Cellular Oncology

, Volume 41, Issue 2, pp 123–140 | Cite as

Organ-specific metastasis of breast cancer: molecular and cellular mechanisms underlying lung metastasis

  • Meysam Yousefi
  • Rahim Nosrati
  • Arash Salmaninejad
  • Sadegh Dehghani
  • Alireza Shahryari
  • Alihossein Saberi



Breast cancer (BC) is the most common type of cancer in women and the second cause of cancer-related mortality world-wide. The majority of BC-related deaths is due to metastasis. Bone, lung, brain and liver are the primary target sites of BC metastasis. The clinical implications and mechanisms underlying bone metastasis have been reviewed before. Given the fact that BC lung metastasis (BCLM) usually produces symptoms only after the lungs have been vastly occupied with metastatic tumor masses, it is of paramount importance for diagnostic and prognostic, as well as therapeutic purposes to comprehend the molecular and cellular mechanisms underlying BCLM. Here, we review current insights into the organ-specificity of BC metastasis, including the role of cancer stem cells in triggering BC spread, the traveling of tumor cells in the blood stream and their migration across endothelial barriers, their adaptation to the lung microenvironment and the initiation of metastatic colonization within the lung.


Detailed understanding of the mechanisms underlying BCLM will shed a new light on the identification of novel molecular targets to impede daunting pulmonary metastases in patients with breast cancer.


Breast cancer Lung metastasis Epithelial-mesenchymal transition Cancer stem cell Pulmonary vasculature Lung micro-environment 



The authors would like to thank the faculty members at Mashhad University of Medical Sciences for their assistance in the preparation of the paper.

Compliance with ethical standards

Conflict of Interest

The authors declare that they have no conflict of interest.


