Advertisement

Cancer and Metastasis Reviews

, Volume 32, Issue 3–4, pp 449–464 | Cite as

The pre-metastatic niche: finding common ground

  • Jaclyn Sceneay
  • Mark J. SmythEmail author
  • Andreas MöllerEmail author
NON-THEMATIC REVIEW

Abstract

It is rapidly becoming evident that the formation of tumor-promoting pre-metastatic niches in secondary organs adds a previously unrecognized degree of complexity to the challenge of curing metastatic disease. Primary tumor cells orchestrate pre-metastatic niche formation through secretion of a variety of cytokines and growth factors that promote mobilization and recruitment of bone marrow-derived cells to future metastatic sites. Hypoxia within the primary tumor, and secretion of specific microvesicles termed exosomes, are emerging as important processes and vehicles for tumor-derived factors to modulate pre-metastatic sites. It has also come to light that reduced immune surveillance is a novel mechanism through which primary tumors create favorable niches in secondary organs. This review provides an overview of our current understanding of underlying mechanisms of pre-metastatic niche formation and highlights the common links as well as discrepancies between independent studies. Furthermore, the possible clinical implications, links to metastatic persistence and dormancy, and novel approaches for treatment of metastatic disease through reversal of pre-metastatic niche formation are identified and explored.

Keywords

Pre-metastatic niche Hypoxia Immunosuppression Myeloid-derived suppressor cells Exosomes Tumor dormancy 

Notes

Acknowledgments

The authors would like to thank the members of the Möller and Smyth groups for valuable suggestions for the review. The authors acknowledge the generous support of a State Trustees Australia Foundation scholarship to JS; National Health and Medical Research Council (NH&MRC) Australia Fellowship, NH&MRC Program Grant, and Victorian Cancer Agency support to MJS; and an Association of International Cancer Research Project Grant and a National Breast Cancer Foundation Fellowship to AM.

Conflict of interest

The authors declare no conflict of interest.

