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The metastasis-promoting roles of tumor-associated immune cells

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Abstract

Tumor metastasis is driven not only by the accumulation of intrinsic alterations in malignant cells, but also by the interactions of cancer cells with various stromal cell components of the tumor microenvironment. In particular, inflammation and infiltration of the tumor tissue by host immune cells, such as tumor-associated macrophages, myeloid-derived suppressor cells, and regulatory T cells, have been shown to support tumor growth in addition to invasion and metastasis. Each step of tumor development, from initiation through metastatic spread, is promoted by communication between tumor and immune cells via the secretion of cytokines, growth factors, and proteases that remodel the tumor microenvironment. Invasion and metastasis require neovascularization, breakdown of the basement membrane, and remodeling of the extracellular matrix for tumor cell invasion and extravasation into the blood and lymphatic vessels. The subsequent dissemination of tumor cells to distant organ sites necessitates a treacherous journey through the vasculature, which is fostered by close association with platelets and macrophages. Additionally, the establishment of the pre-metastatic niche and specific metastasis organ tropism is fostered by neutrophils and bone marrow-derived hematopoietic immune progenitor cells and other inflammatory cytokines derived from tumor and immune cells, which alter the local environment of the tissue to promote adhesion of circulating tumor cells. This review focuses on the interactions between tumor cells and immune cells recruited to the tumor microenvironment and examines the factors allowing these cells to promote each stage of metastasis.

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References

  1. Ruffell B, DeNardo DG, Affara NI, Coussens LM (2010) Lymphocytes in cancer development: polarization towards pro-tumor immunity. Cytokine Growth Factor Rev 21:3–10

    Article  PubMed  CAS  Google Scholar 

  2. Garcia-Lora A, Algarra I, Garrido F (2003) MHC class I antigens, immune surveillance, and tumor immune escape. J Cell Physiol 195:346–355

    Article  PubMed  CAS  Google Scholar 

  3. Bui JD, Schreiber RD (2007) Cancer immunosurveillance, immunoediting and inflammation: independent or interdependent processes? Curr Opin Immunol 19:203–208

    Article  PubMed  CAS  Google Scholar 

  4. de Visser KE, Eichten A, Coussens LM (2006) Paradoxical roles of the immune system during cancer development. Nat Rev Cancer 6:24–37

    Article  PubMed  CAS  Google Scholar 

  5. Ostrand-Rosenberg S (2008) Immune surveillance: a balance between protumor and antitumor immunity. Curr Opin Genet Dev 18:11–18

    Article  PubMed  CAS  Google Scholar 

  6. Galli SJ, Borregaard N, Wynn TA (2011) Phenotypic and functional plasticity of cells of innate immunity: macrophages, mast cells and neutrophils. Nat Immunol 12:1035–1044

    Article  PubMed  CAS  Google Scholar 

  7. Nakayamada S, Takahashi H, Kanno Y, O’Shea JJ (2012) Helper T cell diversity and plasticity. Curr Opin Immunol 24:297–302

    Article  PubMed  CAS  Google Scholar 

  8. Lanca T, Silva-Santos B (2012) The split nature of tumor-infiltrating leukocytes: implications for cancer surveillance and immunotherapy. Oncoimmunology 1:717–725

    Article  PubMed  Google Scholar 

  9. Joyce JA, Pollard JW (2009) Microenvironmental regulation of metastasis. Nat Rev Cancer 9:239–252

    Article  PubMed  CAS  Google Scholar 

  10. Thiery JP, Acloque H, Huang RY, Nieto MA (2009) Epithelial–mesenchymal transitions in development and disease. Cell 139:871–890

    Article  PubMed  CAS  Google Scholar 

  11. Lowe DB, Storkus WJ (2011) Chronic inflammation and immunologic-based constraints in malignant disease. Immunotherapy 3:1265–1274

    Article  PubMed  Google Scholar 

  12. Erez N, Coussens LM (2011) Leukocytes as paracrine regulators of metastasis and determinants of organ-specific colonization. Int J Cancer J Int Du Cancer 128:2536–2544

    Article  CAS  Google Scholar 

  13. Dvorak HF (1986) Tumors: wounds that do not heal. Similarities between tumor stroma generation and wound healing. N Engl J Med 315:1650–1659

    Article  PubMed  CAS  Google Scholar 

  14. Mantovani A, Allavena P, Sica A, Balkwill F (2008) Cancer-related inflammation. Nature 454:436–444

    Article  PubMed  CAS  Google Scholar 

  15. Waldner MJ, Neurath MF (2009) Colitis-associated cancer: the role of T cells in tumor development. Semin Immunopathol 31:249–256

    Article  PubMed  CAS  Google Scholar 

  16. Aggarwal BB, Vijayalekshmi RV, Sung B (2009) Targeting inflammatory pathways for prevention and therapy of cancer: short-term friend, long-term foe. Clin Cancer Res Off J Am Assoc Cancer Res 15:425–430

    Article  CAS  Google Scholar 

  17. Karin M (2006) Nuclear factor-kappaB in cancer development and progression. Nature 441:431–436

    Article  PubMed  CAS  Google Scholar 

  18. Wu S, Rhee KJ, Albesiano E, Rabizadeh S, Wu X, Yen HR, Huso DL, Brancati FL, Wick E, McAllister F et al (2009) A human colonic commensal promotes colon tumorigenesis via activation of T helper type 17T cell responses. Nat Med 15:1016–1022

    Article  PubMed  CAS  Google Scholar 

  19. Balkwill F, Mantovani A (2001) Inflammation and cancer: back to Virchow? Lancet 357:539–545

    Article  PubMed  CAS  Google Scholar 

  20. Grivennikov SI, Greten FR, Karin M (2010) Immunity, inflammation, and cancer. Cell 140:883–899

    Article  PubMed  CAS  Google Scholar 

  21. Soucek L, Lawlor ER, Soto D, Shchors K, Swigart LB, Evan GI (2007) Mast cells are required for angiogenesis and macroscopic expansion of Myc-induced pancreatic islet tumors. Nat Med 13:1211–1218

    Article  PubMed  CAS  Google Scholar 

  22. Sparmann A, Bar-Sagi D (2004) Ras-induced interleukin-8 expression plays a critical role in tumor growth and angiogenesis. Cancer Cell 6:447–458. doi:10.1016/j.ccr.2004.09.028

    Article  PubMed  CAS  Google Scholar 

  23. Vakkila J, Lotze MT (2004) Inflammation and necrosis promote tumour growth. Nat Rev Immunol 4:641–648

    Article  PubMed  CAS  Google Scholar 

  24. Rabinovich GA, Gabrilovich D, Sotomayor EM (2007) Immunosuppressive strategies that are mediated by tumor cells. Annu Rev Immunol 25:267–296

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  26. Ostrand-Rosenberg S (2010) Myeloid-derived suppressor cells: more mechanisms for inhibiting antitumor immunity. Cancer Immunol Immunother CII 59:1593–1600

    Article  Google Scholar 

  27. Pikarsky E, Porat RM, Stein I, Abramovitch R, Amit S, Kasem S, Gutkovich-Pyest E, Urieli-Shoval S, Galun E, Ben-Neriah Y (2004) NF-kappaB functions as a tumour promoter in inflammation-associated cancer. Nature 431:461–466

    Article  PubMed  CAS  Google Scholar 

  28. Wang T, Niu G, Kortylewski M, Burdelya L, Shain K, Zhang S, Bhattacharya R, Gabrilovich D, Heller R, Coppola D et al (2004) Regulation of the innate and adaptive immune responses by Stat-3 signaling in tumor cells. Nat Med 10:48–54

    Article  PubMed  CAS  Google Scholar 

  29. Kortylewski M, Kujawski M, Wang T, Wei S, Zhang S, Pilon-Thomas S, Niu G, Kay H, Mule J, Kerr WG et al (2005) Inhibiting Stat3 signaling in the hematopoietic system elicits multicomponent antitumor immunity. Nat Med 11:1314–1321

