasis of the extracellular matrix: implications for fibrotic diseases and cancer. Dis. Model. Mech. 4, 165–178 (2011).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  182. 182

    Lim, C. et al. Hepatic ischemia-reperfusion increases circulating bone marrow-derived progenitor cells and tumor growth in a mouse model of colorectal liver metastases. J. Surg. Res. 184, 888–897 (2013).

    Article  PubMed  Google Scholar 

  183. 183

    Govaert, K. M. et al. Hypoxia after liver surgery imposes an aggressive cancer stem cell phenotype on residual tumor cells. Ann. Surg. 259, 750–759 (2014).

    Article  PubMed  Google Scholar 

  184. 184

    Jiao, S. F. et al. Inhibition of tumor necrosis factor alpha reduces the outgrowth of hepatic micrometastasis of colorectal tumors in a mouse model of liver ischemia-reperfusion injury. J. Biomed. Sci. 21, 1 (2014).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  185. 185

    van der Bilt, J. D. et al. Ischemia/reperfusion accelerates the outgrowth of hepatic micrometastases in a highly standardized murine model. Hepatology 42, 165–175 (2005).

    Article  CAS  PubMed  Google Scholar 

  186. 186

    Retsky, M. et al. Reduction of breast cancer relapses with perioperative non-steroidal anti-inflammatory drugs: new findings and a review. Curr. Med. Chem. 20, 4163–4176 (2013).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  187. 187

    Jain, R. K. Normalization of tumor vasculature: an emerging concept in antiangiogenic therapy. Science 307, 58–62 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  188. 188

    Scadden, D. T. Nice neighborhood: emerging concepts of the stem cell niche. Cell 157, 41–50 (2014).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  189. 189

    Bergers, G. & Hanahan, D. Modes of resistance to anti-angiogenic therapy. Nat. Rev. Cancer 8, 592–603 (2008).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  190. 190

    Janni, W. et al. Persistence of disseminated tumor cells in the bone marrow of breast cancer patients predicts increased risk for relapse — a European pooled analysis. Clin. Cancer Res. 17, 2967–2976 (2011).

    Article  PubMed  Google Scholar 

  191. 191

    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 

  192. 192

    Suzuki, M., Mose, E. S., Montel, V. & Tarin, D. Dormant cancer cells retrieved from metastasis-free organs regain tumorigenic and metastatic potency. Am. J. Pathol. 169, 673–681 (2006).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  193. 193

    Gao, H. et al. The BMP inhibitor Coco reactivates breast cancer cells at lung metastatic sites. Cell 150, 764–779 (2012). This landmark study screening for modifiers of metastatic dormancy identified organ-specific BMP signalling as a microenvironmental suppressor of metastasis.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  194. 194

    Bragado, P. et al. TGF-beta2 dictates disseminated tumour cell fate in target organs through TGF-beta-RIII and p38alpha/beta signalling. Nat. Cell Biol. 15, 1351–1361 (2013).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  195. 195

    Kobayashi, A. et al. Bone morphogenetic protein 7 in dormancy and metastasis of prostate cancer stem-like cells in bone. J. Exp. Med. 208, 2641–2655 (2011).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  196. 196

    Ghajar, C. M. et al. The perivascular niche regulates breast tumour dormancy. Nat. Cell Biol. 15, 807–817 (2013). This is an elegant dissection of the role of vascular niches in tumour dormancy, demonstrating that stable microvasculature is required to maintain dormancy.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  197. 197

    Kobayashi, H. et al. Angiocrine factors from Akt-activated endothelial cells balance self-renewal and differentiation of haematopoietic stem cells. Nat. Cell Biol. 12, 1046–1056 (2010).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  198. 198

    Franses, J. W., Drosu, N. C., Gibson, W. J., Chitalia, V. C. & Edelman, E. R. Dysfunctional endothelial cells directly stimulate cancer inflammation and metastasis. Int. J. Cancer 133, 1334–1344 (2013).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  199. 199

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  200. 200

    Friedl, P. & Wolf, K. Tumour-cell invasion and migration: diversity and escape mechanisms. Nat. Rev. Cancer 3, 362–374 (2003).

    Article  CAS  PubMed  Google Scholar 

  201. 201

    Wong, S. Y. & Hynes, R. O. Lymphatic or hematogenous dissemination: how does a metastatic tumor cell decide? Cell Cycle 5, 812–817 (2006).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  202. 202

    Hall, C. L. et al. Type I collagen receptor (α2β1) signaling promotes prostate cancer invasion through RhoC GTPase. Neoplasia 10, 797–803 (2008).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  203. 203

    Zhou, B. et al. Integrin α3β1 can function to promote spontaneous metastasis and lung colonization of invasive breast carcinoma. Mol. Cancer Res. 12, 143–154 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  204. 204

    Mori, Y. et al. Anti-α4 integrin antibody suppresses the development of multiple myeloma and associated osteoclastic osteolysis. Blood 104, 2149–2154 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  205. 205

    Clezardin, P. Integrins in bone metastasis formation and potential therapeutic implications. Curr. Cancer Drug Targets 9, 801–806 (2009).