References

  1. 1.
    Gupta, G. P., & Massague, J. (2006). Cancer metastasis: building a framework. Cell, 127(4), 679–695.PubMedGoogle Scholar
  2. 2.
    Klein, C. A. (2008). Cancer. The metastasis cascade. Science, 321(5897), 1785–1787.PubMedGoogle Scholar
  3. 3.
    Joyce, J. A., & Pollard, J. W. (2009). Microenvironmental regulation of metastasis. Nature Reviews. Cancer, 9(4), 239–252.PubMedGoogle Scholar
  4. 4.
    Hanahan, D., & Weinberg, R. A. (2011). Hallmarks of cancer: the next generation. Cell, 144(5), 646–674.PubMedGoogle Scholar
  5. 5.
    Paget, G. (1889). Remarks on a case of alternate partial anaesthesia. British Medical Journal, 1(1462), 1–3.PubMedGoogle Scholar
  6. 6.
    Muller, A., et al. (2001). Involvement of chemokine receptors in breast cancer metastasis. Nature, 410(6824), 50–56.PubMedGoogle Scholar
  7. 7.
    Weigelt, B., et al. (2005). No common denominator for breast cancer lymph node metastasis. British Journal of Cancer, 93(8), 924–932.PubMedGoogle Scholar
  8. 8.
    Kaplan, R. N., et al. (2005). VEGFR1-positive haematopoietic bone marrow progenitors initiate the pre-metastatic niche. Nature, 438(7069), 820–827.PubMedGoogle Scholar
  9. 9.
    Psaila, B., & Lyden, D. (2009). The metastatic niche: adapting the foreign soil. Nature Reviews. Cancer, 9(4), 285–293.PubMedGoogle Scholar
  10. 10.
    Duda, D. G., & Jain, R. K. (2010). Premetastatic lung “niche”: is vascular endothelial growth factor receptor 1 activation required? Cancer Research, 70(14), 5670–5673.PubMedGoogle Scholar
  11. 11.
    Dawson, M. R., et al. (2009). VEGFR1-activity-independent metastasis formation. Nature, 461(7262), E4. Discussion, E5.PubMedGoogle Scholar
  12. 12.
    Lin, E. Y., et al. (2006). Macrophages regulate the angiogenic switch in a mouse model of breast cancer. Cancer Research, 66(23), 11238–11246.PubMedGoogle Scholar
  13. 13.
    Nozawa, H., Chiu, C., & Hanahan, D. (2006). Infiltrating neutrophils mediate the initial angiogenic switch in a mouse model of multistage carcinogenesis. Proceedings of the National Academy of Sciences of the United States of America, 103(33), 12493–12498.PubMedGoogle Scholar
  14. 14.
    Coussens, L. M., et al. (1999). Inflammatory mast cells up-regulate angiogenesis during squamous epithelial carcinogenesis. Genes & Development, 13(11), 1382–1397.Google Scholar
  15. 15.
    Hiratsuka, S., et al. (2006). Tumour-mediated upregulation of chemoattractants and recruitment of myeloid cells predetermines lung metastasis. Nature Cell Biology, 8(12), 1369–1375.PubMedGoogle Scholar
  16. 16.
    Kowanetz, M., et al. (2010). Granulocyte-colony stimulating factor promotes lung metastasis through mobilization of Ly6G + Ly6C + granulocytes. Proceedings of the National Academy of Sciences of the United States of America, 107(50), 21248–21255.PubMedGoogle Scholar
  17. 17.
    Harris, A. L. (2002). Hypoxia—a key regulatory factor in tumour growth. Nature Reviews. Cancer, 2(1), 38–47.PubMedGoogle Scholar
  18. 18.
    Semenza, G. L. (2012). Hypoxia-inducible factors: mediators of cancer progression and targets for cancer therapy. Trends in Pharmacological Sciences, 33(4), 207–214.PubMedGoogle Scholar
  19. 19.
    Bos, R., et al. (2003). Levels of hypoxia-inducible factor-1alpha independently predict prognosis in patients with lymph node negative breast carcinoma. Cancer, 97(6), 1573–1581.PubMedGoogle Scholar
  20. 20.
    Dales, J. P., et al. (2005). Overexpression of hypoxia-inducible factor HIF-1alpha predicts early relapse in breast cancer: retrospective study in a series of 745 patients. International Journal of Cancer, 116(5), 734–739.Google Scholar
  21. 21.
    Erler, J. T., et al. (2009). Hypoxia-induced lysyl oxidase is a critical mediator of bone marrow cell recruitment to form the premetastatic niche. Cancer Cell, 15(1), 35–44.PubMedGoogle Scholar
  22. 22.
    Wong, C. C., et al. (2011). Hypoxia-inducible factor 1 is a master regulator of breast cancer metastatic niche formation. Proceedings of the National Academy of Sciences of the United States of America, 108(39), 16369–16374.PubMedGoogle Scholar
  23. 23.
    Bondareva, A., et al. (2009). The lysyl oxidase inhibitor, beta-aminopropionitrile, diminishes the metastatic colonization potential of circulating breast cancer cells. PLoS One, 4(5), e5620.PubMedGoogle Scholar
  24. 24.
    Sceneay, J., et al. (2012). Primary tumor hypoxia recruits CD11b+/Ly6Cmed/Ly6G+ immune suppressor cells and compromises NK cell cytotoxicity in the premetastatic niche. Cancer Research, 72, 3906–11.PubMedGoogle Scholar
  25. 25.
    Chioda, M., et al. (2011). Myeloid cell diversification and complexity: an old concept with new turns in oncology. Cancer Metastasis Reviews, 30(1), 27–43.PubMedGoogle Scholar
  26. 26.
    Yan, H. H., et al. (2010). Gr-1 + CD11b + myeloid cells tip the balance of immune protection to tumor promotion in the premetastatic lung. Cancer Research, 70(15), 6139–6149.PubMedGoogle Scholar
  27. 27.
    Kim, S., et al. (2009). Carcinoma-produced factors activate myeloid cells through TLR2 to stimulate metastasis. Nature, 457(7225), 102–106.PubMedGoogle Scholar
  28. 28.
    Granot, Z., et al. (2011). Tumor entrained neutrophils inhibit seeding in the premetastatic lung. Cancer Cell, 20(3), 300–314.PubMedGoogle Scholar
  29. 29.
    Filipazzi, P., et al. (2007). Identification of a new subset of myeloid suppressor cells in peripheral blood of melanoma patients with modulation by a granulocyte-macrophage colony-stimulation factor-based antitumor vaccine. Journal of Clinical Oncology, 25(18), 2546–2553.PubMedGoogle Scholar
  30. 30.
    Gabrilovich, D. I., & Nagaraj, S. (2009). Myeloid-derived suppressor cells as regulators of the immune system. Nature Reviews Immunology, 9(3), 162–174.PubMedGoogle Scholar
  31. 31.
    Poschke, I., et al. (2010). Immature immunosuppressive CD14+HLA-DR-/low cells in melanoma patients are Stat3hi and overexpress CD80, CD83, and DC-sign. Cancer Research, 70(11), 4335–4345.PubMedGoogle Scholar
  32. 32.
    Rodriguez, P. C., & Ochoa, A. C. (2006). T cell dysfunction in cancer: role of myeloid cells and tumor cells regulating amino acid availability and oxidative stress. Seminars in Cancer Biology, 16(1), 66–72.PubMedGoogle Scholar
  33. 33.
    Serafini, P., Borrello, I., & Bronte, V. (2006). Myeloid suppressor cells in cancer: recruitment, phenotype, properties, and mechanisms of immune suppression. Seminars in Cancer Biology, 16(1), 53–65.PubMedGoogle Scholar
  34. 34.
    Youn, J. I., et al. (2008). Subsets of myeloid-derived suppressor cells in tumor-bearing mice. Journal of Immunology, 181(8), 5791–5802.Google Scholar
  35. 35.
    Almand, B., et al. (2001). Increased production of immature myeloid cells in cancer patients: a mechanism of immunosuppression in cancer. Journal of Immunology, 166(1), 678–689.Google Scholar
  36. 36.
    Gabrilovich, D. I., Ostrand-Rosenberg, S., & Bronte, V. (2012). Coordinated regulation of myeloid cells by tumours. Nature Reviews Immunology, 12(4), 253–268.PubMedGoogle Scholar
  37. 37.
    Huang, B., et al. (2007). CCL2/CCR2 pathway mediates recruitment of myeloid suppressor cells to cancers. Cancer Letters, 252(1), 86–92.PubMedGoogle Scholar
  38. 38.
    Yang, L., et al. (2008). Abrogation of TGF beta signaling in mammary carcinomas recruits Gr-1+CD11b+ myeloid cells that promote metastasis. Cancer Cell, 13(1), 23–35.PubMedGoogle Scholar
  39. 39.
    Shojaei, F., et al. (2007). Bv8 regulates myeloid-cell-dependent tumour angiogenesis. Nature, 450(7171), 825–831.PubMedGoogle Scholar
  40. 40.
    Sica, A., & Bronte, V. (2007). Altered macrophage differentiation and immune dysfunction in tumor development. The Journal of Clinical Investigation, 117(5), 1155–1166.PubMedGoogle Scholar
  41. 41.
    Gao, D., et al. (2012). Myeloid progenitor cells in the premetastatic lung promote metastases by inducing mesenchymal to epithelial transition. Cancer Research, 72(6), 1384–1394.PubMedGoogle Scholar
  42. 42.
    Corzo, C. A., et al. (2010). HIF-1α regulates function and differentiation of myeloid-derived suppressor cells in the tumor microenvironment. The Journal of Experimental Medicine, 207(11), 2439–2453.PubMedGoogle Scholar
  43. 43.
    Deng, J., et al. (2012). S1PR1-STAT3 signaling is crucial for myeloid cell colonization at future metastatic sites. Cancer Cell, 21(5), 642–654.PubMedGoogle Scholar
  44. 44.
    Movahedi, K., et al. (2008). Identification of discrete tumor-induced myeloid-derived suppressor cell subpopulations with distinct T cell-suppressive activity. Blood, 111(8), 4233–4244.PubMedGoogle Scholar
  45. 45.
    Dolcetti, L., et al. (2010). Hierarchy of immunosuppressive strength among myeloid-derived suppressor cell subsets is determined by GM-CSF. European Journal of Immunology, 40(1), 22–35.PubMedGoogle Scholar
  46. 46.
    Mauti, L. A., et al. (2011). Myeloid-derived suppressor cells are implicated in regulating permissiveness for tumor metastasis during mouse gestation. The Journal of Clinical Investigation, 121(7), 2794–2807.PubMedGoogle Scholar
  47. 47.
    Li, H., et al. (2009). Cancer-expanded myeloid-derived suppressor cells induce anergy of NK cells through membrane-bound TGF-beta 1. Journal of Immunology, 182(1), 240–249.Google Scholar
  48. 48.
    Hoechst, B., et al. (2009). Myeloid derived suppressor cells inhibit natural killer cells in patients with hepatocellular carcinoma via the NKp30 receptor. Hepatology, 50(3), 799–807.PubMedGoogle Scholar
  49. 49.
    Zhu, J., Huang, X., & Yang, Y. (2012). Myeloid-derived suppressor cells regulate natural killer cell response to adenovirus-mediated gene transfer. Journal of Virology, 86, 13689–96.PubMedGoogle Scholar
  50. 50.
    Liu, C., et al. (2007). Expansion of spleen myeloid suppressor cells represses NK cell cytotoxicity in tumor-bearing host. Blood, 109(10), 4336–4342.PubMedGoogle Scholar
  51. 51.
    Nagaraj, S., et al. (2012). Antigen-specific CD4(+) T cells regulate function of myeloid-derived suppressor cells in cancer via retrograde MHC class II signaling. Cancer Research, 72(4), 928–938.PubMedGoogle Scholar
  52. 52.
    Doedens, A. L., et al. (2010). Macrophage expression of hypoxia-inducible factor-1 alpha suppresses T-cell function and promotes tumor progression. Cancer Research, 70(19), 7465–7475.PubMedGoogle Scholar
  53. 53.
    Corzo, C. A., et al. (2010). HIF-1alpha regulates function and differentiation of myeloid-derived suppressor cells in the tumor microenvironment. The Journal of Experimental Medicine, 207(11), 2439–2453.PubMedGoogle Scholar
  54. 54.
    Gallina, G., et al. (2006). Tumors induce a subset of inflammatory monocytes with immunosuppressive activity on CD8+ T cells. The Journal of Clinical Investigation, 116(10), 2777–2790.PubMedGoogle Scholar
  55. 55.
    Watanabe, S., et al. (2008). Tumor-induced CD11b+Gr-1+ myeloid cells suppress T cell sensitization in tumor-draining lymph nodes. Journal of Immunology, 181(5), 3291–3300.Google Scholar
  56. 56.
    Nagaraj, S., et al. (2007). Altered recognition of antigen is a mechanism of CD8+ T cell tolerance in cancer. Nature Medicine, 13(7), 828–835.PubMedGoogle Scholar
  57. 57.
    Serafini, P., et al. (2008). Myeloid-derived suppressor cells promote cross-tolerance in B-cell lymphoma by expanding regulatory T cells. Cancer Research, 68(13), 5439–5449.PubMedGoogle Scholar
  58. 58.
    Huang, B., et al. (2006). Gr-1+CD115+ immature myeloid suppressor cells mediate the development of tumor-induced T regulatory cells and T-cell anergy in tumor-bearing host. Cancer Research, 66(2), 1123–1131.PubMedGoogle Scholar
  59. 59.
    Pan, P. Y., et al. (2010). Immune stimulatory receptor CD40 is required for T-cell suppression and T regulatory cell activation mediated by myeloid-derived suppressor cells in cancer. Cancer Research, 70(1), 99–108.PubMedGoogle Scholar
  60. 60.
    Paez, D., et al. (2012). Cancer dormancy: a model of early dissemination and late cancer recurrence. Clinical Cancer Research, 18(3), 645–653.PubMedGoogle Scholar
  61. 61.
    Pavlidis, N., & Pentheroudakis, G. (2012). Cancer of unknown primary site. Lancet, 379(9824), 1428–1435.PubMedGoogle Scholar
  62. 62.
    Uhr, J. W., & Pantel, K. (2011). Controversies in clinical cancer dormancy. Proceedings of the National Academy of Sciences of the United States of America, 108(30), 12396–12400.PubMedGoogle Scholar
  63. 63.
    Almog, N. (2010). Molecular mechanisms underlying tumor dormancy. Cancer Letters, 294(2), 139–146.PubMedGoogle Scholar
  64. 64.
    Ringel, M. D. (2011). Metastatic dormancy and progression in thyroid cancer: targeting cells in the metastatic frontier. Thyroid, 21(5), 487–492.PubMedGoogle Scholar
  65. 65.
    Chaput, N., & Thery, C. (2011). Exosomes: immune properties and potential clinical implementations. Seminars in Immunopathology, 33(5), 419–440.PubMedGoogle Scholar
  66. 66.
    Ratajczak, J., et al. (2006). Membrane-derived microvesicles: important and underappreciated mediators of cell-to-cell communication. Leukemia, 20(9), 1487–1495.PubMedGoogle Scholar
  67. 67.
    Peinado, H., Lavotshkin, S., & Lyden, D. (2011). The secreted factors responsible for pre-metastatic niche formation: old sayings and new thoughts. Seminars in Cancer Biology, 21(2), 139–146.PubMedGoogle Scholar
  68. 68.
    Peinado, H., et al. (2012). Melanoma exosomes educate bone marrow progenitor cells toward a pro-metastatic phenotype through MET. Nature Medicine, 18, 883–91.PubMedGoogle Scholar
  69. 69.
    Jung, T., et al. (2009). CD44v6 dependence of premetastatic niche preparation by exosomes. Neoplasia, 11(10), 1093–1105.PubMedGoogle Scholar
  70. 70.
    Grange, C., et al. (2011). Microvesicles released from human renal cancer stem cells stimulate angiogenesis and formation of lung premetastatic niche. Cancer Research, 71(15), 5346–5356.PubMedGoogle Scholar
  71. 71.
    Gabrilovich, D. (2004). Mechanisms and functional significance of tumour-induced dendritic-cell defects. Nature Reviews Immunology, 4(12), 941–952.PubMedGoogle Scholar
  72. 72.
    Do, T. H., et al. (2004). Impaired circulating myeloid DCs from myeloma patients. Cytotherapy, 6(3), 196–203.PubMedGoogle Scholar
  73. 73.
    Liu, C., et al. (2006). Murine mammary carcinoma exosomes promote tumor growth by suppression of NK cell function. Journal of Immunology, 176(3), 1375–1385.Google Scholar
  74. 74.
    Huber, V., et al. (2005). Human colorectal cancer cells induce T-cell death through release of proapoptotic microvesicles: role in immune escape. Gastroenterology, 128(7), 1796–1804.PubMedGoogle Scholar
  75. 75.
    Valenti, R., et al. (2006). Human tumor-released microvesicles promote the differentiation of myeloid cells with transforming growth factor-β-mediated suppressive activity on T lymphocytes. Cancer Research, 66(18), 9290–9298.PubMedGoogle Scholar
  76. 76.
    Xiang, X., et al. (2009). Induction of myeloid-derived suppressor cells by tumor exosomes. International Journal of Cancer, 124(11), 2621–2633.Google Scholar
  77. 77.
    Liu, Y., et al. (2010). Contribution of MyD88 to the tumor exosome-mediated induction of myeloid derived suppressor cells. The American Journal of Pathology, 176(5), 2490–2499.PubMedGoogle Scholar
  78. 78.
    Yu, S., et al. (2007). Tumor exosomes inhibit differentiation of bone marrow dendritic cells. Journal of Immunology, 178(11), 6867–6875.Google Scholar
  79. 79.
    Park, J. E., et al. (2010). Hypoxic tumor cell modulates its microenvironment to enhance angiogenic and metastatic potential by secretion of proteins and exosomes. Molecular & Cellular Proteomics, 9(6), 1085–1099.Google Scholar
  80. 80.
    Wong, C. C., et al. (2012). Inhibitors of hypoxia-inducible factor 1 block breast cancer metastatic niche formation and lung metastasis. Journal of Molecular Medicine (Berlin), 90, 803–15.Google Scholar
  81. 81.
    Hiratsuka, S., et al. (2008). The S100A8-serum amyloid A3-TLR4 paracrine cascade establishes a pre-metastatic phase. Nature Cell Biology, 10(11), 1349–1355.PubMedGoogle Scholar
  82. 82.
    Skog, J., et al. (2008). Glioblastoma microvesicles transport RNA and proteins that promote tumour growth and provide diagnostic biomarkers. Nature Cell Biology, 10(12), 1470–1476.PubMedGoogle Scholar
  83. 83.
    Noerholm, M., et al. (2012). RNA expression patterns in serum microvesicles from patients with glioblastoma multiforme and controls. BMC Cancer, 12, 22.PubMedGoogle Scholar
  84. 84.
    Khan, S., et al. (2012). Plasma-derived exosomal survivin, a plausible biomarker for early detection of prostate cancer. PLoS One, 7(10), e46737.PubMedGoogle Scholar
  85. 85.
    Chen, T., et al. (2011). Chemokine-containing exosomes are released from heat-stressed tumor cells via lipid raft-dependent pathway and act as efficient tumor vaccine. Journal of Immunology, 186(4), 2219–2228.Google Scholar
  86. 86.
    Levy, E. M., Roberti, M. P., & Mordoh, J. (2011). Natural killer cells in human cancer: from biological functions to clinical applications. Journal of Biomedicine and Biotechnology, 2011, 676198.PubMedGoogle Scholar
  87. 87.
    Jinushi, M., et al. (2008). MHC class I chain-related protein A antibodies and shedding are associated with the progression of multiple myeloma. Proceedings of the National Academy of Sciences of the United States of America, 105(4), 1285–1290.PubMedGoogle Scholar
  88. 88.
    Sibbitt, W. L., Jr., et al. (1984). Defects in natural killer cell activity and interferon response in human lung carcinoma and malignant melanoma. Cancer Research, 44(2), 852–856.PubMedGoogle Scholar
  89. 89.
    Konjevic, G., et al. (2009). Biomarkers of suppressed natural killer (NK) cell function in metastatic melanoma: decreased NKG2D and increased CD158a receptors on CD3-CD16+ NK cells. Biomarkers, 14(4), 258–270.PubMedGoogle Scholar
  90. 90.
    Konjevic, G., et al. (2007). Low expression of CD161 and NKG2D activating NK receptor is associated with impaired NK cell cytotoxicity in metastatic melanoma patients. Clinical & Experimental Metastasis, 24(1), 1–11.Google Scholar
  91. 91.
    Gill, S., Olson, J. A., & Negrin, R. S. (2009). Natural killer cells in allogeneic transplantation: effect on engraftment, graft- versus-tumor, and graft-versus-host responses. Biology of Blood and Marrow Transplantation, 15(7), 765–776.PubMedGoogle Scholar
  92. 92.
    Burke, S., et al. (2010). New views on natural killer cell-based immunotherapy for melanoma treatment. Trends in Immunology, 31(9), 339–345.PubMedGoogle Scholar
  93. 93.
    Koehn, T. A., et al. (2012). Increasing the clinical efficacy of NK and antibody-mediated cancer immunotherapy: potential predictors of successful clinical outcome based on observations in high-risk neuroblastoma. Frontiers in Pharmacology, 3, 91.PubMedGoogle Scholar
  94. 94.
    Sawanobori, Y., et al. (2008). Chemokine-mediated rapid turnover of myeloid-derived suppressor cells in tumor-bearing mice. Blood, 111(12), 5457–5466.PubMedGoogle Scholar
  95. 95.
    Shojaei, F., et al. (2009). G-CSF-initiated myeloid cell mobilization and angiogenesis mediate tumor refractoriness to anti-VEGF therapy in mouse models. Proceedings of the National Academy of Sciences, 106(16), 6742–6747.Google Scholar
  96. 96.
    Mazzoni, A., et al. (2002). Myeloid suppressor lines inhibit T cell responses by an NO-dependent mechanism. The Journal of Immunology, 168(2), 689–695.PubMedGoogle Scholar