  1. 1.
    SEER Stat Fact Sheets: Female Breast Cancer (2017), Available from: Accessed Nov 2017
  2. 2.
    S.A. Rabbani, A.P. Mazar, Evaluating distant metastases in breast cancer: from biology to outcomes. Cancer Metastasis Rev 26, 663–674 (2007)CrossRefPubMedGoogle Scholar
  3. 3.
    S. Valastyan, R.A. Weinberg, Tumor metastasis: molecular insights and evolving paradigms. Cell 147, 275–292 (2011)CrossRefPubMedCentralPubMedGoogle Scholar
  4. 4.
    R. Sharma, R. Sharma, T.P. Khaket, C. Dutta, B. Chakraborty, T.K. Mukherjee, Breast cancer metastasis: Putative therapeutic role of vascular cell adhesion molecule-1. Cell Oncol 40, 199–208 (2017)Google Scholar
  5. 5.
    Y. Huang, Q. Jin, M. Su, F. Ji, N. Wang, C. Zhong, Y. Jiang, Y. Liu, Z. Zhang, J. Yang, L. Wei, T. Chen, B. Li, Leptin promotes the migration and invasion of breast cancer cells by upregulating ACAT2. Cell Oncol 40, 537–547 (2017)Google Scholar
  6. 6.
    C. C. Society, Prognosis and survival for breast cancer Canada: Canadian Cancer Society (2017), Available from: Accessed 2017 Nov
  7. 7.
    L. Ding, M.J. Ellis, S. Li, D.E. Larson, K. Chen, J.W. Wallis, C.C. Harris, M.D. McLellan, R.S. Fulton, L.L. Fulton, R.M. Abbott, J. Hoog, D.J. Dooling, D.C. Koboldt, H. Schmidt, J. Kalicki, Q. Zhang, L. Chen, L. Lin, M.C. Wendl, J.F. McMichael, V.J. Magrini, L. Cook, S.D. McGrath, T.L. Vickery, E. Appelbaum, K. Deschryver, S. Davies, T. Guintoli, L. Lin, R. Crowder, Y. Tao, J.E. Snider, S.M. Smith, A.F. Dukes, G.E. Sanderson, C.S. Pohl, K.D. Delehaunty, C.C. Fronick, K.A. Pape, J.S. Reed, J.S. Robinson, J.S. Hodges, W. Schierding, N.D. Dees, D. Shen, D.P. Locke, M.E. Wiechert, J.M. Eldred, J.B. Peck, B.J. Oberkfell, J.T. Lolofie, F. Du, A.E. Hawkins, M.D. O'Laughlin, K.E. Bernard, M. Cunningham, G. Elliott, M.D. Mason, D.M. Thompson, J.L.I. Jr, P.J. Goodfellow, C.M. Perou, G.M. Weinstock, R. Aft, M. Watson, T.J. Ley, R.K. Wilson, E.R. Mardis, Genome remodelling in a basal-like breast cancer metastasis and xenograft. Nature 464, 999–1005 (2010)CrossRefPubMedCentralPubMedGoogle Scholar
  8. 8.
    C.D. Savci-Heijink, H. Halfwerk, G.K. Hooijer, H.M. Horlings, J. Wesseling, M.J. van de Vijver, Retrospective analysis of metastatic behaviour of breast cancer subtypes. Breast Cancer Res Treat 150, 547–557 (2015)CrossRefPubMedCentralPubMedGoogle Scholar
  9. 9.
    A.C. Obenauf, J. Massague, Surviving at a distance: organ specific metastasis. Trends Cancer 1, 76–91 (2015)CrossRefPubMedCentralGoogle Scholar
  10. 10.
    D. Hanahan, R.A. Weinberg, Hallmarks of cancer: the next generation. Cell 144, 646–674 (2011)CrossRefPubMedGoogle Scholar
  11. 11.
    R. Paduch, The role of lymphangiogenesis and angiogenesis in tumor metastasis. Cell Oncol 39, 397–410 (2016)CrossRefGoogle Scholar
  12. 12.
    J. Massague, A.C. Obenauf, Metastatic colonization by circulating tumour cells. Nature 529, 298–306 (2016)CrossRefPubMedCentralPubMedGoogle Scholar
  13. 13.
    X. Lu, Y. Kang, Organotropism of breast cancer metastasis. J Mammary Gland Biol Neoplasia 12, 153–162 (2007)CrossRefPubMedGoogle Scholar
  14. 14.
    L.R. Yates, S. Knappskog, D. Wedge, J.H.R. Farmery, S. Gonzalez, I. Martincorena, L.B. Alexandrov, P. Van Loo, H.K. Haugland, P.K. Lilleng, G. Gundem, M. Gerstung, E. Pappaemmanuil, P. Gazinska, S.G. Bhosle, D. Jones, K. Raine, L. Mudie, C. Latimer, E. Sawyer, C. Desmedt, C. Sotiriou, M.R. Stratton, A.M. Sieuwerts, A.G. Lynch, J.W. Martens, A.L. Richardson, A. Tutt, P.E. Lønning, P.J. Campbell, Genomic Evolution of Breast Cancer Metastasis and Relapse. Cancer Cell 32, 169–84.e7 (2017)CrossRefPubMedCentralPubMedGoogle Scholar
  15. 15.
    J. Bergh, P.E. Jonsson, B. Glimelius, P. Nygren, A systematic overview of chemotherapy effects in breast cancer. Acta Oncol 40, 253–281 (2001)CrossRefPubMedGoogle Scholar
  16. 16.
    C. Ludwig, E. Stoelben, J. Hasse, Disease-free survival after resection of lung metastases in patients with breast cancer. Eur J Surg Oncol 29, 532–535 (2003)CrossRefPubMedGoogle Scholar
  17. 17.
    B. Tayyeb, M. Parvin, Pathogenesis of Breast Cancer Metastasis to Brain: a Comprehensive Approach to the Signaling Network. Mol Neurobiol 53, 446–454 (2016)CrossRefPubMedGoogle Scholar
  18. 18.
    I.J. Fidler, The pathogenesis of cancer metastasis: the 'seed and soil' hypothesis revisited. Nat Rev Cancer 3, 453–458 (2003)CrossRefPubMedGoogle Scholar
  19. 19.
    K.R. Hess, G.R. Varadhachary, S.H. Taylor, W. Wei, M.N. Raber, R. Lenzi, J.L. Abbruzzese, Metastatic patterns in adenocarcinoma. Cancer 106, 1624–1633 (2006)CrossRefPubMedGoogle Scholar
  20. 20.
    J. Budczies, M. von Winterfeld, F. Klauschen, M. Bockmayr, J.K. Lennerz, C. Denkert, T. Wolf, A. Warth, M. Dietel, I. Anagnostopoulos, W. Weichert, D. Wittschieber, A. Stenzinger, The landscape of metastatic progression patterns across major human cancers. Oncotarget 6, 570–583 (2015)CrossRefPubMedGoogle Scholar
  21. 21.
    I.T. Gavrilovic, J.B. Posner, Brain metastases: epidemiology and pathophysiology. J Neuro-Oncol 75, 5–14 (2005)CrossRefGoogle Scholar
  22. 22.
    A. Mujoomdar, J.H. Austin, R. Malhotra, C.A. Powell, G.D. Pearson, M.C. Shiau, H. Raftopoulos, Clinical predictors of metastatic disease to the brain from non-small cell lung carcinoma: primary tumor size, cell type, and lymph node metastases. Radiology 242, 882–888 (2007)CrossRefPubMedGoogle Scholar
  23. 23.
    M. Yousefi, T. Bahrami, A. Salmaninejad, R. Nosrati, P. Ghaffari, S.H. Ghaffari, Lung cancer-associated brain metastasis: Molecular mechanisms and therapeutic options. Cell Oncol 40, 419–441 (2017)Google Scholar
  24. 24.
    S. Paget, The distribution of secondary growths in cancer of the breast. Cancer Metastasis Rev 8, 98–101 (1989)PubMedGoogle Scholar
  25. 25.
    G. Lorusso, C. Ruegg, New insights into the mechanisms of organ-specific breast cancer metastasis. Semin Cancer Biol 22, 226–233 (2012)CrossRefPubMedGoogle Scholar
  26. 26.
    L. Schito, G.L. Semenza, Hypoxia-Inducible Factors: Master Regulators of Cancer Progression. Trends Cancer 2, 758–770 (2016)CrossRefPubMedGoogle Scholar
  27. 27.
    M. Smid, Y. Wang, Y. Zhang, A.M. Sieuwerts, J. Yu, J.G. Klijn, J.A. Foekens, J.W. Martens, Subtypes of breast cancer show preferential site of relapse. Cancer Res 68, 3108–3114 (2008)CrossRefPubMedGoogle Scholar
  28. 28.
    H. Kennecke, R. Yerushalmi, R. Woods, M.C. Cheang, D. Voduc, C.H. Speers, T.O. Nielsen, K. Gelmon, Metastatic behavior of breast cancer subtypes. J Clin Oncol 28, 3271–3277 (2010)CrossRefPubMedGoogle Scholar
  29. 29.