    Article  CAS  PubMed  Google Scholar 

  206. 206

    Schneider, J. G., Amend, S. R. & Weilbaecher, K. N. Integrins and bone metastasis: integrating tumor cell and stromal cell interactions. Bone 48, 54–65 (2011).

    Article  CAS  PubMed  Google Scholar 

  207. 207

    Tome, Y. et al. High lung-metastatic variant of human osteosarcoma cells, selected by passage of lung metastasis in nude mice, is associated with increased expression of αvβ3 integrin. Anticancer Res. 33, 3623–3627 (2013).

    CAS  PubMed  Google Scholar 

  208. 208

    Hatano, M. et al. Cadherin-11 regulates the metastasis of Ewing sarcoma cells to bone. Clin. Exp. Metastasis 32, 579–591 (2015).

    Article  CAS  PubMed  Google Scholar 

  209. 209

    Muller, A. et al. Involvement of chemokine receptors in breast cancer metastasis. Nature 410, 50–56 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  210. 210

    Cheng, H. C., Abdel-Ghany, M., Elble, R. C. & Pauli, B. U. Lung endothelial dipeptidyl peptidase IV promotes adhesion and metastasis of rat breast cancer cells via tumor cell surface-associated fibronectin. J. Biol. Chem. 273, 24207–24215 (1998).

    Article  CAS  PubMed  Google Scholar 

  211. 211

    Petretti, T., Kemmner, W., Schulze, B. & Schlag, P. M. Altered mRNA expression of glycosyltransferases in human colorectal carcinomas and liver metastases. Gut 46, 359–366 (2000).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  212. 212

    Yasmin-Karim, S., King, M. R., Messing, E. M. & Lee, Y. F. E-Selectin ligand-1 controls circulating prostate cancer cell rolling/adhesion and metastasis. Oncotarget 5, 12097–12110 (2014).

    PubMed  PubMed Central  Article  Google Scholar 

  213. 213

    Dimitroff, C. J. et al. Identification of leukocyte E-selectin ligands, P-selectin glycoprotein ligand-1 and E-selectin ligand-1, on human metastatic prostate tumor cells. Cancer Res. 65, 5750–5760 (2005).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  214. 214

    Kang, Y. et al. Breast cancer bone metastasis mediated by the Smad tumor suppressor pathway. Proc. Natl Acad. Sci. USA 102, 13909–13914 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  215. 215

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

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  216. 216

    Narita, T. et al. Induction of E-selectin expression on vascular endothelium by digestive system cancer cells. J. Gastroenterol. 31, 299–301 (1996).

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

The authors gratefully acknowledge support from the following funding sources: the US National Cancer Institute (CA169538 to D.L., M.J.B. and H.P. and CA169416 to D.L. and H.P.), the US Department of Defense (W81XWH-13-1-0427 to Y.K., D.L. and J.B., W81XWH-13-1-0249 and W81XWH-14-1-0199 to D.L.), the Hartwell Foundation, the Manning Foundation, the Sohn Foundation, the STARR Consortium, the POETIC Consortium, the Paduano Foundation, Alex's Lemonade Stand Foundation, the Champalimaud Foundation, the 5th District AHEPA Cancer Research Foundation (all to D.L.) and the Daedalus Fund (Weill Cornell Medicine, to D.L and H.Z). H.P. is supported by grants from MINECO (SAF2014-54541-R), ATRES-MEDIA – AXA, Asociación Española Contra el Cáncer, WHRI Academy and Worldwide Cancer Research. A.H. is supported by a Susan Komen Foundation For the Cure Fellowship. J.T.E. is supported by a Novo Nordisk Foundation Hallas Møller stipend. G.R. is supported by a Peter Oppenheimer Fellowship, awarded by the American Portuguese Biomedical Research Fund. C.M.G is supported by a US Department of Defense Breast Cancer Research Program Era of Hope Scholar Award (W81XWH-15-1-0201), the US National Cancer Institute (CA193461-01), the National Breast Cancer Coalition's Artemis Project and the Pink Gene Foundation.

Author information

Affiliations

Authors

Corresponding author

Correspondence to David Lyden.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

PowerPoint slides

Glossary

Disseminated tumour cells

(DTCs). Thought to originate from CTCs that reach distant organs and survive in these new distant microenvironments.

Tumour-secreted factors

Also known as the tumour secretome. The totality of factors released by tumour cells into their immediate environment or into the systemic circulation. They include growth factors, hormones, cytokines, chemokines and extracellular matrix components, as well as extracellular vesicles.