  97. 97.
    Yang, L., et al. (2004). Expansion of myeloid immune suppressor Gr+CD11b+ cells in tumor-bearing host directly promotes tumor angiogenesis. Cancer Cell, 6(4), 409–421.PubMedGoogle Scholar
  98. 98.
    Melani, C., et al. (2007). Amino-biphosphonate-mediated MMP-9 inhibition breaks the tumor-bone marrow axis responsible for myeloid-derived suppressor cell expansion and macrophage infiltration in tumor stroma. Cancer Research, 67(23), 11438–11446.PubMedGoogle Scholar
  99. 99.
    Sinha, P., et al. (2008). Proinflammatory S100 proteins regulate the accumulation of myeloid-derived suppressor cells. The Journal of Immunology, 181(7), 4666–4675.PubMedGoogle Scholar
  100. 100.
    Cheng, P., et al. (2008). Inhibition of dendritic cell differentiation and accumulation of myeloid-derived suppressor cells in cancer is regulated by S100A9 protein. The Journal of Experimental Medicine, 205(10), 2235–2249.PubMedGoogle Scholar
  101. 101.
    Terabe, M., et al. (2003). Transforming growth factor-β production and myeloid cells are an effector mechanism through which CD1d-restricted T cells block cytotoxic T lymphocyte-mediated tumor immunosurveillance. The Journal of Experimental Medicine, 198(11), 1741–1752.PubMedGoogle Scholar
  102. 102.
    Xiang, X., et al. (2009). Induction of myeloid-derived suppressor cells by tumor exosomes. International Journal of Cancer, 124(11), 2621–2633.Google Scholar
  103. 103.
    Gabrilovich, D., et al. (1998). Vascular endothelial growth factor inhibits the development of dendritic cells and dramatically affects the differentiation of multiple hematopoietic lineages in vivo. Blood, 92(11), 4150–4166.PubMedGoogle Scholar
  104. 104.
    Kusmartsev, S., et al. (2008). Oxidative stress regulates expression of VEGFR1 in myeloid cells: link to tumor-induced immune suppression in renal cell carcinoma. Journal of Immunology, 181(1), 346–353.Google Scholar
  105. 105.
    Shojaei, F., et al. (2007). Tumor refractoriness to anti-VEGF treatment is mediated by CD11b+Gr1+ myeloid cells. Nature Biotechnology, 25(8), 911–920.PubMedGoogle Scholar
  106. 106.
    van Cruijsen, H., et al. (2007). Defective differentiation of myeloid and plasmacytoid dendritic cells in advanced cancer patients is not normalized by tyrosine kinase inhibition of the vascular endothelial growth factor receptor. Clinical & Developmental Immunology, 2007, 17315–17315.Google Scholar
  107. 107.
    Hiratsuka, S., et al. (2011). Endothelial focal adhesion kinase mediates cancer cell homing to discrete regions of the lungs via E-selectin up-regulation. Proceedings of the National Academy of Sciences of the United States of America, 108(9), 3725–3730.PubMedGoogle Scholar
  108. 108.
    Schelter, F., et al. (2011). Tissue inhibitor of metalloproteinases-1-induced scattered liver metastasis is mediated by hypoxia-inducible factor-1alpha. Clinical & Experimental Metastasis, 28(2), 91–99.Google Scholar
  109. 109.
    Gil-Bernabé, A. M., et al. (2012). Recruitment of monocytes/macrophages by tissue factor-mediated coagulation is essential for metastatic cell survival and premetastatic niche establishment in mice. Blood, 119, 3164–75.PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2013

Authors and Affiliations

  1. 1.Cancer Genomics and Genetics LaboratoryPeter MacCallum Cancer CentreEast MelbourneAustralia
  2. 2.Department of PathologyThe University of MelbourneParkvilleAustralia
  3. 3.Tumour Microenvironment LaboratoryQueensland Institute of Medical ResearchHerstonAustralia
  4. 4.Cancer Immunology ProgramPeter MacCallum Cancer CentreEast MelbourneAustralia
  5. 5.Sir Peter MacCallum Department of OncologyThe University of MelbourneParkvilleAustralia
  6. 6.Immunology in Cancer and Infection LaboratoryQueensland Institute of Medical ResearchHerstonAustralia

Personalised recommendations