    D.X. Nguyen, J. Massagué, Genetic determinants of cancer metastasis. Nat Rev Genet 8, 341–352 (2007)CrossRefPubMedGoogle Scholar
  30. 30.
    K. Jin, T. Li, H. van Dam, F. Zhou, L. Zhang, Molecular insights into tumour metastasis: tracing the dominant events. J Pathol 241(5), 567–577 (2017).
  31. 31.
    E.P. Cuevas, P. Eraso, M.J. Mazón, V. Santos, G. Moreno-Bueno, A. Cano, F. Portillo, LOXL2 drives epithelial-mesenchymal transition via activation of IRE1-XBP1 signalling pathway. Sci Rep 7, 44988 (2017)CrossRefPubMedCentralPubMedGoogle Scholar
  32. 32.
    M. Stankic, S. Pavlovic, Y. Chin, E. Brogi, D. Padua, L. Norton, J. Massague, R. Benezra, TGF-beta-Id1 signaling opposes Twist1 and promotes metastatic colonization via a mesenchymal-to-epithelial transition. Cell Rep 5, 1228–1242 (2013)CrossRefPubMedCentralPubMedGoogle Scholar
  33. 33.
    H. Li, X. Chen, Y. Gao, J. Wu, F. Zeng, F. Song, XBP1 induces snail expression to promote epithelial- to-mesenchymal transition and invasion of breast cancer cells. Cell Signal 27, 82–89 (2015)CrossRefPubMedGoogle Scholar
  34. 34.
    D. Liu, P.S. Rudland, D.R. Sibson, A. Platt-Higgins, R. Barraclough, Human homologue of cement gland protein, a novel metastasis inducer associated with breast carcinomas. Cancer Res 65, 3796–3805 (2005)CrossRefPubMedGoogle Scholar
  35. 35.
    A.J. Minn, G.P. Gupta, P.M. Siegel, P.D. Bos, W. Shu, D.D. Giri, A. Viale, A.B. Olshen, W.L. Gerald, J. Massague, Genes that mediate breast cancer metastasis to lung. Nature 436, 518–524 (2005)CrossRefPubMedCentralPubMedGoogle Scholar
  36. 36.
    R.L. Huang, Z. Teo, H.C. Chong, P. Zhu, M.J. Tan, C.K. Tan, C.R. Lam, M.K. Sng, D.T. Leong, S.M. Tan, S. Kersten, J.L. Ding, H.Y. Li, N.S. Tan, ANGPTL4 modulates vascular junction integrity by integrin signaling and disruption of intercellular VE-cadherin and claudin-5 clusters. Blood 118, 3990–4002 (2011)CrossRefPubMedGoogle Scholar
  37. 37.
    Y. Huang, N. Song, Y. Ding, S. Yuan, X. Li, H. Cai, H. Shi, Y. Luo, Pulmonary vascular destabilization in the premetastatic phase facilitates lung metastasis. Cancer Res 69, 7529–7537 (2009)CrossRefPubMedGoogle Scholar
  38. 38.
    S. Hiratsuka, S. Ishibashi, T. Tomita, A. Watanabe, S. Akashi-Takamura, M. Murakami, H. Kijima, K. Miyake, H. Aburatani, Y. Maru, Primary tumours modulate innate immune signalling to create pre-metastatic vascular hyperpermeability foci. Nat Commun 4, 1853 (2013)CrossRefPubMedCentralPubMedGoogle Scholar
  39. 39.
    M.-A.D. Cao, Z. Zhang, A. Gilchrist, CCR1 as a Target for Metastatic Breast Cancer. FASEB J 31, 823.11-.11 (2017)Google Scholar
  40. 40.
    D. Padua, X.H. Zhang, Q. Wang, C. Nadal, W.L. Gerald, R.R. Gomis, J. Massague, TGFbeta primes breast tumors for lung metastasis seeding through angiopoietin-like 4. Cell 133, 66–77 (2008)CrossRefPubMedCentralPubMedGoogle Scholar
  41. 41.
    D.M. Brown, E. Ruoslahti, Metadherin, a cell surface protein in breast tumors that mediates lung metastasis. Cancer Cell 5, 365–374 (2004)CrossRefPubMedGoogle Scholar
  42. 42.
    M.Z. Dewan, S. Ahmed, Y. Iwasaki, K. Ohba, M. Toi, N. Yamamoto, Stromal cell-derived factor-1 and CXCR4 receptor interaction in tumor growth and metastasis of breast cancer. Biomed Pharmacother 60, 273–276 (2006)CrossRefPubMedGoogle Scholar
  43. 43.
    B. Furusato, A. Mohamed, M. Uhlen, J.S. Rhim, CXCR4 and cancer. Pathol Int 60, 497–505 (2010)CrossRefPubMedGoogle Scholar
  44. 44.
    Z. Yu, N.E. Willmarth, J. Zhou, S. Katiyar, M. Wang, Y. Liu, P.A. McCue, A.A. Quong, M.P. Lisanti, R.G. Pestell, microRNA 17/20 inhibits cellular invasion and tumor metastasis in breast cancer by heterotypic signaling. Proc Natl Acad Sci USA 107, 8231–8236 (2010)Google Scholar
  45. 45.
    S.S. McAllister, A.M. Gifford, A.L. Greiner, S.P. Kelleher, M.P. Saelzler, T.A. Ince, F. Reinhardt, L.N. Harris, B.L. Hylander, E.A. Repasky, R.A. Weinberg, Systemic endocrine instigation of indolent tumor growth requires osteopontin. Cell 133, 994–1005 (2008)CrossRefPubMedCentralPubMedGoogle Scholar
  46. 46.
    K. Gumireddy, A. Li, P.A. Gimotty, A.J. Klein-Szanto, L.C. Showe, D. Katsaros, G. Coukos, L. Zhang, Q. Huang, KLF17 is a negative regulator of epithelial–mesenchymal transition and metastasis in breast cancer. Nat Cell Biol 11, 1297–1304 (2009)CrossRefPubMedCentralPubMedGoogle Scholar
  47. 47.
    P. Papageorgis, S. Ozturk, A.W. Lambert, C.M. Neophytou, A. Tzatsos, C.K. Wong, S. Thiagalingam, A.I. Constantinou, Targeting IL13Ralpha2 activates STAT6-TP63 pathway to suppress breast cancer lung metastasis. Breast Cancer Res 17, 98 (2015)CrossRefPubMedCentralPubMedGoogle Scholar
  48. 48.
    N. Todorović-Raković, J. Milovanović, Interleukin-8 in breast cancer progression. J Interf Cytokine Res 33, 563–570 (2013)CrossRefGoogle Scholar
  49. 49.
    C. Qian, A. Worrede-Mahdi, R. Kaur, F. Shen, J. Salvino, O. Meucci, A. Fatatis, Targeting CX3CR1 impairs the reseeding of cancer cells recirculating from metastatic tumors. Abstract In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5799.
  50. 50.
    J. Lee, G. Kim, M. Park, J. Yoon, Up-regulation of SPARC is associated with breast tumor progression and epithelial SPARC expression is correlated with poor survival and MMP-2 expression in patients with breast carcinoma. Abstract In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P4–12–11Google Scholar
  51. 51.
    J. Ma, S. Gao, X. Xie, E. Sun, M. Zhang, Q. Zhou, C. Lu, SPARC inhibits breast cancer bone metastasis and may be a clinical therapeutic target. Oncol Lett 14, 5876–5882 (2017)PubMedCentralPubMedGoogle Scholar
  52. 52.
    C.C.-L. Wong, D.M. Gilkes, H. Zhang, J. Chen, H. Wei, P. Chaturvedi, S.I. Fraley, C.-M. Wong, U.-S. Khoo, I.O.-L. Ng, D. Wirtz, G.L. Semenza, Hypoxia-inducible factor 1 is a master regulator of breast cancer metastatic niche formation. Proc Natl Acad Sci USA 108, 16369–16374 (2011)Google Scholar
  53. 53.
    Q. Chen, X.H. Zhang, J. Massague, Macrophage binding to receptor VCAM-1 transmits survival signals in breast cancer cells that invade the lungs. Cancer Cell 20, 538–549 (2011)CrossRefPubMedCentralPubMedGoogle Scholar
  54. 54.
    T.F. Borin, K. Angara, M. Rashid, A. Shankar, A. Iskander, R. Ara, M. Jain, B.R. Achyut, A.S. Arbab, CSF-1R inhibitor prevented pre-metastatic lung niches in metastatic mammary tumor. Abstract In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1043.
  55. 55.
    K.E. Luker, G.D. Luker, Functions of CXCL12 and CXCR4 in breast cancer. Cancer Lett 238, 30–41 (2006)CrossRefPubMedGoogle Scholar