    Article  PubMed  CAS  Google Scholar 

  30. Olkhanud PB, Damdinsuren B, Bodogai M, Gress RE, Sen R, Wejksza K, Malchinkhuu E, Wersto RP, Biragyn A (2011) Tumor-evoked regulatory B cells promote breast cancer metastasis by converting resting CD4(+) T cells to T-regulatory cells. Cancer Res 71:3505–3515

    Article  PubMed  CAS  Google Scholar 

  31. Sica A, Porta C, Riboldi E, Locati M (2010) Convergent pathways of macrophage polarization: the role of B cells. Eur J Immunol 40:2131–2133

    Article  PubMed  CAS  Google Scholar 

  32. Harrell MI, Iritani BM, Ruddell A (2007) Tumor-induced sentinel lymph node lymphangiogenesis and increased lymph flow precede melanoma metastasis. Am J Pathol 170:774–786

    Article  PubMed  Google Scholar 

  33. Ruddell A, Harrell MI, Furuya M, Kirschbaum SB, Iritani BM (2011) B lymphocytes promote lymphogenous metastasis of lymphoma and melanoma. Neoplasia 13:748–757

    PubMed  CAS  Google Scholar 

  34. Bjordahl RL, Gapin L, Marrack P, Refaeli Y (2012) iNKT cells suppress the CD8+ T cell response to a murine Burkitt’s-like B cell lymphoma. PLoS One 7:e42635

    Article  PubMed  CAS  Google Scholar 

  35. Coussens LM, Werb Z (2002) Inflammation and cancer. Nature 420:860–867

    Article  PubMed  CAS  Google Scholar 

  36. Rius J, Guma M, Schachtrup C, Akassoglou K, Zinkernagel AS, Nizet V, Johnson RS, Haddad GG, Karin M (2008) NF-kappaB links innate immunity to the hypoxic response through transcriptional regulation of HIF-1alpha. Nature 453:807–811

    Article  PubMed  CAS  Google Scholar 

  37. Polyak K, Weinberg RA (2009) Transitions between epithelial and mesenchymal states: acquisition of malignant and stem cell traits. Nat Rev Cancer 9:265–273

    Article  PubMed  CAS  Google Scholar 

  38. Kalluri R (2009) EMT: when epithelial cells decide to become mesenchymal-like cells. J Clin Invest 119:1417–1419

    Article  PubMed  CAS  Google Scholar 

  39. Stockinger A, Eger A, Wolf J, Beug H, Foisner R (2001) E-cadherin regulates cell growth by modulating proliferation-dependent beta-catenin transcriptional activity. J Cell Biol 154:1185–1196

    Article  PubMed  CAS  Google Scholar 

  40. Kang Y, Massague J (2004) Epithelial–mesenchymal transitions: twist in development and metastasis. Cell 118:277–279

    Article  PubMed  CAS  Google Scholar 

  41. Zhou C, Liu J, Tang Y, Liang X (2012) Inflammation linking EMT and cancer stem cells. Oral Oncol 48:1068–1075

    Article  PubMed  CAS  Google Scholar 

  42. Chaffer CL, Weinberg RA (2011) A perspective on cancer cell metastasis. Science 331:1559–1564

    Article  PubMed  CAS  Google Scholar 

  43. Singh A, Settleman J (2010) EMT, cancer stem cells and drug resistance: an emerging axis of evil in the war on cancer. Oncogene 29:4741–4751

    Article  PubMed  CAS  Google Scholar 

  44. Lopez-Novoa JM, Nieto MA (2009) Inflammation and EMT: an alliance towards organ fibrosis and cancer progression. EMBO Mol Med 1:303–314

    Article  PubMed  CAS  Google Scholar 

  45. Scheel C, Eaton EN, Li SH, Chaffer CL, Reinhardt F, Kah KJ, Bell G, Guo W, Rubin J, Richardson AL et al (2011) Paracrine and autocrine signals induce and maintain mesenchymal and stem cell states in the breast. Cell 145:926–940

    Article  PubMed  CAS  Google Scholar 

  46. Oft M, Peli J, Rudaz C, Schwarz H, Beug H, Reichmann E (1996) TGF-beta1 and Ha-Ras collaborate in modulating the phenotypic plasticity and invasiveness of epithelial tumor cells. Genes Dev 10:2462–2477

    Article  PubMed  CAS  Google Scholar 

  47. Bates RC, Mercurio AM (2003) Tumor necrosis factor-alpha stimulates the epithelial-to-mesenchymal transition of human colonic organoids. Mol Biol Cell 14:1790–1800

    Article  PubMed  CAS  Google Scholar 

  48. Karhadkar SS, Bova GS, Abdallah N, Dhara S, Gardner D, Maitra A, Isaacs JT, Berman DM, Beachy PA (2004) Hedgehog signalling in prostate regeneration, neoplasia and metastasis. Nature 431:707–712

    Article  PubMed  CAS  Google Scholar 

  49. Ren G, Zhao X, Wang Y, Zhang X, Chen X, Xu C, Yuan ZR, Roberts AI, Zhang L, Zheng B et al (2012) CCR2-dependent recruitment of macrophages by tumor-educated mesenchymal stromal cells promotes tumor development and is mimicked by TNFalpha. Cell Stem Cell 11:812–824

    Google Scholar 

  50. Wu Y, Deng J, Rychahou PG, Qiu S, Evers BM, Zhou BP (2009) Stabilization of snail by NF-kappaB is required for inflammation-induced cell migration and invasion. Cancer Cell 15:416–428

    Article  PubMed  CAS  Google Scholar 

  51. Maier HJ, Schmidt-Strassburger U, Huber MA, Wiedemann EM, Beug H, Wirth T (2010) NF-kappaB promotes epithelial–mesenchymal transition, migration and invasion of pancreatic carcinoma cells. Cancer Lett 295:214–228

    Article  PubMed  CAS  Google Scholar 

  52. Zhou BP, Deng J, Xia W, Xu J, Li YM, Gunduz M, Hung MC (2004) Dual regulation of Snail by GSK-3beta-mediated phosphorylation in control of epithelial–mesenchymal transition. Nat Cell Biol 6:931–940

    Article  PubMed  CAS  Google Scholar 

  53. Cheng GZ, Zhang WZ, Sun M, Wang Q, Coppola D, Mansour M, Xu LM, Costanzo C, Cheng JQ, Wang LH (2008) Twist is transcriptionally induced by activation of STAT3 and mediates STAT3 oncogenic function. J Biol Chem 283:14665–14673

    Article  PubMed  CAS  Google Scholar 

  54. Yu H, Pardoll D, Jove R (2009) STATs in cancer inflammation and immunity: a leading role for STAT3. Nat Rev Cancer 9:798–809

    Article  PubMed  CAS  Google Scholar 

  55. Sullivan NJ, Sasser AK, Axel AE, Vesuna F, Raman V, Ramirez N, Oberyszyn TM, Hall BM (2009) Interleukin-6 induces an epithelial–mesenchymal transition phenotype in human breast cancer cells. Oncogene 28:2940–2947

    Article  PubMed  CAS  Google Scholar 

  56. Kudo-Saito C, Shirako H, Takeuchi T, Kawakami Y (2009) Cancer metastasis is accelerated through immunosuppression during Snail-induced EMT of cancer cells. Cancer Cell 15:195–206

    Article  PubMed  CAS  Google Scholar 

  57. Kudo-Saito C, Shirako H, Ohike M, Tsukamoto N, Kawakami Y (2012) CCL2 is critical for immunosuppression to promote cancer metastasis. Clin Exp Metastasis. doi:10.1007/s10585-012-9545-6

  58. Bachelder RE, Yoon SO, Franci C, de Herreros AG, Mercurio AM (2005) Glycogen synthase kinase-3 is an endogenous inhibitor of Snail transcription: implications for the epithelial–mesenchymal transition. J Cell Biol 168:29–33

    Article  PubMed  CAS  Google Scholar 

  59. Chua HL, Bhat-Nakshatri P, Clare SE, Morimiya A, Badve S, Nakshatri H (2007) NF-kappaB represses E-cadherin expression and enhances epithelial to mesenchymal transition of mammary epithelial cells: potential involvement of ZEB-1 and ZEB-2. Oncogene 26:711–724