Extracellular vesicles

(EVs). A heterogeneous population of membrane- surrounded structures released by cells into the intercellular space and the circulation. Their sizes range from 30 nm to 5 μm in diameter and they include exosomes (typically 30–150 nm), microvesicles (150–1,000 nm) and apoptotic bodies (1–5 μm).

Vascular leakiness

Loss of vascular integrity resulting in increased permeability of vessels to macromolecules and cells that normally face resistance or do not cross endothelial barriers.

Circulating tumour cells

(CTCs). Rare cells shed by solid tumours into the systemic circulation at an estimated frequency of 1:500,000–1:1,000,000 circulating cells.

Metastatic niche

Microenvironment in distant organs that supports the survival and outgrowth of tumour cells.

Extracellular matrix

(ECM). Comprising molecules, specifically proteoglycans and fibrous proteins (fibronectin, collagen, elastin and laminin) secreted by stromal cells into the microenvironment, that generate an intricate network of macromolecules that fill the intercellular space.

Orthotopic

Derived from the Greek orthos, meaning right and topos, meaning place, this terminology refers to grafting a tumour into the place in the body where it would normally arise and grow.

Transgenic

Relating to or denoting an organism that contains genetic material into which DNA from an unrelated organism has been artificially introduced.

Omental tissues

A double fold of peritoneum attached to the stomach and connecting it with certain organs of the abdominal viscera, composed of the greater and the lesser omentum, which are the membranes of the bowels.

Neutrophils

Also known as polymorphonuclear leukocytes. Mature granular white blood cells with a multilobular nucleus and cytoplasm containing very fine granules. They are typically the first responders to acute inflammation, such as bacterial infection, injury or certain cancers.

Exosomes

Extracellular vesicles (typically 30–150 nm in diameter) of endocytic origin, released into the extracellular space by all cell types through the fusion of multivesicular bodies with the plasma membrane.

Kupffer cells

Specialized liver-resident phagocytic macrophages that line the walls of the liver sinusoid blood vessels.

Stellate cells

Pericytes that reside in the area between liver sinusoid blood vessels and hepatocytes. They play a prominent role in liver fibrosis and may function as liver-resident antigen-presenting cells.

Blood–brain barrier

(BBB). A complex structure formed by the tight interactions between the brain endothelium, surrounded by the basal lamina and stabilized by pericytes, glial cells and neurons.

Micrometastasis

The formation of a microscopic metastasis, usually defined as a cluster of 10–12 cells in mouse models of metastasis.

Cancer stem cells

A subset of cancer cells that share features of normal stem cells, such as self-renewal and differentiation and that can regenerate the tumour.

Fenestrated vasculature

A permeable type of vasculature that contains ultramicroscopic pores of variable sizes, usually found in kidneys and glands as well as in the circumventricular organs of the brain.

Venous thromboembolism

(VTE). Refers to either of two blood clot-related conditions: deep vein thrombosis (DVT) or pulmonary embolism (PE). DVT occurs when a blood clot forms in a deep vein whereas a PE occurs when a blood clot breaks off and circulates to the lung.

Disseminated intravascular coagulation

Systemic activation of blood coagulation, leading to fibrin accumulation, which in turn results in the formation of microvascular thrombi in vital organs.

T helper 1 (TH1) cell

Member of a subset of CD4+ T cells that can activate macrophages and mediate cellular immunity through secretion of interferon-γ (IFNγ), interleukin-2 (IL-2) and tumour necrosis factor-α (TNFα).

Metastasis-initiating cells

Rare tumour cells that have the capacity to survive and proliferate in distant metastatic sites.

Myeloid-derived suppressor cells

(MDSCs). A heterogeneous population of myeloid-derived immunosuppresive and pro-tumorigenic cells that suppress T cell function. They expand in number in pathological conditions and interact with other innate and adaptive immune cells to modulate their function. They universally express CD11b, but can be further categorized in both mice and humans on the basis of expression of additional markers into granulocytic and monocytic lineages.

Macrometastases

The outgrowth of micrometastases that are histologically or radiologically detectable.

Type I interferon

A class II α-helical cytokine essential for protection against viral infections that also plays important roles in bacterial infections, shock, autoimmunity and cancer.

Leukotrienes

Products of the eicosanoid metabolism of leukocytes that mediate inflammation and allergic reactions.

Dormancy

A latent state in which individual tumour cells are quiescent and reversibly arrested in G0 phase of the cell cycle.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Peinado, H., Zhang, H., Matei, I. et al. Pre-metastatic niches: organ-specific homes for metastases. Nat Rev Cancer 17, 302–317 (2017). https://doi.org/10.1038/nrc.2017.6

Download citation

Further reading

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing