Explanation of Metastasis by Homeostatic Inflammation

  • Yoshiro Maru


If inflammation caused by either non-self or self molecules can disseminate throughout the body and inflammatory sites actively allow entry of circulating tumor cells and assist regrowth, then circulating tumor cells metastasize to the sites of inflammation. However, disrupted sites of homeostatic inflammation do not necessarily guarantee metastatic spread and subsequent regrowth.


Lung Metastasis Circulate Tumor Cell B16F10 Melanoma Cell S100A9 Protein Club Cell 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


  1. 1.
    Biswas S, Guix M, Rinehart C, et al. Inhibition of TGF-β with neutralizing antibodies prevents radiation-induced acceleration of metastatic cancer progression. J Clin Invest. 2007;117:1305–13.PubMedPubMedCentralCrossRefGoogle Scholar
  2. 2.
    Bald T, Quast T, Landsberg J, et al. Ultraviolet-radiation-induced inflammation promotes angiotropism and metastasis in melanoma. Nature. 2014;507:109–13.PubMedCrossRefGoogle Scholar
  3. 3.
    Augustin G, Bruketa T, Korolija D, et al. Lower incidence of hepatic metastases of colorectal cancer in patients with chronic liver diseases: meta-analysis. Hepatogastroenterology. 2013;60:1164–8.PubMedGoogle Scholar
  4. 4.
    Qi K, Qiu H, Sun D, et al. Impact of cirrhosis on the development of experimental hepatic metastases by B16F1 melanoma cells in C57BL/6 mice. Hepatology. 2004;40:1144–50.PubMedCrossRefGoogle Scholar
  5. 5.
    Andreani V, Gatti G, Simonella L, et al. Activation of toll-like receptor 4 on tumor cells in vitro inhibits subsequent tumor growth in vivo. Cancer Res. 2007;67:10519–27.PubMedCrossRefGoogle Scholar
  6. 6.
    Yan L, Cai Q, Xu Y. The ubiquitin-CXCR4 axis plays an important role in acute lung infection-enhanced lung tumor metastasis. Clin Cancer Res. 2013;19:4706–16.PubMedPubMedCentralCrossRefGoogle Scholar
  7. 7.
    Roy LD, Ghosh S, Pathangey LB, et al. Collagen induced arthritis increases secondary metastasis in MMTV-PyV MT mouse model of mammary cancer. BMC Cancer. 2011;11:365.PubMedPubMedCentralCrossRefGoogle Scholar
  8. 8.
    Das Roy L, Curry JM, Sahraei M, et al. Arthritis augments breast cancer metastasis: role of mast cells and SCF/c-Kit signaling. Breast Cancer Res. 2013;15:R32.PubMedCrossRefGoogle Scholar
  9. 9.
    Zhang Y, Lamm WJ, Albert RK, et al. Influence of the route of allergen administration and genetic background on the murine allergic pulmonary response. Am J Respir Crit Care Med. 1997;155:661–9.PubMedCrossRefGoogle Scholar
  10. 10.
    Lee JJ, Dimina D, Macias MP, et al. Defining a link with asthma in mice congenitally deficient in eosinophils. Science. 2004;305:1773–6.PubMedCrossRefGoogle Scholar
  11. 11.
    Taranova AG, Maldonado 3rd D, Vachon CM, et al. Allergic pulmonary inflammation promotes the recruitment of circulating tumor cells to the lung. Cancer Res. 2008;68:8582–9.PubMedPubMedCentralCrossRefGoogle Scholar
  12. 12.
    Snyder JC, Reynolds SD, Hollingsworth JW, et al. Clara cells attenuate the inflammatory response through regulation of macrophage behavior. Am J Respir Cell Mol Biol. 2010;42:161–71.PubMedCrossRefGoogle Scholar
  13. 13.
    Saha A, Lee YC, Zhang Z, et al. Lack of an endogenous anti-inflammatory protein in mice enhances colonization of B16F10 melanoma cells in the lungs. J Biol Chem. 2010;285:10822–31.PubMedPubMedCentralCrossRefGoogle Scholar
  14. 14.
    Minami T, Horiuchi K, Miura M, et al. Vascular endothelial growth factor- and thrombin-induced termination factor, Down syndrome critical region-1, attenuates endothelial cell proliferation and angiogenesis. J Biol Chem. 2004;279:50537–54.PubMedCrossRefGoogle Scholar
  15. 15.
    Rothermel B, Vega RB, Yang J, et al. A protein encoded within the Down syndrome critical region is enriched in striated muscles and inhibits calcineurin signaling. J Biol Chem. 2000;275:8719–25.PubMedCrossRefGoogle Scholar
  16. 16.
    Minami T, Miura M, Aird WC, et al. Thrombin-induced autoinhibitory factor, Down syndrome critical region-1, attenuates NFAT-dependent vascular cell adhesion molecule-1 expression and inflammation in the endothelium. J Biol Chem. 2006;281:20503–20.PubMedCrossRefGoogle Scholar
  17. 17.
    Ryeom S, Baek KH, Rioth MJ, et al. Targeted deletion of the calcineurin inhibitor DSCR1 suppresses tumor growth. Cancer Cell. 2008;13:420–31.PubMedCrossRefGoogle Scholar
  18. 18.
    Besse B, Lasserre SF, Compton P, et al. Bevacizumab safety in patients with central nervous system metastases. Clin Cancer Res. 2010;16:269–78.PubMedCrossRefGoogle Scholar
  19. 19.
    Ferrara N, Carver-Moore K, Chen H, et al. Heterozygous embryonic lethality induced by targeted inactivation of the VEGF gene. Nature. 1996;380:439–42.PubMedCrossRefGoogle Scholar
  20. 20.
    Minami T, Jiang S, Schadler K, et al. The calcineurin-NFAT-angiopoietin-2 signaling axis in lung endothelium is critical for the establishment of lung metastases. Cell Rep. 2013;4:709–23.PubMedPubMedCentralCrossRefGoogle Scholar
  21. 21.
    Robertson AL, Khairallah PA. Effects of angiotensin II and some analogues on vascular permeability in the rabbit. Circ Res. 1972;31:923–31.PubMedCrossRefGoogle Scholar
  22. 22.
    De Ciuceis C, Amiri F, Brassard P, et al. Reduced vascular remodeling, endothelial dysfunction, and oxidative stress in resistance arteries of angiotensin II-infused macrophage colony-stimulating factor-deficient mice: evidence for a role in inflammation in angiotensin-induced vascular injury. Arterioscler Thromb Vasc Biol. 2005;25:2106–13.PubMedCrossRefGoogle Scholar
  23. 23.
    Daugherty A, Rateri DL, Lu H, et al. Hypercholesterolemia stimulates angiotensin peptide synthesis and contributes to atherosclerosis through the AT1A receptor. Circulation. 2004;110:3849–57.PubMedCrossRefGoogle Scholar
  24. 24.
    Ide N, Hirase T, Nishimoto-Hazuku A, et al. Angiotensin II increases expression of IP-10 and the renin-angiotensin system in endothelial cells. Hypertens Res. 2008;31:1257–67.PubMedCrossRefGoogle Scholar
  25. 25.
    Sano H, Hosokawa K, Kidoya H, et al. Negative regulation of VEGF-induced vascular leakage by blockade of angiotensin II type 1 receptor. Arterioscler Thromb Vasc Biol. 2006;26:2673–80.PubMedCrossRefGoogle Scholar
  26. 26.
    Imai Y, Kuba K, Rao S, et al. Angiotensin-converting enzyme 2 protects from severe acute lung failure. Nature. 2005;436:112–6.PubMedCrossRefGoogle Scholar
  27. 27.
    Amano H, Ito Y, Ogawa F, et al. Angiotensin II type 1A receptor signaling facilitates tumor metastasis formation through P-selectin–mediated interaction of tumor cells with platelets and endothelial cells. Am J Pathol. 2013;182:553–64.PubMedCrossRefGoogle Scholar
  28. 28.
    Ager EI, Neo J, Christophi C. The renin-angiotensin system and malignancy. Carcinogenesis. 2008;29:1675–84.PubMedCrossRefGoogle Scholar
  29. 29.
    Kohlstedt K, Trouvain C, Namgaladze D, et al. Adipocyte-derived lipids increase angiotensin-converting enzyme (ACE) expression and modulate macrophage phenotype. Basic Res Cardiol. 2011;106:205–15.PubMedCrossRefGoogle Scholar
  30. 30.
    Fujita M, Mason RJ, Cool C, et al. Pulmonary hypertension in TNF-alpha-overexpressing mice is associated with decreased VEGF gene expression. J Appl Physiol (1985). 2002;93:2162–70.Google Scholar
  31. 31.
    Jahr J, Grande PO. In vivo effects of tumor necrosis factor-alpha on capillary permeability and vascular tone in a skeletal muscle. Acta Anaesthesiol Scand. 1996;40:256–61.PubMedCrossRefGoogle Scholar
  32. 32.
    Oliver PM, Fox JE, Kim R, et al. Hypertension, cardiac hypertrophy, and sudden death in mice lacking natriuretic peptide receptor A. Proc Natl Acad Sci U S A. 1997;94:14730–5.PubMedPubMedCentralCrossRefGoogle Scholar
  33. 33.
    Klinger JR, Tsai SW, Green S, et al. Atrial natriuretic peptide attenuates agonist-induced pulmonary edema in mice with targeted disruption of the gene for natriuretic peptide receptor-A. J Appl Physiol (1985). 2013;114:307–15.Google Scholar
  34. 34.
    Takashi Nojiri HH, Ishikane S, Kimura T, Kangawa K. ANP/GC-A signaling attenuates pulmonary metastasis of B16 melanoma enhanced by lipopolysaccharide or angiotensin-II. BMC Pharmacol Toxicol. 2013;14 Suppl 1:52.CrossRefGoogle Scholar
  35. 35.
    Miyajima A, Kosaka T, Asano T, et al. Angiotensin II type I antagonist prevents pulmonary metastasis of murine renal cancer by inhibiting tumor angiogenesis. Cancer Res. 2002;62:4176–9.PubMedGoogle Scholar
  36. 36.
    Campbell WB, Falck JR. Arachidonic acid metabolites as endothelium-derived hyperpolarizing factors. Hypertension. 2007;49:590–6.PubMedCrossRefGoogle Scholar
  37. 37.
    Panigrahy D, Edin ML, Lee CR, et al. Epoxyeicosanoids stimulate multiorgan metastasis and tumor dormancy escape in mice. J Clin Invest. 2012;122:178–91.PubMedCrossRefGoogle Scholar
  38. 38.
    Koh YJ, Kang S, Lee HJ, et al. Bone marrow-derived circulating progenitor cells fail to transdifferentiate into adipocytes in adult adipose tissues in mice. J Clin Invest. 2007;117:3684–95.PubMedPubMedCentralCrossRefGoogle Scholar
  39. 39.
    Bannasch P, Klimek F, Mayer D. Early bioenergetic changes in hepatocarcinogenesis: preneoplastic phenotypes mimic responses to insulin and thyroid hormone. J Bioenerg Biomembr. 1997;29:303–13.PubMedCrossRefGoogle Scholar
  40. 40.
    Metzger C, Bannasch P, Mayer D. Enhancement and phenotypic modulation of N-nitrosomorpholine-induced hepatocarcinogenesis by dehydroepiandrosterone. Cancer Lett. 1997;121:125–31.PubMedCrossRefGoogle Scholar
  41. 41.
    Morimoto-Tomita M, Ohashi Y, Matsubara A, et al. Mouse colon carcinoma cells established for high incidence of experimental hepatic metastasis exhibit accelerated and anchorage-independent growth. Clin Exp Metastasis. 2005;22:513–21.PubMedCrossRefGoogle Scholar
  42. 42.
    Hiratsuka S, Watanabe A, Sakurai Y, et al. The S100A8-serum amyloid A3-TLR4 paracrine cascade establishes a pre-metastatic phase. Nat Cell Biol. 2008;10:1349–55.PubMedCrossRefGoogle Scholar
  43. 43.
    Deguchi A, Tomita T, Ohto U, et al. Eritoran inhibits S100A8-mediated TLR4/MD-2 activation and tumor growth by changing the immune microenvironment. Oncogene. 2016;35:1445–56.Google Scholar
  44. 44.
    Deguchi A, Tomita T, Omori T, et al. Serum amyloid A3 binds MD-2 to activate p38 and NF-kappaB pathways in a MyD88-dependent manner. J Immunol. 2013;191:1856–64.PubMedCrossRefGoogle Scholar
  45. 45.
    Simard JC, Cesaro A, Chapeton-Montes J, et al. S100A8 and S100A9 induce cytokine expression and regulate the NLRP3 inflammasome via ROS-dependent activation of NF-kappaB(1.). PLoS One. 2013;8:e72138.PubMedPubMedCentralCrossRefGoogle Scholar
  46. 46.
    Hiratsuka S, Watanabe A, Aburatani H, et al. Tumour-mediated upregulation of chemoattractants and recruitment of myeloid cells predetermines lung metastasis. Nat Cell Biol. 2006;8:1369–75.PubMedCrossRefGoogle Scholar
  47. 47.
    Anceriz N, Vandal K, Tessier PA. S100A9 mediates neutrophil adhesion to fibronectin through activation of beta2 integrins. Biochem Biophys Res Commun. 2007;354:84–9.PubMedPubMedCentralCrossRefGoogle Scholar
  48. 48.
    Martin MD, Carter KJ, Jean-Philippe SR, et al. Effect of ablation or inhibition of stromal matrix metalloproteinase-9 on lung metastasis in a breast cancer model is dependent on genetic background. Cancer Res. 2008;68:6251–9.PubMedPubMedCentralCrossRefGoogle Scholar
  49. 49.
    Wiechert L, Nemeth J, Pusterla T, et al. Hepatocyte-specific S100a8 and S100a9 transgene expression in mice causes Cxcl1 induction and systemic neutrophil enrichment. Cell Commun Signal. 2012;10:40.PubMedPubMedCentralCrossRefGoogle Scholar
  50. 50.
    Ieguchi K, Omori T, Komatsu A, et al. Ephrin-A1 expression induced by S100A8 is mediated by the toll-like receptor 4. Biochem Biophys Res Commun. 2013;440:623–9.PubMedCrossRefGoogle Scholar
  51. 51.
    Larson J, Schomberg S, Schroeder W, et al. Endothelial EphA receptor stimulation increases lung vascular permeability. Am J Physiol Lung Cell Mol Physiol. 2008;295:L431–9.PubMedPubMedCentralCrossRefGoogle Scholar
  52. 52.
    Ieguchi K, Tomita T, Omori T, et al. ADAM12-cleaved ephrin-A1 contributes to lung metastasis. Oncogene. 2014;33:2179–90.PubMedCrossRefGoogle Scholar
  53. 53.
    Yamazaki T, Masuda J, Omori T, et al. EphA1 interacts with integrin-linked kinase and regulates cell morphology and motility. J Cell Sci. 2009;122:243–55.PubMedCrossRefGoogle Scholar
  54. 54.
    Tomita T, Sakurai Y, Ishibashi S, et al. Imbalance of Clara cell-mediated homeostatic inflammation is involved in lung metastasis. Oncogene. 2011;30:3429–39.PubMedCrossRefGoogle Scholar
  55. 55.
    Bessede A, Gargaro M, Pallotta MT, et al. Aryl hydrocarbon receptor control of a disease tolerance defence pathway. Nature. 2014;511:184–90.PubMedPubMedCentralCrossRefGoogle Scholar
  56. 56.
    Patel RD, Murray IA, Flaveny CA, et al. Ah receptor represses acute-phase response gene expression without binding to its cognate response element. Lab Invest. 2009;89:695–707.PubMedPubMedCentralCrossRefGoogle Scholar
  57. 57.
    Qian BZ, Li J, Zhang H, et al. CCL2 recruits inflammatory monocytes to facilitate breast-tumour metastasis. Nature. 2011;475:222–5.PubMedPubMedCentralCrossRefGoogle Scholar
  58. 58.
    Apetoh L, Ghiringhelli F, Tesniere A, et al. Toll-like receptor 4-dependent contribution of the immune system to anticancer chemotherapy and radiotherapy. Nat Med. 2007;13:1050–9.PubMedCrossRefGoogle Scholar
  59. 59.
    von Bernuth H, Picard C, Jin Z, et al. Pyogenic bacterial infections in humans with MyD88 deficiency. Science. 2008;321:691–6.CrossRefGoogle Scholar
  60. 60.
    Ngo VN, Young RM, Schmitz R, et al. Oncogenically active MYD88 mutations in human lymphoma. Nature. 2011;470:115–9.PubMedCrossRefGoogle Scholar
  61. 61.
    St John AL, Abraham SN. Salmonella disrupts lymph node architecture by TLR4-mediated suppression of homeostatic chemokines. Nat Med. 2009;15:1259–65.PubMedPubMedCentralCrossRefGoogle Scholar
  62. 62.
    Yamada M, Kubo H, Kobayashi S, et al. Bone marrow-derived progenitor cells are important for lung repair after lipopolysaccharide-induced lung injury. J Immunol. 2004;172:1266–72.PubMedCrossRefGoogle Scholar
  63. 63.
    Haricharan S, Brown P. TLR4 has a TP53-dependent dual role in regulating breast cancer cell growth. Proc Natl Acad Sci U S A. 2015;112:E3216–25.PubMedPubMedCentralCrossRefGoogle Scholar
  64. 64.
    Andonegui G, Bonder CS, Green F, et al. Endothelium-derived toll-like receptor-4 is the key molecule in LPS-induced neutrophil sequestration into lungs. J Clin Invest. 2003;111:1011–20.PubMedPubMedCentralCrossRefGoogle Scholar
  65. 65.
    Bresnick AR, Weber DJ, Zimmer DB. S100 proteins in cancer. Nat Rev Cancer. 2015;15:96–109.PubMedPubMedCentralCrossRefGoogle Scholar
  66. 66.
    Manitz MP, Horst B, Seeliger S, et al. Loss of S100A9 (MRP14) results in reduced interleukin-8-induced CD11b surface expression, a polarized microfilament system, and diminished responsiveness to chemoattractants in vitro. Mol Cell Biol. 2003;23:1034–43.PubMedPubMedCentralCrossRefGoogle Scholar
  67. 67.
    Leanderson T, Liberg D, Ivars F. S100A9 as a pharmacological target molecule in inflammation and cancer. Endocr Metab Immune Disord Drug Targets. 2015;15:97–104.PubMedCrossRefGoogle Scholar
  68. 68.
    Odink K, Cerletti N, Bruggen J, et al. Two calcium-binding proteins in infiltrate macrophages of rheumatoid arthritis. Nature. 1987;330:80–2.PubMedCrossRefGoogle Scholar
  69. 69.
    Yanamandra K, Alexeyev O, Zamotin V, et al. Amyloid formation by the pro-inflammatory S100A8/A9 proteins in the ageing prostate. PLoS One. 2009;4:e5562.PubMedPubMedCentralCrossRefGoogle Scholar
  70. 70.
    Vogl T, Leukert N, Barczyk K, et al. Biophysical characterization of S100A8 and S100A9 in the absence and presence of bivalent cations. Biochim Biophys Acta. 2006;1763:1298–306.PubMedCrossRefGoogle Scholar
  71. 71.
    Tyden H, Lood C, Gullstrand B, et al. Increased serum levels of S100A8/A9 and S100A12 are associated with cardiovascular disease in patients with inactive systemic lupus erythematosus. Rheumatology (Oxford). 2013;52:2048–55.CrossRefGoogle Scholar
  72. 72.
    Foell D, Wittkowski H, Ren Z, et al. Phagocyte-specific S100 proteins are released from affected mucosa and promote immune responses during inflammatory bowel disease. J Pathol. 2008;216:183–92.PubMedCrossRefGoogle Scholar
  73. 73.
    Keller M, Ruegg A, Werner S, et al. Active caspase-1 is a regulator of unconventional protein secretion. Cell. 2008;132:818–31.PubMedCrossRefGoogle Scholar
  74. 74.
    Ghiringhelli F, Apetoh L, Tesniere A, et al. Activation of the NLRP3 inflammasome in dendritic cells induces IL-1beta-dependent adaptive immunity against tumors. Nat Med. 2009;15:1170–8.PubMedCrossRefGoogle Scholar
  75. 75.
    Grebhardt S, Veltkamp C, Strobel P, et al. Hypoxia and HIF-1 increase S100A8 and S100A9 expression in prostate cancer. Int J Cancer. 2012;131:2785–94.PubMedCrossRefGoogle Scholar
  76. 76.
    Hsu K, Passey RJ, Endoh Y, et al. Regulation of S100A8 by glucocorticoids. J Immunol. 2005;174:2318–26.PubMedCrossRefGoogle Scholar
  77. 77.
    Spijkers-Hagelstein JA, Schneider P, Hulleman E, et al. Elevated S100A8/S100A9 expression causes glucocorticoid resistance in MLL-rearranged infant acute lymphoblastic leukemia. Leukemia. 2012;26:1255–65.PubMedCrossRefGoogle Scholar
  78. 78.
    Vogl T, Tenbrock K, Ludwig S, et al. Mrp8 and Mrp14 are endogenous activators of toll-like receptor 4, promoting lethal, endotoxin-induced shock. Nat Med. 2007;13:1042–9.PubMedCrossRefGoogle Scholar
  79. 79.
    Turovskaya O, Foell D, Sinha P, et al. RAGE, carboxylated glycans and S100A8/A9 play essential roles in colitis-associated carcinogenesis. Carcinogenesis. 2008;29:2035–43.PubMedPubMedCentralCrossRefGoogle Scholar
  80. 80.
    Kislinger T, Fu C, Huber B, et al. N(epsilon)-(carboxymethyl)lysine adducts of proteins are ligands for receptor for advanced glycation end products that activate cell signaling pathways and modulate gene expression. J Biol Chem. 1999;274:31740–9.PubMedCrossRefGoogle Scholar
  81. 81.
    Xie J, Burz DS, He W, et al. Hexameric calgranulin C (S100A12) binds to the receptor for advanced glycated end products (RAGE) using symmetric hydrophobic target-binding patches. J Biol Chem. 2007;282:4218–31.PubMedCrossRefGoogle Scholar
  82. 82.
    Hofmann MA, Drury S, Fu C, et al. RAGE mediates a novel proinflammatory axis: a central cell surface receptor for S100/calgranulin polypeptides. Cell. 1999;97:889–901.PubMedCrossRefGoogle Scholar
  83. 83.
    Leclerc E, Fritz G, Weibel M, et al. S100B and S100A6 differentially modulate cell survival by interacting with distinct RAGE (receptor for advanced glycation end products) immunoglobulin domains. J Biol Chem. 2007;282:31317–31.PubMedCrossRefGoogle Scholar
  84. 84.
    Chen H, Xu C, Jin Q, et al. S100 protein family in human cancer. Am J Cancer Res. 2014;4:89–115.PubMedPubMedCentralGoogle Scholar
  85. 85.
    Zibert JR, Skov L, Thyssen JP, et al. Significance of the S100A4 protein in psoriasis. J Invest Dermatol. 2010;130:150–60.PubMedCrossRefGoogle Scholar
  86. 86.
    Gebhardt C, Riehl A, Durchdewald M, et al. RAGE signaling sustains inflammation and promotes tumor development. J Exp Med. 2008;205:275–85.PubMedPubMedCentralCrossRefGoogle Scholar
  87. 87.
    Bjork P, Bjork A, Vogl T, et al. Identification of human S100A9 as a novel target for treatment of autoimmune disease via binding to quinoline-3-carboxamides. PLoS Biol. 2009;7:e97.PubMedCrossRefGoogle Scholar
  88. 88.
    Hibino T, Sakaguchi M, Miyamoto S, et al. S100A9 is a novel ligand of EMMPRIN that promotes melanoma metastasis. Cancer Res. 2013;73:172–83.PubMedCrossRefGoogle Scholar
  89. 89.
    Arnold V, Cummings JS, Moreno-Nieves UY, et al. S100A9 protein is a novel ligand for the CD85j receptor and its interaction is implicated in the control of HIV-1 replication by NK cells. Retrovirology. 2013;10:122.PubMedPubMedCentralCrossRefGoogle Scholar
  90. 90.
    Gilchrist M, Thorsson V, Li B, et al. Systems biology approaches identify ATF3 as a negative regulator of Toll-like receptor 4. Nature. 2006;441:173–8.PubMedCrossRefGoogle Scholar
  91. 91.
    Boespflug ND, Kumar S, McAlees JW, et al. ATF3 is a novel regulator of mouse neutrophil migration. Blood. 2014;123:2084–93.PubMedPubMedCentralCrossRefGoogle Scholar
  92. 92.
    Gilchrist M, Henderson Jr WR, Clark AE, et al. Activating transcription factor 3 is a negative regulator of allergic pulmonary inflammation. J Exp Med. 2008;205:2349–57.PubMedPubMedCentralCrossRefGoogle Scholar
  93. 93.
    Wolford CC, McConoughey SJ, Jalgaonkar SP, et al. Transcription factor ATF3 links host adaptive response to breast cancer metastasis. J Clin Invest. 2013;123:2893–906.PubMedPubMedCentralCrossRefGoogle Scholar
  94. 94.
    Han C, Jin J, Xu S, et al. Integrin CD11b negatively regulates TLR-triggered inflammatory responses by activating Syk and promoting degradation of MyD88 and TRIF via Cbl-b. Nat Immunol. 2010;11:734–42.PubMedCrossRefGoogle Scholar
  95. 95.
    Kang YJ, Kusler B, Otsuka M, et al. Calcineurin negatively regulates TLR-mediated activation pathways. J Immunol. 2007;179:4598–607.PubMedCrossRefGoogle Scholar
  96. 96.
    Androulidaki A, Iliopoulos D, Arranz A, et al. The kinase Akt1 controls macrophage response to lipopolysaccharide by regulating microRNAs. Immunity. 2009;31:220–31.PubMedPubMedCentralCrossRefGoogle Scholar
  97. 97.
    Kalyana-Sundaram S, Kumar-Sinha C, Shankar S, et al. Expressed pseudogenes in the transcriptional landscape of human cancers. Cell. 2012;149:1622–34.PubMedPubMedCentralCrossRefGoogle Scholar
  98. 98.
    Tomita T, Ieguchi K, Sawamura T, et al. Human serum amyloid A3 (SAA3) protein, expressed as a fusion protein with SAA2, binds the oxidized low density lipoprotein receptor. PLoS One. 2015;10:e0118835.PubMedPubMedCentralCrossRefGoogle Scholar
  99. 99.
    Han CY, Subramanian S, Chan CK, et al. Adipocyte-derived serum amyloid A3 and hyaluronan play a role in monocyte recruitment and adhesion. Diabetes. 2007;56:2260–73.PubMedCrossRefGoogle Scholar
  100. 100.
    Reigstad CS, Lunden GO, Felin J, et al. Regulation of serum amyloid A3 (SAA3) in mouse colonic epithelium and adipose tissue by the intestinal microbiota. PLoS One. 2009;4:e5842.PubMedPubMedCentralCrossRefGoogle Scholar
  101. 101.
    Yan HH, Pickup M, Pang Y, et al. Gr-1+CD11b+ myeloid cells tip the balance of immune protection to tumor promotion in the premetastatic lung. Cancer Res. 2010;70:6139–49.PubMedPubMedCentralCrossRefGoogle Scholar
  102. 102.
    van Hogerlinden M, Rozell BL, Ahrlund-Richter L, et al. Squamous cell carcinomas and increased apoptosis in skin with inhibited Rel/nuclear factor-kappaB signaling. Cancer Res. 1999;59:3299–303.PubMedGoogle Scholar
  103. 103.
    Lind MH, Rozell B, Wallin RP, et al. Tumor necrosis factor receptor 1-mediated signaling is required for skin cancer development induced by NF-kappaB inhibition. Proc Natl Acad Sci U S A. 2004;101:4972–7.PubMedPubMedCentralCrossRefGoogle Scholar
  104. 104.
    Ulvmar MH, Sur I, Memet S, et al. Timed NF-kappaB inhibition in skin reveals dual independent effects on development of HED/EDA and chronic inflammation. J Invest Dermatol. 2009;129:2584–93.PubMedCrossRefGoogle Scholar
  105. 105.
    Asagiri M, Takayanagi H. The molecular understanding of osteoclast differentiation. Bone. 2007;40:251–64.PubMedCrossRefGoogle Scholar
  106. 106.
    Jones DH, Nakashima T, Sanchez OH, et al. Regulation of cancer cell migration and bone metastasis by RANKL. Nature. 2006;440:692–6.PubMedCrossRefGoogle Scholar
  107. 107.
    Mikami S, Katsube K, Oya M, et al. Increased RANKL expression is related to tumour migration and metastasis of renal cell carcinomas. J Pathol. 2009;218:530–9.PubMedCrossRefGoogle Scholar
  108. 108.
    Kikuchi T, Matsuguchi T, Tsuboi N, et al. Gene expression of osteoclast differentiation factor is induced by lipopolysaccharide in mouse osteoblasts via toll-like receptors. J Immunol. 2001;166:3574–9.PubMedCrossRefGoogle Scholar
  109. 109.
    Chakravarti A, Raquil MA, Tessier P, et al. Surface RANKL of toll-like receptor 4-stimulated human neutrophils activates osteoclastic bone resorption. Blood. 2009;114:1633–44.PubMedCrossRefGoogle Scholar
  110. 110.
    Inada M, Takita M, Yokoyama S, et al. Direct melanoma cell contact induces stromal cell autocrine prostaglandin E2-EP4 receptor signaling that drives tumor growth, angiogenesis and metastasis. J Biol Chem. 2015;290:29781–93.PubMedCrossRefGoogle Scholar
  111. 111.
    Liao Y, Day KH, Damon DN, et al. Endothelial cell-specific knockout of connexin 43 causes hypotension and bradycardia in mice. Proc Natl Acad Sci U S A. 2001;98:9989–94.PubMedPubMedCentralCrossRefGoogle Scholar
  112. 112.
    Li K, Yao J, Shi L, et al. Reciprocal regulation between proinflammatory cytokine-induced inducible NO synthase (iNOS) and connexin43 in bladder smooth muscle cells. J Biol Chem. 2011;286:41552–62.PubMedPubMedCentralCrossRefGoogle Scholar
  113. 113.
    Stoletov K, Strnadel J, Zardouzian E, et al. Role of connexins in metastatic breast cancer and melanoma brain colonization. J Cell Sci. 2013;126:904–13.PubMedPubMedCentralCrossRefGoogle Scholar
  114. 114.
    Wang L, Chang EW, Wong SC, et al. Increased myeloid-derived suppressor cells in gastric cancer correlate with cancer stage and plasma S100A8/A9 proinflammatory proteins. J Immunol. 2013;190:794–804.PubMedCrossRefGoogle Scholar
  115. 115.
    Matzinger P. Tolerance, danger, and the extended family. Annu Rev Immunol. 1994;12:991–1045.PubMedCrossRefGoogle Scholar
  116. 116.
    Pradeu T, Cooper EL. The danger theory: 20 years later. Front Immunol. 2012;3:287.PubMedPubMedCentralCrossRefGoogle Scholar

Copyright information

© Springer Japan 2016

Authors and Affiliations

  • Yoshiro Maru
    • 1
  1. 1.Department of PharmacologyTokyo Women’s Medical UniversityTokyoJapan

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