  56. 56.
    N. Nagarsheth, M.S. Wicha, W. Zou, Chemokines in the cancer microenvironment and their relevance in cancer immunotherapy. Nat Rev Immunol 17, 559–572 (2017)Google Scholar
  57. 57.
    J.T. Erler, K.L. Bennewith, T.R. Cox, G. Lang, D. Bird, A. Koong, Q.T. Le, A.J. Giaccia, Hypoxia-induced lysyl oxidase is a critical mediator of bone marrow cell recruitment to form the premetastatic niche. Cancer Cell 15, 35–44 (2009)CrossRefPubMedCentralPubMedGoogle Scholar
  58. 58.
    T. Oskarsson, S. Acharyya, X.H. Zhang, S. Vanharanta, S.F. Tavazoie, P.G. Morris, R.J. Downey, K. Manova-Todorova, E. Brogi, J. Massague, Breast cancer cells produce tenascin C as a metastatic niche component to colonize the lungs. Nat Med 17, 867–874 (2011)CrossRefPubMedCentralPubMedGoogle Scholar
  59. 59.
    R.N. Kaplan, B. Psaila, D. Lyden, Bone marrow cells in the 'pre-metastatic niche': within bone and beyond. Cancer Metastasis Rev 25, 521–529 (2006)CrossRefPubMedGoogle Scholar
  60. 60.
    R.N. Kaplan, R.D. Riba, S. Zacharoulis, A.H. Bramley, L. Vincent, C. Costa, D.D. MacDonald, D.K. Jin, K. Shido, S.A. Kerns, Z. Zhu, D. Hicklin, Y. Wu, J.L. Port, N. Altorki, E.R. Port, D. Ruggero, S.V. Shmelkov, K.K. Jensen, S. Rafii, D. Lyden, VEGFR1-positive haematopoietic bone marrow progenitors initiate the pre-metastatic niche. Nature 438, 820–827 (2005)CrossRefPubMedCentralPubMedGoogle Scholar
  61. 61.
    D.X. Nguyen, P.D. Bos, J. Massagué, Metastasis: from dissemination to organ-specific colonization. Nat Rev Cancer 9, 274–284 (2009)CrossRefPubMedGoogle Scholar
  62. 62.
    J.R. Nevins, A. Potti, Mining gene expression profiles: expression signatures as cancer phenotypes. Nat Rev Genet 8, 601–609 (2007)Google Scholar
  63. 63.
    J.K. Mouw, Y. Yui, L. Damiano, R.O. Bainer, J.N. Lakins, I. Acerbi, G. Ou, A.C. Wijekoon, K.R. Levental, P.M. Gilbert, E.S. Hwang, Y.-Y. Chen, V.M. Weaver, Tissue mechanics modulate microRNA-dependent PTEN expression to regulate malignant progression. Nat Med 20, 360 (2014)CrossRefPubMedCentralPubMedGoogle Scholar
  64. 64.
    J.P. Thiery, H. Acloque, R.Y. Huang, M.A. Nieto, Epithelial-mesenchymal transitions in development and disease. Cell 139, 871–890 (2009)CrossRefPubMedGoogle Scholar
  65. 65.
    S. Heerboth, G. Housman, M. Leary, M. Longacre, S. Byler, K. Lapinska, A. Willbanks, S. Sarkar, EMT and tumor metastasis. Clin Transl Med 4, 6 (2015)CrossRefPubMedCentralPubMedGoogle Scholar
  66. 66.
    M.A. Nieto, R.Y. Huang, R.A. Jackson, J.P. Thiery, EMT: 2016. Cell 166, 21–45 (2016)CrossRefPubMedGoogle Scholar
  67. 67.
    S.Y. Shin, O. Rath, A. Zebisch, S.M. Choo, W. Kolch, K.H. Cho, Functional roles of multiple feedback loops in extracellular signal-regulated kinase and Wnt signaling pathways that regulate epithelial-mesenchymal transition. Cancer Res 70, 6715–6724 (2010)CrossRefPubMedCentralPubMedGoogle Scholar
  68. 68.
    A. Eger, A. Stockinger, J. Park, E. Langkopf, M. Mikula, J. Gotzmann, W. Mikulits, H. Beug, R. Foisner, Beta-Catenin and TGFbeta signalling cooperate to maintain a mesenchymal phenotype after FosER-induced epithelial to mesenchymal transition. Oncogene 23, 2672–2680 (2004)CrossRefPubMedGoogle Scholar
  69. 69.
    L.A. Timmerman, J. Grego-Bessa, A. Raya, E. Bertran, J.M. Perez-Pomares, J. Diez, S. Aranda, S. Palomo, F. McCormick, J.C. Izpisua-Belmonte, J.L. de la Pompa, Notch promotes epithelial-mesenchymal transition during cardiac development and oncogenic transformation. Genes Dev 18, 99–115 (2004)CrossRefPubMedCentralPubMedGoogle Scholar
  70. 70.
    D. Xiao, J. He, Epithelial mesenchymal transition and lung cancer. J Thorac Dis 2, 154–159 (2010)PubMedCentralPubMedGoogle Scholar
  71. 71.
    T.A. DiMeo, K. Anderson, P. Phadke, C. Fan, C.M. Perou, S. Naber, C. Kuperwasser, A novel lung metastasis signature links Wnt signaling with cancer cell self-renewal and epithelial-mesenchymal transition in basal-like breast cancer. Cancer Res 69, 5364–5373 (2009)CrossRefPubMedCentralPubMedGoogle Scholar
  72. 72.
    J. Fuxe, T. Vincent, A. Garcia de Herreros, Transcriptional crosstalk between TGF-beta and stem cell pathways in tumor cell invasion: role of EMT promoting Smad complexes. Cell Cycle 9, 2363–2374 (2010)CrossRefPubMedGoogle Scholar
  73. 73.
    D.S. Micalizzi, C.-A. Wang, S.M. Farabaugh, W.P. Schiemann, H.L. Ford, Homeoprotein Six1 increases TGF-β type I receptor and converts TGF-β signaling from suppressive to supportive for tumor growth. Cancer Res 70, 10371–10380 (2010)CrossRefPubMedCentralPubMedGoogle Scholar
  74. 74.
    F. Zhou, Y. Drabsch, T.J. Dekker, A.G. De Vinuesa, Y. Li, L.J. Hawinkels, K.-A. Sheppard, M.-J. Goumans, R.B. Luwor, C.J. De Vries, Nuclear receptor NR4A1 promotes breast cancer invasion and metastasis by activating TGF-β signalling. Nat Commun 5, 3388 (2014)PubMedGoogle Scholar
  75. 75.
    B. De Craene, G. Berx, Regulatory networks defining EMT during cancer initiation and progression. Nat Rev Cancer 13, 97–110 (2013)CrossRefPubMedGoogle Scholar
  76. 76.
    G. Berx, F. van Roy, Involvement of members of the cadherin superfamily in cancer. Cold Spring Harb Perspect Biol 1, a003129 (2009)CrossRefPubMedCentralPubMedGoogle Scholar
  77. 77.
    K. Polyak, R.A. Weinberg, Transitions between epithelial and mesenchymal states: acquisition of malignant and stem cell traits. Nat Rev Cancer 9, 265–273 (2009)CrossRefPubMedGoogle Scholar
  78. 78.
    C. Gilles, M. Polette, M. Mestdagt, B. Nawrocki-Raby, P. Ruggeri, P. Birembaut, J.M. Foidart, Transactivation of vimentin by beta-catenin in human breast cancer cells. Cancer Res 63, 2658–2664 (2003)PubMedGoogle Scholar
  79. 79.
    J. Cai, H. Guan, L. Fang, Y. Yang, X. Zhu, J. Yuan, J. Wu, M. Li, MicroRNA-374a activates Wnt/beta-catenin signaling to promote breast cancer metastasis. J Clin Invest 123, 566–579 (2013)CrossRefPubMedCentralPubMedGoogle Scholar
  80. 80.
    Y. Liang, J. Hu, J. Li, Y. Liu, J. Yu, X. Zhuang, L. Mu, X. Kong, D. Hong, Q. Yang, Epigenetic Activation of TWIST1 by MTDH Promotes Cancer Stem–like Cell Traits in Breast Cancer. Cancer Res 75, 3672–3680 (2015)CrossRefPubMedGoogle Scholar
  81. 81.
    D.A. Zajchowski, M.F. Bartholdi, Y. Gong, L. Webster, H.L. Liu, A. Munishkin, C. Beauheim, S. Harvey, S.P. Ethier, P.H. Johnson, Identification of gene expression profiles that predict the aggressive behavior of breast cancer cells. Cancer Res 61, 5168–5178 (2001)PubMedGoogle Scholar
  82. 82.
    S. Stinson, M.R. Lackner, A.T. Adai, N. Yu, H.J. Kim, C. O'Brien, J. Spoerke, S. Jhunjhunwala, Z. Boyd, T. Januario, R.J. Newman, P. Yue, R. Bourgon, Z. Modrusan, H.M. Stern, S. Warming, F.J. de Sauvage, L. Amler, R.F. Yeh, D. Dornan, TRPS1 targeting by miR-221/222 promotes the epithelial-to-mesenchymal transition in breast cancer. Sci Signal 4, ra41 (2011)CrossRefPubMedGoogle Scholar
  83. 83.
    H. Chen, G. Zhu, Y. Li, R.N. Padia, Z. Dong, Z.K. Pan, K. Liu, S. Huang, Extracellular signal-regulated kinase signaling pathway regulates breast cancer cell migration by maintaining slug expression. Cancer Res 69, 9228–9235 (2009)CrossRefPubMedCentralPubMedGoogle Scholar
  84. 84.
    C.J. Desmet, T. Gallenne, A. Prieur, F. Reyal, N.L. Visser, B.S. Wittner, M.A. Smit, T.R. Geiger, J. Laoukili, S. Iskit, B. Rodenko, W. Zwart, B. Evers, H. Horlings, A. Ajouaou, J. Zevenhoven, M. van Vliet, S. Ramaswamy, L.F. Wessels, D.S. Peeper, Identification of a pharmacologically tractable Fra-1/ADORA2B axis promoting breast cancer metastasis. Proc Natl Acad Sci USA 110, 5139–5144 (2013)Google Scholar
  85. 85.
    Y. Wu, M. Sarkissyan, J.V. Vadgama, Epithelial-mesenchymal transition and breast cancer. J Clin Med 5, 13 (2016)CrossRefPubMedCentralGoogle Scholar
  86. 86.
    L. Ma, J. Young, H. Prabhala, E. Pan, P. Mestdagh, D. Muth, J. Teruya-Feldstein, F. Reinhardt, T.T. Onder, S. Valastyan, miR-9, a MYC/MYCN-activated microRNA, regulates E-cadherin and cancer metastasis. Nat Cell Biol 12, 247–256 (2010)PubMedCentralPubMedGoogle Scholar
  87. 87.
    K. Yin, W. Yin, Y. Wang, L. Zhou, Y. Liu, G. Yang, J. Wang, J. Lu, MiR-206 suppresses epithelial mesenchymal transition by targeting TGF-β signaling in estrogen receptor positive breast cancer cells. Oncotarget 7, 24537 (2016)PubMedCentralPubMedGoogle Scholar
  88. 88.
    J. Johansson, T. Berg, E. Kurzejamska, M.-F. Pang, V. Tabor, M. Jansson, P. Roswall, K. Pietras, M. Sund, P. Religa, MiR-155-mediated loss of C/EBPβ shifts the TGF-β response from growth inhibition to epithelial-mesenchymal transition, invasion and metastasis in breast cancer. Oncogene 32, 5614–5624 (2013)CrossRefPubMedCentralPubMedGoogle Scholar
  89. 89.
    B. Wang, H. Wang, Z. Yang, MiR-122 inhibits cell proliferation and tumorigenesis of breast cancer by targeting IGF1R. PLoS One 7, e47053 (2012)CrossRefPubMedCentralPubMedGoogle Scholar
  90. 90.
    P. Liu, H. Tang, B. Chen, Z. He, M. Deng, M. Wu, X. Liu, L. Yang, F. Ye, X. Xie, miR-26a suppresses tumour proliferation and metastasis by targeting metadherin in triple negative breast cancer. Cancer Lett 357, 384–392 (2015)CrossRefPubMedGoogle Scholar
  91. 91.
    J. Yu, J.-G. Wang, L. Zhang, H.-P. Yang, L. Wang, D. Ding, Q. Chen, W.-L. Yang, K.-H. Ren, D.-M. Zhou, Q. Zou, Y.-T. Jin, X.-P. Liu, MicroRNA-320a inhibits breast cancer metastasis by targeting metadherin. Oncotarget 7, 38612–38625 (2016)PubMedCentralPubMedGoogle Scholar
  92. 92.
    M. Korpal, Y. Kang, The emerging role of miR-200 family of microRNAs in epithelial-mesenchymal transition and cancer metastasis. RNA Biol 5, 115–119 (2008)CrossRefPubMedCentralPubMedGoogle Scholar
  93. 93.
    S.J. Song, L. Poliseno, M.S. Song, U. Ala, K. Webster, C. Ng, G. Beringer, N.J. Brikbak, X. Yuan, L.C. Cantley, A.L. Richardson, P.P. Pandolfi, MicroRNA-antagonism regulates breast cancer stemness and metastasis via TET-family-dependent chromatin remodeling. Cell 154, 311–324 (2013)CrossRefPubMedCentralPubMedGoogle Scholar
  94. 94.
    M. Korpal, B.J. Ell, F.M. Buffa, T. Ibrahim, M.A. Blanco, T. Celia-Terrassa, L. Mercatali, Z. Khan, H. Goodarzi, Y. Hua, Y. Wei, G. Hu, B.A. Garcia, J. Ragoussis, D. Amadori, A.L. Harris, Y. Kang, Direct targeting of Sec23a by miR-200s influences cancer cell secretome and promotes metastatic colonization. Nat Med 17, 1101–1108 (2011)CrossRefPubMedCentralPubMedGoogle Scholar
  95. 95.
    Z. Liang, X. Bian, H. Shim, Inhibition of breast cancer metastasis with microRNA-302a by downregulation of CXCR4 expression. Breast Cancer Res Treat 146, 535–542 (2014)CrossRefPubMedCentralPubMedGoogle Scholar
  96. 96.
    M.Y. Fong, W. Zhou, L. Liu, A.Y. Alontaga, M. Chandra, J. Ashby, A. Chow, S.T.F. O’Connor, S. Li, A.R. Chin, Breast-cancer-secreted miR-122 reprograms glucose metabolism in premetastatic niche to promote metastasis. Nat Cell Biol 17, 183–194 (2015)CrossRefPubMedCentralPubMedGoogle Scholar
  97. 97.
    M.K. Jolly, M. Boareto, B. Huang, D. Jia, M. Lu, E. Ben-Jacob, J.N. Onuchic, H. Levine, Implications of the Hybrid Epithelial/Mesenchymal Phenotype in Metastasis. Front Oncol 5, 155 (2015)CrossRefPubMedCentralPubMedGoogle Scholar
  98. 98.
    S.A. Mani, W. Guo, M.J. Liao, E.N. Eaton, A. Ayyanan, A.Y. Zhou, M. Brooks, F. Reinhard, C.C. Zhang, M. Shipitsin, L.L. Campbell, K. Polyak, C. Brisken, J. Yang, R.A. Weinberg, The epithelial-mesenchymal transition generates cells with properties of stem cells. Cell 133, 704–715 (2008)CrossRefPubMedCentralPubMedGoogle Scholar
  99. 99.
    M.S. Wicha, S. Liu, G. Dontu, Cancer stem cells: an old idea--a paradigm shift. Cancer Res 66, 1883–1890; discussion 95-6 (2006)CrossRefPubMedGoogle Scholar
  100. 100.
    M. Al-Hajj, M.S. Wicha, A. Benito-Hernandez, S.J. Morrison, M.F. Clarke, Prospective identification of tumorigenic breast cancer cells. Proc Natl Acad Sci USA 100, 3983–3988 (2003)Google Scholar
  101. 101.
    C. Ginestier, M.H. Hur, E. Charafe-Jauffret, F. Monville, J. Dutcher, M. Brown, J. Jacquemier, P. Viens, C.G. Kleer, S. Liu, A. Schott, D. Hayes, D. Birnbaum, M.S. Wicha, G. Dontu, ALDH1 is a marker of normal and malignant human mammary stem cells and a predictor of poor clinical outcome. Cell Stem Cell 1, 555–567 (2007)CrossRefPubMedCentralPubMedGoogle Scholar
  102. 102.
    A.K. Croker, D. Goodale, J. Chu, C. Postenka, B.D. Hedley, D.A. Hess, A.L. Allan, High aldehyde dehydrogenase and expression of cancer stem cell markers selects for breast cancer cells with enhanced malignant and metastatic ability. J Cell Mol Med 13, 2236–2252 (2009)CrossRefPubMedGoogle Scholar
  103. 103.
    C. Sheridan, H. Kishimoto, R.K. Fuchs, S. Mehrotra, P. Bhat-Nakshatri, C.H. Turner, R. Goulet Jr., S. Badve, H. Nakshatri, CD44+/CD24- breast cancer cells exhibit enhanced invasive properties: an early step necessary for metastasis. Breast Cancer Res 8, R59 (2006)CrossRefPubMedCentralPubMedGoogle Scholar
  104. 104.
    E. Charafe-Jauffret, C. Ginestier, F. Iovino, J. Wicinski, N. Cervera, P. Finetti, M.H. Hur, M.E. Diebel, F. Monville, J. Dutcher, M. Brown, P. Viens, L. Xerri, F. Bertucci, G. Stassi, G. Dontu, D. Birnbaum, M.S. Wicha, Breast cancer cell lines contain functional cancer stem cells with metastatic capacity and a distinct molecular signature. Cancer Res 69, 1302–1313 (2009)CrossRefPubMedCentralPubMedGoogle Scholar
  105. 105.
    L.L. Campbell, K. Polyak, Breast tumor heterogeneity: cancer stem cells or clonal evolution? Cell Cycle 6, 2332–2338 (2007)CrossRefPubMedGoogle Scholar
  106. 106.
    S. Liu, M.S. Wicha, Targeting breast cancer stem cells. J Clin Oncol 28, 4006–4012 (2010)CrossRefPubMedCentralPubMedGoogle Scholar
  107. 107.
    M.A. Velasco-Velazquez, N. Homsi, M. De La Fuente, R.G. Pestell, Breast cancer stem cells. Int J Biochem Cell Biol 44, 573–577 (2012)CrossRefPubMedCentralPubMedGoogle Scholar
  108. 108.
    F. Ishikawa, S. Yoshida, Y. Saito, A. Hijikata, H. Kitamura, S. Tanaka, R. Nakamura, T. Tanaka, H. Tomiyama, N. Saito, M. Fukata, T. Miyamoto, B. Lyons, K. Ohshima, N. Uchida, S. Taniguchi, O. Ohara, K. Akashi, M. Harada, L.D. Shultz, Chemotherapy-resistant human AML stem cells home to and engraft within the bone-marrow endosteal region. Nat Biotechnol 25, 1315–1321 (2007)CrossRefPubMedGoogle Scholar
  109. 109.
    K. Engelmann, H. Shen, O.J. Finn, MCF7 side population cells with characteristics of cancer stem/progenitor cells express the tumor antigen MUC1. Cancer Res 68, 2419–2426 (2008)CrossRefPubMedGoogle Scholar
  110. 110.
    C.W. Lee, K. Simin, Q. Liu, J. Plescia, M. Guha, A. Khan, C.C. Hsieh, D.C. Altieri, A functional Notch-survivin gene signature in basal breast cancer. Breast Cancer Res 10, R97 (2008)CrossRefPubMedCentralPubMedGoogle Scholar
  111. 111.
    Z. Madjd, A.Z. Mehrjerdi, A.M. Sharifi, S. Molanaei, S.Z. Shahzadi, M. Asadi-Lari, CD44+ cancer cells express higher levels of the anti-apoptotic protein Bcl-2 in breast tumours. Cancer Immun 9, 4 (2009)PubMedCentralPubMedGoogle Scholar
  112. 112.
    J.E. Draffin, S. McFarlane, A. Hill, P.G. Johnston, D.J. Waugh, CD44 potentiates the adherence of metastatic prostate and breast cancer cells to bone marrow endothelial cells. Cancer Res 64, 5702–5711 (2004)CrossRefPubMedGoogle Scholar
  113. 113.
    G.P. Gupta, J. Perk, S. Acharyya, P. de Candia, V. Mittal, K. Todorova-Manova, W.L. Gerald, E. Brogi, R. Benezra, J. Massague, ID genes mediate tumor reinitiation during breast cancer lung metastasis. Proc Natl Acad Sci USA 104, 19506–19511 (2007)Google Scholar
  114. 114.
    L.S. Orlichenko, D.C. Radisky, Matrix metalloproteinases stimulate epithelial-mesenchymal transition during tumor development. Clin Exp Metastasis 25, 593–600 (2008)CrossRefPubMedGoogle Scholar
  115. 115.
    J.P. Thiery, J.P. Sleeman, Complex networks orchestrate epithelial-mesenchymal transitions. Nat Rev Mol Cell Biol 7, 131–142 (2006)CrossRefPubMedGoogle Scholar
  116. 116.
    B. De Craene, B. Gilbert, C. Stove, E. Bruyneel, F. van Roy, G. Berx, The transcription factor snail induces tumor cell invasion through modulation of the epithelial cell differentiation program. Cancer Res 65, 6237–6244 (2005)CrossRefPubMedGoogle Scholar
  117. 117.
    P.B. Gupta, C.M. Fillmore, G. Jiang, S.D. Shapira, K. Tao, C. Kuperwasser, E.S. Lander, Stochastic state transitions give rise to phenotypic equilibrium in populations of cancer cells. Cell 146, 633–644 (2011)CrossRefPubMedGoogle Scholar
  118. 118.
    K.R. Fischer, A. Durrans, S. Lee, J. Sheng, F. Li, S.T. Wong, H. Choi, T. El Rayes, S. Ryu, J. Troeger, R.F. Schwabe, L.T. Vahdat, N.K. Altorki, V. Mittal, D. Gao, Epithelial-to-mesenchymal transition is not required for lung metastasis but contributes to chemoresistance. Nature 527, 472–476 (2015)CrossRefPubMedCentralPubMedGoogle Scholar
  119. 119.
    X. Zheng, J.L. Carstens, J. Kim, M. Scheible, J. Kaye, H. Sugimoto, C.C. Wu, V.S. LeBleu, R. Kalluri, Epithelial-to-mesenchymal transition is dispensable for metastasis but induces chemoresistance in pancreatic cancer. Nature 527, 525–530 (2015)CrossRefPubMedCentralPubMedGoogle Scholar
  120. 120.
    P. Yu, Y. Huang, C. Xu, L. Lin, Y. Han, W. Sun, G. Hu, A. Rabson, Y. Wang, Y. Shi, Downregulation of CXCL12 in mesenchymal stromal cells by TGFβ promotes breast cancer metastasis. Oncogene 36, 840–849 (2017)Google Scholar
  121. 121.
    G.L. Semenza, Molecular mechanisms mediating metastasis of hypoxic breast cancer cells. Trends Mol Med 18, 534–543 (2012)CrossRefPubMedCentralPubMedGoogle Scholar
  122. 122.
    R. Sullivan, C.H. Graham, Hypoxia-driven selection of the metastatic phenotype. Cancer Metastasis Rev 26, 319–331 (2007)CrossRefPubMedGoogle Scholar
  123. 123.
    H. Zhang, C.C. Wong, H. Wei, D.M. Gilkes, P. Korangath, P. Chaturvedi, L. Schito, J. Chen, B. Krishnamachary, P.T. Winnard Jr., V. Raman, L. Zhen, W.A. Mitzner, S. Sukumar, G.L. Semenza, HIF-1-dependent expression of angiopoietin-like 4 and L1CAM mediates vascular metastasis of hypoxic breast cancer cells to the lungs. Oncogene 31, 1757–1770 (2012)CrossRefPubMedGoogle Scholar
  124. 124.
    R. Krutilina, W. Sun, A. Sethuraman, M. Brown, T.N. Seagroves, L.M. Pfeffer, T. Ignatova, M. Fan, MicroRNA-18a inhibits hypoxia-inducible factor 1alpha activity and lung metastasis in basal breast cancers. Breast Cancer Res 16, R78 (2014)CrossRefPubMedCentralPubMedGoogle Scholar
  125. 125.
    S. Maheswaran, D.A. Haber, Circulating tumor cells: a window into cancer biology and metastasis. Curr Opin Genet Dev 20, 96–99 (2010)CrossRefPubMedCentralPubMedGoogle Scholar
  126. 126.
    M. Yu, A. Bardia, B.S. Wittner, S.L. Stott, M.E. Smas, D.T. Ting, S.J. Isakoff, J.C. Ciciliano, M.N. Wells, A.M. Shah, Circulating breast tumor cells exhibit dynamic changes in epithelial and mesenchymal composition. Science 339, 580–584 (2013)CrossRefPubMedCentralPubMedGoogle Scholar
  127. 127.
    N. Aceto, A. Bardia, D.T. Miyamoto, M.C. Donaldson, B.S. Wittner, J.A. Spencer, M. Yu, A. Pely, A. Engstrom, H. Zhu, Circulating tumor cell clusters are oligoclonal precursors of breast cancer metastasis. Cell 158, 1110–1122 (2014)CrossRefPubMedCentralPubMedGoogle Scholar
  128. 128.
    W. Goto, S. Kashiwagi, Y. Asano, K. Takada, K. Takahashi, T. Hatano, T. Takashima, S. Tomita, H. Motomura, M. Ohsawa, Circulating tumor cell clusters-associated gene plakoglobin is a significant prognostic predictor in patients with breast cancer. Biomarker Res 5, 19 (2017)CrossRefGoogle Scholar
  129. 129.
    I. Baccelli, A. Schneeweiss, S. Riethdorf, A. Stenzinger, A. Schillert, V. Vogel, C. Klein, M. Saini, T. Bäuerle, M. Wallwiener, Identification of a population of blood circulating tumor cells from breast cancer patients that initiates metastasis in a xenograft assay. Nat Biotechnol 31, 539–544 (2013)CrossRefPubMedGoogle Scholar
  130. 130.
    A.M. Dehnavi, M.R. Sehhati, H. Rabbani, Hybrid method for prediction of metastasis in breast cancer patients using gene expression signals. J Med Signals Sens 3(2), 79–86 (2013)Google Scholar
  131. 131.
    H. Laubli, L. Borsig, Selectins promote tumor metastasis. Semin Cancer Biol 20, 169–177 (2010)CrossRefPubMedGoogle Scholar
  132. 132.
    G. Bendas, L. Borsig, Cancer cell adhesion and metastasis: selectins, integrins, and the inhibitory potential of heparins. Int J Cell Biol 2012, 676731 (2012)CrossRefPubMedCentralPubMedGoogle Scholar
  133. 133.
    M. Jiang, X. Xu, Y. Bi, J. Xu, C. Qin, M. Han, Systemic inflammation promotes lung metastasis via E-selectin upregulation in mouse breast cancer model. Cancer Biol Ther 15, 789–796 (2014)CrossRefPubMedCentralPubMedGoogle Scholar
  134. 134.
    G.P. Gupta, D.X. Nguyen, A.C. Chiang, P.D. Bos, J.Y. Kim, C. Nadal, R.R. Gomis, K. Manova-Todorova, J. Massague, Mediators of vascular remodelling co-opted for sequential steps in lung metastasis. Nature 446, 765–770 (2007)CrossRefPubMedGoogle Scholar
  135. 135.
    R.S. Muraoka-Cook, H. Kurokawa, Y. Koh, J.T. Forbes, L.R. Roebuck, M.H. Barcellos-Hoff, S.E. Moody, L.A. Chodosh, C.L. Arteaga, Conditional overexpression of active transforming growth factor beta1 in vivo accelerates metastases of transgenic mammary tumors. Cancer Res 64, 9002–9011 (2004)CrossRefPubMedGoogle Scholar
  136. 136.
    R.S. Muraoka, N. Dumont, C.A. Ritter, T.C. Dugger, D.M. Brantley, J. Chen, E. Easterly, L.R. Roebuck, S. Ryan, P.J. Gotwals, V. Koteliansky, C.L. Arteaga, Blockade of TGF-beta inhibits mammary tumor cell viability, migration, and metastases. J Clin Invest 109, 1551–1559 (2002)CrossRefPubMedCentralPubMedGoogle Scholar
  137. 137.
    Y. Kang, Pro-metastasis function of TGFbeta mediated by the Smad pathway. J Cell Biochem 98, 1380–1390 (2006)CrossRefPubMedGoogle Scholar
  138. 138.
    F. Tian, S. DaCosta Byfield, W.T. Parks, S. Yoo, A. Felici, B. Tang, E. Piek, L.M. Wakefield, A.B. Roberts, Reduction in Smad2/3 signaling enhances tumorigenesis but suppresses metastasis of breast cancer cell lines. Cancer Res 63, 8284–8292 (2003)PubMedGoogle Scholar
  139. 139.
    D. Dankort, B. Maslikowski, N. Warner, N. Kanno, H. Kim, Z. Wang, M.F. Moran, R.G. Oshima, R.D. Cardiff, W.J. Muller, Grb2 and Shc adapter proteins play distinct roles in Neu (ErbB-2)-induced mammary tumorigenesis: implications for human breast cancer. Mol Cell Biol 21, 1540–1551 (2001)CrossRefPubMedCentralPubMedGoogle Scholar
  140. 140.
    P.M. Siegel, W. Shu, R.D. Cardiff, W.J. Muller, J. Massague, Transforming growth factor beta signaling impairs Neu-induced mammary tumorigenesis while promoting pulmonary metastasis. Proc Natl Acad Sci USA 100, 8430–8435 (2003)Google Scholar
  141. 141.
    Y. Ye, S. Liu, C. Wu, Z. Sun, TGFbeta modulates inflammatory cytokines and growth factors to create premetastatic microenvironment and stimulate lung metastasis. J Mol Histol 46, 365–375 (2015)CrossRefPubMedGoogle Scholar
  142. 142.
    J.M. Yingling, K.L. Blanchard, J.S. Sawyer, Development of TGF-beta signalling inhibitors for cancer therapy. Nat Rev Drug Discov 3, 1011–1022 (2004)CrossRefPubMedGoogle Scholar
  143. 143.
    M. Tichet, V. Prod'Homme, N. Fenouille, D. Ambrosetti, Tumour-derived SPARC drives vascular permeability and extravasation through endothelial VCAM1 signalling to promote metastasis. Nat Commun 6, 6993 (2015)CrossRefPubMedGoogle Scholar
  144. 144.
    A. Muller, B. Homey, H. Soto, N. Ge, D. Catron, M.E. Buchanan, T. McClanahan, E. Murphy, W. Yuan, S.N. Wagner, J.L. Barrera, A. Mohar, E. Verastegui, A. Zlotnik, Involvement of chemokine receptors in breast cancer metastasis. Nature 410, 50–56 (2001)CrossRefPubMedGoogle Scholar
  145. 145.
    M. Abdel-Ghany, H.C. Cheng, R.C. Elble, B.U. Pauli, The breast cancer beta 4 integrin and endothelial human CLCA2 mediate lung metastasis. J Biol Chem 276, 25438–25446 (2001)CrossRefPubMedGoogle Scholar
  146. 146.
    H.C. Cheng, M. Abdel-Ghany, R.C. Elble, B.U. Pauli, 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)CrossRefPubMedGoogle Scholar
  147. 147.
    A.J. Minn, Y. Kang, I. Serganova, G.P. Gupta, D.D. Giri, M. Doubrovin, V. Ponomarev, W.L. Gerald, R. Blasberg, J. Massague, Distinct organ-specific metastatic potential of individual breast cancer cells and primary tumors. J Clin Invest 115, 44–55 (2005)CrossRefPubMedCentralPubMedGoogle Scholar
  148. 148.
    S.R. Nielsen, M.C. Schmid, Macrophages as Key Drivers of Cancer Progression and Metastasis. Mediat Inflamm 2017, 9624760 (2017)CrossRefGoogle Scholar
  149. 149.
    C.B. Williams, E.S. Yeh, A.C. Soloff, Tumor-associated macrophages: unwitting accomplices in breast cancer malignancy. NPJ Breast Cancer 2, 1–12 (2016)CrossRefGoogle Scholar
  150. 150.
    L.M. Nusblat, M.J. Carroll, C.M. Roth, Crosstalk between M2 macrophages and glioma stem cells. Cell Oncol 40, 471–482 (2017)Google Scholar
  151. 151.
    B.Z. Qian, J.W. Pollard, Macrophage diversity enhances tumor progression and metastasis. Cell 141, 39–51 (2010)CrossRefPubMedCentralPubMedGoogle Scholar
  152. 152.
    B.Z. Qian, J. Li, H. Zhang, T. Kitamura, J. Zhang, L.R. Campion, E.A. Kaiser, L.A. Snyder, J.W. Pollard, CCL2 recruits inflammatory monocytes to facilitate breast-tumour metastasis. Nature 475, 222–225 (2011)CrossRefPubMedCentralPubMedGoogle Scholar
  153. 153.
    L. Cassetta, J.W. Pollard, Repolarizing macrophages improves breast cancer therapy. Cell Res 27, 963–964 (2017)Google Scholar
  154. 154.
    J.L. Guerriero, A. Sotayo, H.E. Ponichtera, J.A. Castrillon, A.L. Pourzia, S. Schad, S.F. Johnson, R.D. Carrasco, S. Lazo, R.T. Bronson, S.P. Davis, M. Lobera, M.A. Nolan, A. Letai, Class IIa HDAC inhibition reduces breast tumours and metastases through anti-tumour macrophages. Nature 543, 428–432 (2017)CrossRefPubMedGoogle Scholar
  155. 155.
    A.F. Chambers, A.C. Groom, I.C. MacDonald, Dissemination and growth of cancer cells in metastatic sites. Nat Rev Cancer 2, 563–572 (2002)CrossRefPubMedGoogle Scholar
  156. 156.
    C.W. Wong, A. Lee, L. Shientag, J. Yu, Y. Dong, G. Kao, A.B. Al-Mehdi, E.J. Bernhard, R.J. Muschel, Apoptosis: an early event in metastatic inefficiency. Cancer Res 61, 333–338 (2001)PubMedGoogle Scholar
  157. 157.
    K.J. Luzzi, I.C. MacDonald, E.E. Schmidt, N. Kerkvliet, V.L. Morris, A.F. Chambers, A.C. Groom, Multistep nature of metastatic inefficiency: dormancy of solitary cells after successful extravasation and limited survival of early micrometastases. Am J Pathol 153, 865–873 (1998)CrossRefPubMedCentralPubMedGoogle Scholar