    Article  PubMed  CAS  Google Scholar 

  60. Barbera MJ, Puig I, Dominguez D, Julien-Grille S, Guaita-Esteruelas S, Peiro S, Baulida J, Franci C, Dedhar S, Larue L et al (2004) Regulation of Snail transcription during epithelial to mesenchymal transition of tumor cells. Oncogene 23:7345–7354

    Article  PubMed  CAS  Google Scholar 

  61. Julien S, Puig I, Caretti E, Bonaventure J, Nelles L, van Roy F, Dargemont C, de Herreros AG, Bellacosa A, Larue L (2007) Activation of NF-kappaB by Akt upregulates Snail expression and induces epithelium mesenchyme transition. Oncogene 26:7445–7456

    Article  PubMed  CAS  Google Scholar 

  62. Lin K, Baritaki S, Militello L, Malaponte G, Bevelacqua Y, Bonavida B (2010) The role of B-RAF mutations in melanoma and the induction of EMT via dysregulation of the NF-kappaB/Snail/RKIP/PTEN circuit. Genes & Cancer 1:409–420

    Article  CAS  Google Scholar 

  63. Baritaki S, Chapman A, Yeung K, Spandidos DA, Palladino M, Bonavida B (2009) Inhibition of epithelial to mesenchymal transition in metastatic prostate cancer cells by the novel proteasome inhibitor, NPI-0052: pivotal roles of Snail repression and RKIP induction. Oncogene 28:3573–3585

    Article  PubMed  CAS  Google Scholar 

  64. Li QQ, Chen ZQ, Cao XX, Xu JD, Xu JW, Chen YY, Wang WJ, Chen Q, Tang F, Liu XP et al (2011) Involvement of NF-kappaB/miR-448 regulatory feedback loop in chemotherapy-induced epithelial–mesenchymal transition of breast cancer cells. Cell Death Differ 18:16–25

    Article  PubMed  CAS  Google Scholar 

  65. Blackwell TS, Christman JW (1997) The role of nuclear factor-kappa B in cytokine gene regulation. Am J Respir Cell Mol Biol 17:3–9

    Article  PubMed  CAS  Google Scholar 

  66. Massague J (2008) TGFbeta in cancer. Cell 134:215–230

    Article  PubMed  CAS  Google Scholar 

  67. Fuxe J, Karlsson MC (2012) TGF-beta-induced epithelial–mesenchymal transition: a link between cancer and inflammation. Semin Cancer Biol 22:455–461

    Article  PubMed  CAS  Google Scholar 

  68. Labelle M, Begum S, Hynes RO (2011) Direct signaling between platelets and cancer cells induces an epithelial–mesenchymal-like transition and promotes metastasis. Cancer Cell 20:576–590

    Article  PubMed  CAS  Google Scholar 

  69. Yu H, Kortylewski M, Pardoll D (2007) Crosstalk between cancer and immune cells: role of STAT3 in the tumour microenvironment. Nat Rev Immunol 7:41–51

    Article  PubMed  CAS  Google Scholar 

  70. Sullivan DE, Ferris M, Nguyen H, Abboud E, Brody AR (2009) TNF-alpha induces TGF-beta1 expression in lung fibroblasts at the transcriptional level via AP-1 activation. J Cell Mol Med 13:1866–1876

    Article  PubMed  Google Scholar 

  71. Adorno M, Cordenonsi M, Montagner M, Dupont S, Wong C, Hann B, Solari A, Bobisse S, Rondina MB, Guzzardo V et al (2009) A mutant–p53/Smad complex opposes p63 to empower TGFbeta-induced metastasis. Cell 137:87–98

    Article  PubMed  CAS  Google Scholar 

  72. Peinado H, Quintanilla M, Cano A (2003) Transforming growth factor beta-1 induces snail transcription factor in epithelial cell lines: mechanisms for epithelial mesenchymal transitions. J Biol Chem 278:21113–21123

    Article  PubMed  CAS  Google Scholar 

  73. de Graauw M, van Miltenburg MH, Schmidt MK, Pont C, Lalai R, Kartopawiro J, Pardali E, Le Devedec SE, Smit VT, van der Wal A et al (2010) Annexin A1 regulates TGF-beta signaling and promotes metastasis formation of basal-like breast cancer cells. Proc Natl Acad Sci USA 107:6340–6345

    Article  PubMed  Google Scholar 

  74. Papageorgis P, Lambert AW, Ozturk S, Gao F, Pan H, Manne U, Alekseyev YO, Thiagalingam A, Abdolmaleky HM, Lenburg M et al (2010) Smad signaling is required to maintain epigenetic silencing during breast cancer progression. Cancer Res 70:968–978

    Article  PubMed  CAS  Google Scholar 

  75. Bakin AV, Rinehart C, Tomlinson AK, Arteaga CL (2002) p38 mitogen-activated protein kinase is required for TGFbeta-mediated fibroblastic transdifferentiation and cell migration. J Cell Sci 115:3193–3206

    PubMed  CAS  Google Scholar 

  76. Perlman R, Schiemann WP, Brooks MW, Lodish HF, Weinberg RA (2001) TGF-beta-induced apoptosis is mediated by the adapter protein Daxx that facilitates JNK activation. Nat Cell Biol 3:708–714

    Article  PubMed  CAS  Google Scholar 

  77. Zavadil J, Bitzer M, Liang D, Yang YC, Massimi A, Kneitz S, Piek E, Bottinger EP (2001) Genetic programs of epithelial cell plasticity directed by transforming growth factor-beta. Proc Natl Acad Sci USA 98:6686–6691

    Article  PubMed  CAS  Google Scholar 

  78. Arsura M, Panta GR, Bilyeu JD, Cavin LG, Sovak MA, Oliver AA, Factor V, Heuchel R, Mercurio F, Thorgeirsson SS et al (2003) Transient activation of NF-kappaB through a TAK1/IKK kinase pathway by TGF-beta1 inhibits AP-1/SMAD signaling and apoptosis: implications in liver tumor formation. Oncogene 22:412–425

    Article  PubMed  CAS  Google Scholar 

  79. Chaudhury A, Hussey GS, Ray PS, Jin G, Fox PL, Howe PH (2010) TGF-beta-mediated phosphorylation of hnRNP E1 induces EMT via transcript-selective translational induction of Dab2 and ILEI. NatureCell Biology 12:286–293

    CAS  Google Scholar 

  80. Neil JR, Schiemann WP (2008) Altered TAB1:I kappaB kinase interaction promotes transforming growth factor beta-mediated nuclear factor-kappaB activation during breast cancer progression. Cancer Res 68:1462–1470

    Article  PubMed  CAS  Google Scholar 

  81. Park JI, Lee MG, Cho K, Park BJ, Chae KS, Byun DS, Ryu BK, Park YK, Chi SG (2003) Transforming growth factor-beta1 activates interleukin-6 expression in prostate cancer cells through the synergistic collaboration of the Smad2, p38-NF-kappaB, JNK, and Ras signaling pathways. Oncogene 22:4314–4332

    Article  PubMed  CAS  Google Scholar 

  82. Moreno-Bueno G, Portillo F, Cano A (2008) Transcriptional regulation of cell polarity in EMT and cancer. Oncogene 27:6958–6969

    Article  PubMed  CAS  Google Scholar 

  83. Rajasekaran SA, Huynh TP, Wolle DG, Espineda CE, Inge LJ, Skay A, Lassman C, Nicholas SB, Harper JF, Reeves AE et al (2010) Na, K-ATPase subunits as markers for epithelial–mesenchymal transition in cancer and fibrosis. Mol Cancer Ther 9:1515–1524

    Article  PubMed  CAS  Google Scholar 

  84. Peinado H, Olmeda D, Cano A (2007) Snail, Zeb and bHLH factors in tumour progression: an alliance against the epithelial phenotype? Nat Rev Cancer 7:415–428

    Article  PubMed  CAS  Google Scholar 

  85. Natsuizaka M, Ohashi S, Wong GS, Ahmadi A, Kalman RA, Budo D, Klein-Szanto AJ, Herlyn M, Diehl JA, Nakagawa H (2010) Insulin-like growth factor-binding protein-3 promotes transforming growth factor-{beta}1-mediated epithelial-to-mesenchymal transition and motility in transformed human esophageal cells. Carcinogenesis 31:1344–1353

    Article  PubMed  CAS  Google Scholar 

  86. Kong B, Michalski CW, Hong X, Valkovskaya N, Rieder S, Abiatari I, Streit S, Erkan M, Esposito I, Friess H et al (2010) AZGP1 is a tumor suppressor in pancreatic cancer inducing mesenchymal-to-epithelial transdifferentiation by inhibiting TGF-beta-mediated ERK signaling. Oncogene 29:5146–5158

    Article  PubMed  CAS  Google Scholar 

  87. Micalizzi DS, Wang CA, Farabaugh SM, Schiemann WP, Ford HL (2010) Homeoprotein Six1 increases TGF-beta type I receptor and converts TGF-beta signaling from suppressive to supportive for tumor growth. Cancer Res 70:10371–10380

    Article  PubMed  CAS  Google Scholar 

  88. Braun J, Hoang-Vu C, Dralle H, Huttelmaier S (2010) Downregulation of microRNAs directs the EMT and invasive potential of anaplastic thyroid carcinomas. Oncogene 29:4237–4244

    Article  PubMed  CAS  Google Scholar 

  89. Korpal M, Lee ES, Hu G, Kang Y (2008) The miR-200 family inhibits epithelial–mesenchymal transition and cancer cell migration by direct targeting of E-cadherin transcriptional repressors ZEB1 and ZEB2. J Biol Chem 283:14910–14914

    Article  PubMed  CAS  Google Scholar 

  90. Gregory PA, Bert AG, Paterson EL, Barry SC, Tsykin A, Farshid G, Vadas MA, Khew-Goodall Y, Goodall GJ (2008) The miR-200 family and miR-205 regulate epithelial to mesenchymal transition by targeting ZEB1 and SIP1. Nat Cell Biol 10:593–601

    Article  PubMed  CAS  Google Scholar 

  91. Gregory PA, Bracken CP, Smith E, Bert AG, Wright JA, Roslan S, Morris M, Wyatt L, Farshid G, Lim YY et al (2011) An autocrine TGF-beta/ZEB/miR-200 signaling network regulates establishment and maintenance of epithelial–mesenchymal transition. Mol Biol Cell 22:1686–1698

    Article  PubMed  CAS  Google Scholar 

  92. Burk U, Schubert J, Wellner U, Schmalhofer O, Vincan E, Spaderna S, Brabletz T (2008) A reciprocal repression between ZEB1 and members of the miR-200 family promotes EMT and invasion in cancer cells. EMBO Rep 9:582–589

    Article  PubMed  CAS  Google Scholar 

  93. Park SM, Gaur AB, Lengyel E, Peter ME (2008) The miR-200 family determines the epithelial phenotype of cancer cells by targeting the E-cadherin repressors ZEB1 and ZEB2. Genes Dev 22:894–907

    Article  PubMed  CAS  Google Scholar 

  94. Zhu S, Si ML, Wu H, Mo YY (2007) MicroRNA-21 targets the tumor suppressor gene tropomyosin 1 (TPM1). J Biol Chem 282:14328–14336

    Article  PubMed  CAS  Google Scholar 

  95. Kong W, Yang H, He L, Zhao JJ, Coppola D, Dalton WS, Cheng JQ (2008) MicroRNA-155 is regulated by the transforming growth factor beta/Smad pathway and contributes to epithelial cell plasticity by targeting RhoA. Mol Cell Biol 28:6773–6784

    Article  PubMed  CAS  Google Scholar 

  96. Gocheva V, Joyce JA (2007) Cysteine cathepsins and the cutting edge of cancer invasion. Cell Cycle 6:60–64

    Article  PubMed  CAS  Google Scholar 

  97. Berdowska I (2004) Cysteine proteases as disease markers. Clin Chim Acta Int J Clin Chem 342:41–69

    Article  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  99. Orimo A, Gupta PB, Sgroi DC, Arenzana-Seisdedos F, Delaunay T, Naeem R, Carey VJ, Richardson AL, Weinberg RA (2005) Stromal fibroblasts present in invasive human breast carcinomas promote tumor growth and angiogenesis through elevated SDF-1/CXCL12 secretion. Cell 121:335–348

    Article  PubMed  CAS  Google Scholar 

  100. Coussens LM, Raymond WW, Bergers G, Laig-Webster M, Behrendtsen O, Werb Z, Caughey GH, Hanahan D (1999) Inflammatory mast cells up-regulate angiogenesis during squamous epithelial carcinogenesis. Genes Dev 13:1382–1397

    Article  PubMed  CAS  Google Scholar 

  101. Coussens LM, Tinkle CL, Hanahan D, Werb Z (2000) MMP-9 supplied by bone marrow-derived cells contributes to skin carcinogenesis. Cell 103:481–490

    Article  PubMed  CAS  Google Scholar 

  102. Pahler JC, Tazzyman S, Erez N, Chen YY, Murdoch C, Nozawa H, Lewis CE, Hanahan D (2008) Plasticity in tumor-promoting inflammation: impairment of macrophage recruitment evokes a compensatory neutrophil response. Neoplasia 10:329–340

    PubMed  CAS  Google Scholar 

  103. Xiang M, Gu Y, Zhao F, Lu H, Chen S, Yin L (2010) Mast cell tryptase promotes breast cancer migration and invasion. Oncol Rep 23:615–619

    PubMed  CAS  Google Scholar 

  104. Condeelis J, Pollard JW (2006) Macrophages: obligate partners for tumor cell migration, invasion, and metastasis. Cell 124:263–266

    Article  PubMed  CAS  Google Scholar 

  105. Vasiljeva O, Papazoglou A, Kruger A, Brodoefel H, Korovin M, Deussing J, Augustin N, Nielsen BS, Almholt K, Bogyo M et al (2006) Tumor cell-derived and macrophage-derived cathepsin B promotes progression and lung metastasis of mammary cancer. Cancer Res 66:5242–5250

    Article  PubMed  CAS  Google Scholar 

  106. Mohamed MM, Cavallo-Medved D, Rudy D, Anbalagan A, Moin K, Sloane BF (2010) Interleukin-6 increases expression and secretion of cathepsin B by breast tumor-associated monocytes. Cell Physiol Biochem Int J Exp Cell Physiol Biochem Pharmacol 25:315–324

    Article  CAS  Google Scholar 

  107. Li Y, Yang J, Dai C, Wu C, Liu Y (2003) Role for integrin-linked kinase in mediating tubular epithelial to mesenchymal transition and renal interstitial fibrogenesis. J Clin Invest 112:503–516

    PubMed  CAS  Google Scholar 

  108. Strutz F, Zeisberg M, Ziyadeh FN, Yang CQ, Kalluri R, Muller GA, Neilson EG (2002) Role of basic fibroblast growth factor-2 in epithelial–mesenchymal transformation. Kidney Int 61:1714–1728

    Article  PubMed  CAS  Google Scholar 

  109. Kitamura T, Kometani K, Hashida H, Matsunaga A, Miyoshi H, Hosogi H, Aoki M, Oshima M, Hattori M, Takabayashi A et al (2007) SMAD4-deficient intestinal tumors recruit CCR1+ myeloid cells that promote invasion. Nat Genet 39:467–475

    Article  PubMed  CAS  Google Scholar 

  110. Gocheva V, Wang HW, Gadea BB, Shree T, Hunter KE, Garfall AL, Berman T, Joyce JA (2010) IL-4 induces cathepsin protease activity in tumor-associated macrophages to promote cancer growth and invasion. Genes Dev 24:241–255

    Article  PubMed  CAS  Google Scholar 

  111. Solinas G, Schiarea S, Liguori M, Fabbri M, Pesce S, Zammataro L, Pasqualini F, Nebuloni M, Chiabrando C, Mantovani A et al (2010) Tumor-conditioned macrophages secrete migration-stimulating factor: a new marker for M2-polarization, influencing tumor cell motility. J Immunol 185:642–652

    Article  PubMed  CAS  Google Scholar 

  112. Luo JL, Tan W, Ricono JM, Korchynskyi O, Zhang M, Gonias SL, Cheresh DA, Karin M (2007) Nuclear cytokine-activated IKKalpha controls prostate cancer metastasis by repressing Maspin. Nature 446:690–694

    Article  PubMed  CAS  Google Scholar 

  113. Sevenich L, Werner F, Gajda M, Schurigt U, Sieber C, Muller S, Follo M, Peters C, Reinheckel T (2011) Transgenic expression of human cathepsin B promotes progression and metastasis of polyoma-middle-T-induced breast cancer in mice. Oncogene 30:54–64

    Article  PubMed  CAS  Google Scholar 

  114. Kawakubo T, Okamoto K, Iwata J, Shin M, Okamoto Y, Yasukochi A, Nakayama KI, Kadowaki T, Tsukuba T, Yamamoto K (2007) Cathepsin E prevents tumor growth and metastasis by catalyzing the proteolytic release of soluble TRAIL from tumor cell surface. Cancer Res 67:10869–10878

    Article  PubMed  CAS  Google Scholar 

  115. Wang L, Yi T, Kortylewski M, Pardoll DM, Zeng D, Yu H (2009) IL-17 can promote tumor growth through an IL-6-Stat3 signaling pathway. J Exp Med 206:1457–1464

    Article  PubMed  CAS  Google Scholar 

  116. DeNardo DG, Barreto JB, Andreu P, Vasquez L, Tawfik D, Kolhatkar N, Coussens LM (2009) CD4(+) T cells regulate pulmonary metastasis of mammary carcinomas by enhancing protumor properties of macrophages. Cancer Cell 16:91–102

    Article  PubMed  CAS  Google Scholar 

  117. Kim S, Takahashi H, Lin WW, Descargues P, Grivennikov S, Kim Y, Luo JL, Karin M (2009) Carcinoma-produced factors activate myeloid cells through TLR2 to stimulate metastasis. Nature 457:102–106

    Article  PubMed  CAS  Google Scholar 

  118. Nguyen DX, Bos PD, Massague J (2009) Metastasis: from dissemination to organ-specific colonization. Nat Rev Cancer 9:274–284

    Article  PubMed  CAS  Google Scholar 

  119. Gassmann P, Haier J (2008) The tumor cell–host organ interface in the early onset of metastatic organ colonisation. Clin Exp Metastasis 25:171–181

    Article  PubMed  CAS  Google Scholar 

  120. Luo JL, Maeda S, Hsu LC, Yagita H, Karin M (2004) Inhibition of NF-kappaB in cancer cells converts inflammation-induced tumor growth mediated by TNFalpha to TRAIL-mediated tumor regression. Cancer Cell 6:297–305

    Article  PubMed  CAS  Google Scholar 

  121. Pawelek JM, Chakraborty AK (2008) Fusion of tumour cells with bone marrow-derived cells: a unifying explanation for metastasis. Nat Rev Cancer 8:377–386

    Article  PubMed  CAS  Google Scholar 

  122. Camerer E, Qazi AA, Duong DN, Cornelissen I, Advincula R, Coughlin SR (2004) Platelets, protease-activated receptors, and fibrinogen in hematogenous metastasis. Blood 104:397–401

    Article  PubMed  CAS  Google Scholar 

  123. Im JH, Fu W, Wang H, Bhatia SK, Hammer DA, Kowalska MA, Muschel RJ (2004) Coagulation facilitates tumor cell spreading in the pulmonary vasculature during early metastatic colony formation. Cancer Res 64:8613–8619

    Article  PubMed  CAS  Google Scholar 

  124. Palumbo JS, Talmage KE, Massari JV, La Jeunesse CM, Flick MJ, Kombrinck KW, Hu Z, Barney KA, Degen JL (2007) Tumor cell-associated tissue factor and circulating hemostatic factors cooperate to increase metastatic potential through natural killer cell-dependent and-independent mechanisms. Blood 110:133–141

    Article  PubMed  CAS  Google Scholar 

  125. Jurasz P, Alonso-Escolano D, Radomski MW (2004) Platelet–cancer interactions: mechanisms and pharmacology of tumour cell-induced platelet aggregation. Br J Pharmacol 143:819–826

    Article  PubMed  CAS  Google Scholar 

  126. Nash GF, Turner LF, Scully MF, Kakkar AK (2002) Platelets and cancer. Lancet Oncol 3:425–430

    Article  PubMed  CAS  Google Scholar 

  127. Bonecchi R, Galliera E, Borroni EM, Corsi MM, Locati M, Mantovani A (2009) Chemokines and chemokine receptors: an overview. Front Biosci J Virtual Libr 14:540–551

    Article  CAS  Google Scholar 

  128. McDonald B, Spicer J, Giannais B, Fallavollita L, Brodt P, Ferri LE (2009) Systemic inflammation increases cancer cell adhesion to hepatic sinusoids by neutrophil mediated mechanisms. Int J Cancer J Int du Cancer 125:1298–1305

    Article  CAS  Google Scholar 

  129. Slattery MJ, Dong C (2003) Neutrophils influence melanoma adhesion and migration under flow conditions. Int J Cancer J International du Cancer 106:713–722

    Article  CAS  Google Scholar 

  130. Slattery MJ, Liang S, Dong C (2005) Distinct role of hydrodynamic shear in leukocyte-facilitated tumor cell extravasation. Am J Physiol Cell Physiol 288:C831–C839

    Article  PubMed  CAS  Google Scholar 

  131. Spicer JD, McDonald B, Cools-Lartigue JJ, Chow SC, Giannias B, Kubes P, Ferri LE (2012) Neutrophils promote liver metastasis via Mac-1-mediated interactions with circulating tumor cells. Cancer Res 72:3919–3927

    Article  PubMed  CAS  Google Scholar 

  132. Oppenheimer SB (2006) Cellular basis of cancer metastasis: a review of fundamentals and new advances. Acta Histochem 108:327–334

    Article  PubMed  CAS  Google Scholar 

  133. Wu TC (2007) The role of vascular cell adhesion molecule-1 in tumor immune evasion. Cancer Res 67:6003–6006

    Article  PubMed  CAS  Google Scholar 

  134. Lin KY, Lu D, Hung CF, Peng S, Huang L, Jie C, Murillo F, Rowley J, Tsai YC, He L et al (2007) Ectopic expression of vascular cell adhesion molecule-1 as a new mechanism for tumor immune evasion. Cancer Res 67:1832–1841

    Article  PubMed  CAS  Google Scholar 

  135. Chen Q, Zhang XH, Massague J (2011) Macrophage binding to receptor VCAM-1 transmits survival signals in breast cancer cells that invade the lungs. Cancer Cell 20:538–549

    Article  PubMed  CAS  Google Scholar 

  136. Lu X, Mu E, Wei Y, Riethdorf S, Yang Q, Yuan M, Yan J, Hua Y, Tiede BJ, Haffty BG et al (2011) VCAM-1 promotes osteolytic expansion of indolent bone micrometastasis of breast cancer by engaging alpha4beta1-positive osteoclast progenitors. Cancer Cell 20:701–714

    Article  PubMed  CAS  Google Scholar 

  137. Kochetkova M, Kumar S, McColl SR (2009) Chemokine receptors CXCR4 and CCR7 promote metastasis by preventing anoikis in cancer cells. Cell Death Differ 16:664–673

    Article  PubMed  CAS  Google Scholar 

  138. Das S, Skobe M (2008) Lymphatic vessel activation in cancer. Ann N Y Acad Sci 1131:235–241

    Article  PubMed  CAS  Google Scholar 

  139. Saharinen P, Tammela T, Karkkainen MJ, Alitalo K (2004) Lymphatic vasculature: development, molecular regulation and role in tumor metastasis and inflammation. Trends Immunol 25:387–395

    Article  PubMed  CAS  Google Scholar 

  140. Kaplan RN, Psaila B, Lyden D (2006) Bone marrow cells in the ‘pre-metastatic niche’: within bone and beyond. Cancer Metastasis Rev 25:521–529

    Article  PubMed  Google Scholar 

  141. Kaplan RN, Riba RD, Zacharoulis S, Bramley AH, Vincent L, Costa C, MacDonald DD, Jin DK, Shido K, Kerns SA et al (2005) VEGFR1-positive haematopoietic bone marrow progenitors initiate the pre-metastatic niche. Nature 438:820–827

    Article  PubMed  CAS  Google Scholar 

  142. Yan HH, Pickup M, Pang Y, Gorska AE, Li Z, Chytil A, Geng Y, Gray JW, Moses HL, Yang L (2010) Gr-1+CD11b+ myeloid cells tip the balance of immune protection to tumor promotion in the premetastatic lung. Cancer Res 70:6139–6149

    Article  PubMed  CAS  Google Scholar 

  143. Olkhanud PB, Baatar D, Bodogai M, Hakim F, Gress R, Anderson RL, Deng J, Xu M, Briest S, Biragyn A (2009) Breast cancer lung metastasis requires expression of chemokine receptor CCR4 and regulatory T cells. Cancer Res 69:5996–6004

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  145. Hiratsuka S, Watanabe A, Sakurai Y, Akashi-Takamura S, Ishibashi S, Miyake K, Shibuya M, Akira S, Aburatani H, Maru Y (2008) The S100A8-serum amyloid A3-TLR4 paracrine cascade establishes a pre-metastatic phase. Nat Cell Biol 10:1349–1355

    Article  PubMed  CAS  Google Scholar 

  146. Erler JT, Bennewith KL, Nicolau M, Dornhofer N, Kong C, Le QT, Chi JT, Jeffrey SS, Giaccia AJ (2006) Lysyl oxidase is essential for hypoxia-induced metastasis. Nature 440:1222–1226

    Article  PubMed  CAS  Google Scholar 

  147. Finger EC, Giaccia AJ (2010) Hypoxia, inflammation, and the tumor microenvironment in metastatic disease. Cancer Metastasis Rev 29:285–293

    Article  PubMed  CAS  Google Scholar 

  148. Li YM, Pan Y, Wei Y, Cheng X, Zhou BP, Tan M, Zhou X, Xia W, Hortobagyi GN, Yu D et al (2004) Upregulation of CXCR4 is essential for HER2-mediated tumor metastasis. Cancer Cell 6:459–469

    Article  PubMed  CAS  Google Scholar 

  149. Marchesi F, Piemonti L, Fedele G, Destro A, Roncalli M, Albarello L, Doglioni C, Anselmo A, Doni A, Bianchi P et al (2008) The chemokine receptor CX3CR1 is involved in the neural tropism and malignant behavior of pancreatic ductal adenocarcinoma. Cancer Res 68:9060–9069

    Article  PubMed  CAS  Google Scholar 

  150. Psaila B, Kaplan RN, Port ER, Lyden D (2006) Priming the ‘soil’ for breast cancer metastasis: the pre-metastatic niche. Breast Dis 26:65–74

    PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  152. Rucci N, Sanita P, Angelucci A (2011) Roles of metalloproteases in metastatic niche. Curr Mol Med 11:609–622

    Article  PubMed  CAS  Google Scholar 

  153. Jin DK, Shido K, Kopp HG, Petit I, Shmelkov SV, Young LM, Hooper AT, Amano H, Avecilla ST, Heissig B et al (2006) Cytokine-mediated deployment of SDF-1 induces revascularization through recruitment of CXCR4+ hemangiocytes. Nat Med 12:557–567

    Article  PubMed  CAS  Google Scholar 

  154. Mendoza L, Valcarcel M, Carrascal T, Egilegor E, Salado C, Sim BK, Vidal-Vanaclocha F (2004) Inhibition of cytokine-induced microvascular arrest of tumor cells by recombinant endostatin prevents experimental hepatic melanoma metastasis. Cancer Res 64:304–310

    Article  PubMed  CAS  Google Scholar 

  155. Vidal-Vanaclocha F (2008) The prometastatic microenvironment of the liver. Cancer microenviron Off J Int Cancer Microenviron Soc 1:113–129

    Article  CAS  Google Scholar 

  156. Brown KS, Blair D, Reid SD, Nicholson EK, Harnett MM (2004) FcgammaRIIb-mediated negative regulation of BCR signalling is associated with the recruitment of the MAPkinase-phosphatase, Pac-1, and the 3′-inositol phosphatase, PTEN. Cell Signal 16:71–80

    Article  PubMed  CAS  Google Scholar 

  157. Cohen-Solal JF, Cassard L, Fournier EM, Loncar SM, Fridman WH, Sautes-Fridman C (2010) Metastatic melanomas express inhibitory low affinity fc gamma receptor and escape humoral immunity. Dermatol res pract 2010:657406

    PubMed  Google Scholar 

  158. Lu X, Kang Y (2009) 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

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  160. Ara T, Declerck YA (2010) Interleukin-6 in bone metastasis and cancer progression. Eur J Cancer 46:1223–1231

    Article  PubMed  CAS  Google Scholar 

  161. Park BK, Zhang H, Zeng Q, Dai J, Keller ET, Giordano T, Gu K, Shah V, Pei L, Zarbo RJ et al (2007) NF-kappaB in breast cancer cells promotes osteolytic bone metastasis by inducing osteoclastogenesis via GM-CSF. Nat Med 13:62–69

    Article  PubMed  CAS  Google Scholar 

  162. Fitzgerald DP, Palmieri D, Hua E, Hargrave E, Herring JM, Qian Y, Vega-Valle E, Weil RJ, Stark AM, Vortmeyer AO et al (2008) Reactive glia are recruited by highly proliferative brain metastases of breast cancer and promote tumor cell colonization. Clin Exp Metastasis 25:799–810

    Article  PubMed  Google Scholar 

  163. Husemann Y, Geigl JB, Schubert F, Musiani P, Meyer M, Burghart E, Forni G, Eils R, Fehm T, Riethmuller G et al (2008) Systemic spread is an early step in breast cancer. Cancer Cell 13:58–68

    Article  PubMed  CAS  Google Scholar 

  164. Klein CA (2009) Parallel progression of primary tumours and metastases. Nat Rev Cancer 9:302–312

    Article  PubMed  CAS  Google Scholar 

  165. Sethi N, Kang Y (2011) Unravelling the complexity of metastasis—molecular understanding and targeted therapies. Nat Rev Cancer 11:735–748

    Article  PubMed  CAS  Google Scholar 

  166. Koh BI, Kang Y (2012) The pro-metastatic role of bone marrow-derived cells: a focus on MSCs and regulatory T cells. EMBO Rep 13:412–422

    Article  PubMed  CAS  Google Scholar 

  167. Tlsty TD, Coussens LM (2006) Tumor stroma and regulation of cancer development. Annu Rev Pathol 1:119–150

    Article  PubMed  CAS  Google Scholar 

  168. Fordyce CA, Patten KT, Fessenden TB, Defilippis R, Hwang ES, Zhao J, Tlsty TD (2012) Cell-extrinsic consequences of epithelial stress: activation of protumorigenic tissue phenotypes: BCR. Breast Cancer Res 14:R155

    Article  PubMed  CAS  Google Scholar 

  169. Liao D, Luo Y, Markowitz D, Xiang R, Reisfeld RA (2009) Cancer associated fibroblasts promote tumor growth and metastasis by modulating the tumor immune microenvironment in a 4T1 murine breast cancer model. PLoS One 4:e7965

    Article  PubMed  CAS  Google Scholar 

  170. Stagg J (2008) Mesenchymal stem cells in cancer. Stem Cell Rev 4:119–124

    Article  PubMed  Google Scholar 

  171. Dwyer RM, Potter-Beirne SM, Harrington KA, Lowery AJ, Hennessy E, Murphy JM, Barry FP, O’Brien T, Kerin MJ (2007) Monocyte chemotactic protein-1 secreted by primary breast tumors stimulates migration of mesenchymal stem cells. Clin cancer res off J Am Assoc Cancer Res 13:5020–5027

    Article  CAS  Google Scholar 

  172. Klopp AH, Gupta A, Spaeth E, Andreeff M, Marini F 3rd (2011) Concise review: dissecting a discrepancy in the literature: do mesenchymal stem cells support or suppress tumor growth? Stem Cells 29:11–19

    Article  PubMed  CAS  Google Scholar 

  173. Oh JY, Kim MK, Shin MS, Lee HJ, Ko JH, Wee WR, Lee JH (2008) The anti-inflammatory and anti-angiogenic role of mesenchymal stem cells in corneal wound healing following chemical injury. Stem Cells 26:1047–1055

    Article  PubMed  CAS  Google Scholar 

  174. Sacchetti B, Funari A, Michienzi S, Di Cesare S, Piersanti S, Saggio I, Tagliafico E, Ferrari S, Robey PG, Riminucci M et al (2007) Self-renewing osteoprogenitors in bone marrow sinusoids can organize a hematopoietic microenvironment. Cell 131:324–336

    Article  PubMed  CAS  Google Scholar 

  175. Beckermann BM, Kallifatidis G, Groth A, Frommhold D, Apel A, Mattern J, Salnikov AV, Moldenhauer G, Wagner W, Diehlmann A et al (2008) VEGF expression by mesenchymal stem cells contributes to angiogenesis in pancreatic carcinoma. Br J Cancer 99:622–631

    Article  PubMed  CAS  Google Scholar 

  176. Karnoub AE, Dash AB, Vo AP, Sullivan A, Brooks MW, Bell GW, Richardson AL, Polyak K, Tubo R, Weinberg RA (2007) Mesenchymal stem cells within tumour stroma promote breast cancer metastasis. Nature 449:557–563

    Article  PubMed  CAS  Google Scholar 

  177. Goldstein RH, Reagan MR, Anderson K, Kaplan DL, Rosenblatt M (2010) Human bone marrow-derived MSCs can home to orthotopic breast cancer tumors and promote bone metastasis. Cancer Res 70:10044–10050

    Article  PubMed  CAS  Google Scholar 

  178. Dunn L, Demichele A (2009) Genomic predictors of outcome and treatment response in breast cancer. Mol Diagn Ther 13:73–90

    Article  PubMed  CAS  Google Scholar 

  179. Kolls JK, Linden A (2004) Interleukin-17 family members and inflammation. Immunity 21:467–476

    Article  PubMed  CAS  Google Scholar 

  180. Weaver CT, Hatton RD, Mangan PR, Harrington LE (2007) IL-17 family cytokines and the expanding diversity of effector T cell lineages. Annu Rev Immunol 25:821–852

    Article  PubMed  CAS  Google Scholar 

  181. Numasaki M, Fukushi J, Ono M, Narula SK, Zavodny PJ, Kudo T, Robbins PD, Tahara H, Lotze MT (2003) Interleukin-17 promotes angiogenesis and tumor growth. Blood 101:2620–2627

    Article  PubMed  CAS  Google Scholar 

  182. Numasaki M, Lotze MT, Sasaki H (2004) Interleukin-17 augments tumor necrosis factor-alpha-induced elaboration of proangiogenic factors from fibroblasts. Immunol Lett 93:39–43

    Article  PubMed  CAS  Google Scholar 

  183. Takahashi H, Numasaki M, Lotze MT, Sasaki H (2005) Interleukin-17 enhances bFGF-, HGF- and VEGF-induced growth of vascular endothelial cells. Immunol Lett 98:189–193

    Article  PubMed  CAS  Google Scholar 

  184. Letuve S, Lajoie-Kadoch S, Audusseau S, Rothenberg ME, Fiset PO, Ludwig MS, Hamid Q (2006) IL-17E upregulates the expression of proinflammatory cytokines in lung fibroblasts. J Allergy Clin Immunol 117:590–596

    Article  PubMed  CAS  Google Scholar 

  185. Iida T, Iwahashi M, Katsuda M, Ishida K, Nakamori M, Nakamura M, Naka T, Ojima T, Ueda K, Hayata K et al (2011) Tumor-infiltrating CD4+ Th17 cells produce IL-17 in tumor microenvironment and promote tumor progression in human gastric cancer. Oncol Rep 25:1271–1277

    Article  PubMed  CAS  Google Scholar 

  186. Pelletier M, Maggi L, Micheletti A, Lazzeri E, Tamassia N, Costantini C, Cosmi L, Lunardi C, Annunziato F, Romagnani S et al (2010) Evidence for a cross-talk between human neutrophils and Th17 cells. Blood 115:335–343

    Article  PubMed  CAS  Google Scholar 

  187. Heath VL, Bicknell R (2009) Anticancer strategies involving the vasculature. Nat Rev Clin Oncol 6:395–404

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  189. Qian CN, Huang D, Wondergem B, Teh BT (2009) Complexity of tumor vasculature in clear cell renal cell carcinoma. Cancer 115:2282–2289

    Article  PubMed  CAS  Google Scholar 

  190. Lin EY, Li JF, Gnatovskiy L, Deng Y, Zhu L, Grzesik DA, Qian H, Xue XN, Pollard JW (2006) Macrophages regulate the angiogenic switch in a mouse model of breast cancer. Cancer Res 66:11238–11246

    Article  PubMed  CAS  Google Scholar 

  191. De Palma M, Venneri MA, Galli R, Sergi Sergi L, Politi LS, Sampaolesi M, Naldini L (2005) Tie2 identifies a hematopoietic lineage of proangiogenic monocytes required for tumor vessel formation and a mesenchymal population of pericyte progenitors. Cancer Cell 8:211–226

    Article  PubMed  CAS  Google Scholar 

  192. Nozawa H, Chiu C, Hanahan D (2006) Infiltrating neutrophils mediate the initial angiogenic switch in a mouse model of multistage carcinogenesis. Proc Natl Acad Sci USA 103:12493–12498

    Article  PubMed  CAS  Google Scholar 

  193. Ivy SP, Wick JY, Kaufman BM (2009) An overview of small-molecule inhibitors of VEGFR signaling. Nat Rev Clin Oncol 6:569–579

    Article  PubMed  CAS  Google Scholar 

  194. Kujawski M, Kortylewski M, Lee H, Herrmann A, Kay H, Yu H (2008) Stat3 mediates myeloid cell-dependent tumor angiogenesis in mice. J Clin Invest 118:3367–3377

    Article  PubMed  CAS  Google Scholar 

  195. Shojaei F, Wu X, Malik AK, Zhong C, Baldwin ME, Schanz S, Fuh G, Gerber HP, Ferrara N (2007) Tumor refractoriness to anti-VEGF treatment is mediated by CD11b+Gr1+ myeloid cells. Nat Biotechnol 25:911–920

    Article  PubMed  CAS  Google Scholar 

  196. Coffelt SB, Tal AO, Scholz A, De Palma M, Patel S, Urbich C, Biswas SK, Murdoch C, Plate KH, Reiss Y et al (2010) Angiopoietin-2 regulates gene expression in TIE2-expressing monocytes and augments their inherent proangiogenic functions. Cancer Res 70:5270–5280

    Article  PubMed  CAS  Google Scholar 

  197. Lewis CE, De Palma M, Naldini L (2007) Tie2-expressing monocytes and tumor angiogenesis: regulation by hypoxia and angiopoietin-2. Cancer Res 67:8429–8432

    Article  PubMed  CAS  Google Scholar 

  198. Capobianco A, Monno A, Cottone L, Venneri MA, Biziato D, Di Puppo F, Ferrari S, De Palma M, Manfredi AA, Rovere-Querini P (2011) Proangiogenic Tie2(+) macrophages infiltrate human and murine endometriotic lesions and dictate their growth in a mouse model of the disease. Am J Pathol 179:2651–2659

    Article  PubMed  CAS  Google Scholar 

  199. De Palma M, Mazzieri R, Politi LS, Pucci F, Zonari E, Sitia G, Mazzoleni S, Moi D, Venneri MA, Indraccolo S et al (2008) Tumor-targeted interferon-alpha delivery by Tie2-expressing monocytes inhibits tumor growth and metastasis. Cancer Cell 14:299–311

    Article  PubMed  CAS  Google Scholar 

  200. Lyden D, Hattori K, Dias S, Costa C, Blaikie P, Butros L, Chadburn A, Heissig B, Marks W, Witte L et al (2001) Impaired recruitment of bone-marrow-derived endothelial and hematopoietic precursor cells blocks tumor angiogenesis and growth. Nat Med 7:1194–1201

    Article  PubMed  CAS  Google Scholar 

  201. Vallet S, Smith MR, Raje N (2010) Novel bone-targeted strategies in oncology. Clin Cancer Res Off J Am Assoc Cancer Res 16:4084–4093

    Article  CAS  Google Scholar 

  202. Dinarello C (2010) Why not treat human cancer with interleukin-1 blockade? Cancer Metastasis Rev 29:317–329

    Article  PubMed  CAS  Google Scholar 

  203. Grosso JF, Jure-Kunkel MN (2013) CTLA-4 blockade in tumor models: an overview of preclinical and translational research. Cancer Immun 13:5

    PubMed  Google Scholar 

  204. Hodi FS, O’Day SJ, McDermott DF, Weber RW, Sosman JA, Haanen JB, Gonzalez R, Robert C, Schadendorf D, Hassel JC et al (2010) Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med 363:711–723

    Article  PubMed  CAS  Google Scholar 

  205. Dulos J, Carven GJ, van Boxtel SJ, Evers S, Driessen-Engels LJ, Hobo W, Gorecka MA, de Haan AF, Mulders P, Punt CJ et al (2012) PD-1 blockade augments Th1 and Th17 and suppresses Th2 responses in peripheral blood from patients with prostate and advanced melanoma cancer. J Immunother 35:169–178

    Article  PubMed  CAS  Google Scholar 

  206. Simeone E, Ascierto PA (2012) Immunomodulating antibodies in the treatment of metastatic melanoma: the experience with anti-CTLA-4, anti-CD137, and anti-PD1. J Immunotoxicol 9:241–247

    Article  PubMed  CAS  Google Scholar 

  207. Lipson EJ, Drake CG (2011) Ipilimumab: an anti-CTLA-4 antibody for metastatic melanoma. Clin Cancer Res Off J Am Assoc Cancer Res 17:6958–6962

    Article  CAS  Google Scholar 

  208. Karnezis T, Shayan R, Fox S, Achen MG, Stacker SA (2012) The connection between lymphangiogenic signalling and prostaglandin biology: a missing link in the metastatic pathway. Oncotarget 3:893–906

    PubMed  Google Scholar 

  209. Sanz-Motilva V, Martorell-Calatayud A, Nagore E (2012) Non-steroidal anti-inflammatory drugs and melanoma. Curr Pharm Des 18:3966–3978

    Article  PubMed  CAS  Google Scholar 

  210. Clevers H (2006) Colon cancer—understanding how NSAIDs work. N Engl J Med 354:761–763

    Article  PubMed  CAS  Google Scholar 

  211. Lee DY, Park K, Kim SK, Park RW, Kwon IC, Kim SY, Byun Y (2008) Antimetastatic effect of an orally active heparin derivative on experimentally induced metastasis. Clin Cancer Res Off J Am Assoc Cancer Res 14:2841–2849

    Article  CAS  Google Scholar 

  212. Schmid MC, Varner JA (2012) Myeloid cells in tumor inflammation. Vascular cell 4:14

    Article  PubMed  Google Scholar 

  213. Ilkovitch D, Carrio R, Lopez DM (2012) uPA and uPA-receptor are involved in cancer-associated myeloid-derived suppressor cell accumulation. Anticancer Res 32:4263–4270

    PubMed  CAS  Google Scholar 

  214. Obermajer N, Wong JL, Edwards RP, Odunsi K, Moysich K, Kalinski P (2012) PGE(2)-driven induction and maintenance of cancer-associated myeloid-derived suppressor cells. Immunol Invest 41:635–657

    Article  PubMed  CAS  Google Scholar 

  215. Wu CT, Hsieh CC, Lin CC, Chen WC, Hong JH, Chen MF (2012) Significance of IL-6 in the transition of hormone-resistant prostate cancer and the induction of myeloid-derived suppressor cells. J Mol Med (Berl) 90:1343–1355

    Article  CAS  Google Scholar 

  216. Jayaraman P, Parikh F, Lopez-Rivera E, Hailemichael Y, Clark A, Ma G, Cannan D, Ramacher M, Kato M, Overwijk WW et al (2012) Tumor-expressed inducible nitric oxide synthase controls induction of functional myeloid-derived suppressor cells through modulation of vascular endothelial growth factor release. J Immunol 188:5365–5376

    Article  PubMed  CAS  Google Scholar 

  217. Toh B, Wang X, Keeble J, Sim WJ, Khoo K, Wong WC, Kato M, Prevost-Blondel A, Thiery JP, Abastado JP (2011) Mesenchymal transition and dissemination of cancer cells is driven by myeloid-derived suppressor cells infiltrating the primary tumor. PLoS Biol 9:e1001162

    Article  PubMed  CAS  Google Scholar 

  218. Facciabene A, Santoro S, Coukos G (2012) Know thy enemy: why are tumor-infiltrating regulatory T cells so deleterious? Oncoimmunology 1:575–577

    Article  PubMed  Google Scholar 

  219. Wainwright DA, Balyasnikova IV, Chang AL, Ahmed AU, Moon KS, Auffinger B, Tobias AL, Han Y, Lesniak MS (2012) IDO expression in brain tumors increases the recruitment of regulatory T cells and negatively impacts survival. Clin Cancer Res Off J Am Assoc Cancer Res 18:6110–6121

    Article  CAS  Google Scholar 

  220. Gobert M, Treilleux I, Bendriss-Vermare N, Bachelot T, Goddard-Leon S, Arfi V, Biota C, Doffin AC, Durand I, Olive D et al (2009) Regulatory T cells recruited through CCL22/CCR4 are selectively activated in lymphoid infiltrates surrounding primary breast tumors and lead to an adverse clinical outcome. Cancer Res 69:2000–2009

    Article  PubMed  CAS  Google Scholar 

  221. Mantovani A (2009) The yin-yang of tumor-associated neutrophils. Cancer Cell 16:173–174

    Article  PubMed  CAS  Google Scholar 

  222. Bellocq A, Antoine M, Flahault A, Philippe C, Crestani B, Bernaudin JF, Mayaud C, Milleron B, Baud L, Cadranel J (1998) Neutrophil alveolitis in bronchioloalveolar carcinoma: induction by tumor-derived interleukin-8 and relation to clinical outcome. Am J Pathol 152:83–92

    PubMed  CAS  Google Scholar 

  223. Fridlender ZG, Albelda SM (2012) Tumor-associated neutrophils: friend or foe? Carcinogenesis 33:949–955

    Article  PubMed  CAS  Google Scholar 

  224. Bambace NM, Holmes CE (2011) The platelet contribution to cancer progression. J Thromb Haemostasis JTH 9:237–249

    Article  CAS  Google Scholar 

  225. Melillo RM, Guarino V, Avilla E, Galdiero MR, Liotti F, Prevete N, Rossi FW, Basolo F, Ugolini C, de Paulis A et al (2010) Mast cells have a protumorigenic role in human thyroid cancer. Oncogene 29:6203–6215

    Article  PubMed  CAS  Google Scholar 

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Correspondence to Yibin Kang.

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Smith, H.A., Kang, Y. The metastasis-promoting roles of tumor-associated immune cells. J Mol Med 91, 411–429 (2013). https://doi.org/10.1007/s00109-013-1021-5

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  • DOI: https://doi.org/10.1007/s00109-013-1021-5

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