  158. 158.
    M.D. Cameron, E.E. Schmidt, N. Kerkvliet, K.V. Nadkarni, V.L. Morris, A.C. Groom, A.F. Chambers, I.C. MacDonald, Temporal progression of metastasis in lung: cell survival, dormancy, and location dependence of metastatic inefficiency. Cancer Res 60, 2541–2546 (2000)PubMedGoogle Scholar
  159. 159.
    S.S. McAllister, R.A. Weinberg, Tumor-host interactions: a far-reaching relationship. J Clin Oncol 28, 4022–4028 (2010)CrossRefPubMedGoogle Scholar
  160. 160.
    C. Coghlin, G.I. Murray, Current and emerging concepts in tumour metastasis. J Pathol 222, 1–15 (2010)CrossRefPubMedGoogle Scholar
  161. 161.
    K. Pakravan, S. Babashah, M. Sadeghizadeh, S.J. Mowla, M. Mossahebi-Mohammadi, F. Ataei, N. Dana, M. Javan, MicroRNA-100 shuttled by mesenchymal stem cell-derived exosomes suppresses in vitro angiogenesis through modulating the mTOR/HIF-1alpha/VEGF signaling axis in breast cancer cells. Cell Oncol 40, 457–470 (2017)Google Scholar
  162. 162.
    A. Hoshino, B. Costa-Silva, T.L. Shen, G. Rodrigues, A. Hashimoto, M. Tesic Mark, H. Molina, S. Kohsaka, A. Di Giannatale, S. Ceder, S. Singh, C. Williams, N. Soplop, K. Uryu, L. Pharmer, T. King, L. Bojmar, A.E. Davies, Y. Ararso, T. Zhang, H. Zhang, J. Hernandez, J.M. Weiss, V.D. Dumont-Cole, K. Kramer, L.H. Wexler, A. Narendran, G.K. Schwartz, J.H. Healey, P. Sandstrom, K.J. Labori, E.H. Kure, P.M. Grandgenett, M.A. Hollingsworth, M. de Sousa, S. Kaur, M. Jain, K. Mallya, S.K. Batra, W.R. Jarnagin, M.S. Brady, O. Fodstad, V. Muller, K. Pantel, A.J. Minn, M.J. Bissell, B.A. Garcia, Y. Kang, V.K. Rajasekhar, C.M. Ghajar, I. Matei, H. Peinado, J. Bromberg, D. Lyden, Tumour exosome integrins determine organotropic metastasis. Nature 527, 329–335 (2015)CrossRefPubMedCentralPubMedGoogle Scholar
  163. 163.
    S. Maji, P. Chaudhary, I. Akopova, P.M. Nguyen, R.J. Hare, I. Gryczynski, J.K. Vishwanatha, Exosomal annexin II promotes angiogenesis and breast cancer metastasis. Mol Cancer Res 15, 93–105 (2017)CrossRefPubMedGoogle Scholar
  164. 164.
    F. Salvador, A. Martin, C. López-Menéndez, G. Moreno-Bueno, V. Santos, A. Vázquez-Naharro, P.G. Santamaria, S. Morales, P.R. Dubus, L. Muinelo-Romay, Lysyl Oxidase–like Protein LOXL2 Promotes Lung Metastasis of Breast Cancer. Cancer Res 77, 5846–5859 (2017)CrossRefPubMedGoogle Scholar
  165. 165.
    S.K. Wculek, I. Malanchi, Neutrophils support lung colonization of metastasis-initiating breast cancer cells. Nature 528, 413–417 (2015)CrossRefPubMedCentralPubMedGoogle Scholar
  166. 166.
    P.B. Olkhanud, D. Baatar, M. Bodogai, F. Hakim, R. Gress, R.L. Anderson, J. Deng, M. Xu, S. Briest, A. Biragyn, Breast cancer lung metastasis requires expression of chemokine receptor CCR4 and regulatory T cells. Cancer Res 69, 5996–6004 (2009)CrossRefPubMedCentralPubMedGoogle Scholar
  167. 167.
    P.B. Olkhanud, B. Damdinsuren, M. Bodogai, R.E. Gress, R. Sen, K. Wejksza, E. Malchinkhuu, R.P. Wersto, A. Biragyn, Tumor-evoked regulatory B cells promote breast cancer metastasis by converting resting CD4(+) T cells to T-regulatory cells. Cancer Res 71, 3505–3515 (2011)CrossRefPubMedCentralPubMedGoogle Scholar
  168. 168.
    H. Gao, G. Chakraborty, A.P. Lee-Lim, Q. Mo, M. Decker, A. Vonica, R. Shen, E. Brogi, A.H. Brivanlou, F.G. Giancotti, The BMP inhibitor Coco reactivates breast cancer cells at lung metastatic sites. Cell 150, 764–779 (2012)CrossRefPubMedCentralPubMedGoogle Scholar
  169. 169.
    I. Malanchi, A. Santamaria-Martinez, E. Susanto, H. Peng, H.A. Lehr, J.F. Delaloye, J. Huelsken, Interactions between cancer stem cells and their niche govern metastatic colonization. Nature 481, 85–89 (2011)CrossRefPubMedGoogle Scholar
  170. 170.
    X. Zhuang, H. Zhang, X. Li, X. Li, M. Cong, F. Peng, J. Yu, X. Zhang, Q. Yang, G. Hu, Differential effects on lung and bone metastasis of breast cancer by Wnt signalling inhibitor DKK1. Nat Cell Biol 19, ncb3613 (2017)CrossRefGoogle Scholar
  171. 171.
    I. Kii, T. Nishiyama, M. Li, K. Matsumoto, M. Saito, N. Amizuka, A. Kudo, Incorporation of tenascin-C into the extracellular matrix by periostin underlies an extracellular meshwork architecture. J Biol Chem 285, 2028–2039 (2010)CrossRefPubMedGoogle Scholar
  172. 172.
    S. Hiratsuka, A. Watanabe, H. Aburatani, Y. Maru, Tumour-mediated upregulation of chemoattractants and recruitment of myeloid cells predetermines lung metastasis. Nat Cell Biol 8, 1369–1375 (2006)CrossRefPubMedGoogle Scholar
  173. 173.
    S. Rafii, D. Lyden, S100 chemokines mediate bookmarking of premetastatic niches. Nat Cell Biol 8, 1321–1323 (2006)CrossRefPubMedCentralPubMedGoogle Scholar
  174. 174.
    V. Baud, M. Karin, Is NF-kappaB a good target for cancer therapy? Hopes and pitfalls. Nat Rev Drug Discov 8, 33–40 (2009)CrossRefPubMedCentralPubMedGoogle Scholar
  175. 175.
    S.Y. Yang, A. Miah, A. Pabari, M. Winslet, Growth Factors and their receptors in cancer metastases. Front Biosci (Landmark Ed) 16, 531–538 (2011)CrossRefGoogle Scholar
  176. 176.
    M.A. Huber, N. Azoitei, B. Baumann, S. Grunert, A. Sommer, H. Pehamberger, N. Kraut, H. Beug, T. Wirth, NF-kappaB is essential for epithelial-mesenchymal transition and metastasis in a model of breast cancer progression. J Clin Invest 114, 569–581 (2004)CrossRefPubMedCentralPubMedGoogle Scholar
  177. 177.
    M. Dai, C. Wu, L. Chen, C. Chen, T. Chao, Tartrate-resistant acid phosphatase (TRACP) modulates breast cancer pre-metastatic niche. Abstract In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P4-03-17Google Scholar

Copyright information

© International Society for Cellular Oncology 2018

Authors and Affiliations

  • Meysam Yousefi
    • 1
  • Rahim Nosrati
    • 2
  • Arash Salmaninejad
    • 3
  • Sadegh Dehghani
    • 4
  • Alireza Shahryari
    • 5
  • Alihossein Saberi
    • 6
  1. 1.Department of Medical Genetics, Faculty of MedicineMashhad University of Medical SciencesMashhadIran
  2. 2.Department of Pharmaceutical Biotechnology, School of PharmacyMashhad University of Medical SciencesMashhadIran
  3. 3.Drug Applied Research CenterTabriz University of Medical SciencesTabrizIran
  4. 4.Department of Medical Biotechnology, Faculty of MedicineMashhad University of Medical SciencesMashhadIran
  5. 5.Stem Cell Research CenterGolestan University of Medical SciencesGorganIran
  6. 6.Department of Medical Genetics, Faculty of MedicineAhvaz Jundishapur University of Medical SciencesAhvazIran

Personalised recommendations