The Multifaceted S100A4 Protein in Cancer and Inflammation

  • Noona AmbartsumianEmail author
  • Jörg Klingelhöfer
  • Mariam Grigorian
Part of the Methods in Molecular Biology book series (MIMB, volume 1929)


The metastasis-promoting S100A4 protein, a member of the S100 family, has recently been discovered as a potent factor implicated in various inflammation-associated diseases. S100A4 is involved in a range of biological functions such as angiogenesis, cell differentiation, apoptosis, motility, and invasion. Moreover, S100A4 is also a potent trigger of inflammatory processes and induces the release of cytokines and growth factors under different pathological conditions.

Indeed, the release of S100A4 upon stress and mainly its pro-inflammatory role emerges as the most decisive activity in disease development, such as rheumatoid arthritis (RA), systemic sclerosis (SSc) allergy, psoriasis, and cancer. In the scope of this review, we will focus on the role of S100A4 as a mediator of pro-inflammatory pathways and its associated biological processes involved in the pathogenesis of various human noncommunicable diseases (NCDs) including cancer.

Key words

S100A4 protein Calcium EF-hand DAMP proteins Inflammation Cancer progression Noncommunicable diseases 


  1. 1.
    Fei F, Qu J, Zhang M, Li Y, Zhang S (2017) S100A4 in cancer progression and metastasis: a systematic review. Oncotarget 8(42):73219–73239. Scholar
  2. 2.
    Kim EJ, Helfman DM (2003) Characterization of the metastasis-associated protein, S100A4. Roles of calcium binding and dimerization in cellular localization and interaction with myosin. J Biol Chem 278(32):30063–30073. Scholar
  3. 3.
    Fei F, Qu J, Li C, Wang X, Li Y, Zhang S (2017) Role of metastasis-induced protein S100A4 in human non-tumor pathophysiologies. Cell Biosci 7:64. Scholar
  4. 4.
    Grigorian M, Andresen S, Tulchinsky E, Kriajevska M, Carlberg C, Kruse C, Cohn M, Ambartsumian N, Christensen A, Selivanova G, Lukanidin E (2001) Tumor suppressor p53 protein is a new target for the metastasis-associated Mts1/S100A4 protein: functional consequences of their interaction. J Biol Chem 276(25):22699–22708. Scholar
  5. 5.
    Semov A, Moreno MJ, Onichtchenko A, Abulrob A, Ball M, Ekiel I, Pietrzynski G, Stanimirovic D, Alakhov V (2005) Metastasis-associated protein S100A4 induces angiogenesis through interaction with Annexin II and accelerated plasmin formation. J Biol Chem 280(21):20833–20841. Scholar
  6. 6.
    Dahlmann M, Kobelt D, Walther W, Mudduluru G, Stein U (2016) S100A4 in cancer metastasis: Wnt signaling-driven interventions for metastasis restriction. Cancers (Basel) 8(6). Scholar
  7. 7.
    Ito M, Kizawa K (2001) Expression of calcium-binding S100 proteins A4 and A6 in regions of the epithelial sac associated with the onset of hair follicle regeneration. J Invest Dermatol 116(6):956–963. Scholar
  8. 8.
    Chow KH, Park HJ, George J, Yamamoto K, Gallup AD, Graber JH, Chen Y, Jiang W, Steindler DA, Neilson EG, Kim BYS, Yun K (2017) S100A4 is a biomarker and regulator of glioma stem cells that is critical for mesenchymal transition in glioblastoma. Cancer Res 77(19):5360–5373. Scholar
  9. 9.
    Tumbar T, Guasch G, Greco V, Blanpain C, Lowry WE, Rendl M, Fuchs E (2004) Defining the epithelial stem cell niche in skin. Science 303(5656):359–363. Scholar
  10. 10.
    Bresnick AR, Weber DJ, Zimmer DB (2015) S100 proteins in cancer. Nat Rev Cancer 15(2):96–109. Scholar
  11. 11.
    Boye K, Maelandsmo GM (2010) S100A4 and metastasis: a small actor playing many roles. Am J Pathol 176(2):528–535. Scholar
  12. 12.
    Nasser MW, Elbaz M, Ahirwar DK, Ganju RK (2015) Conditioning solid tumor microenvironment through inflammatory chemokines and S100 family proteins. Cancer Lett 365(1):11–22. Scholar
  13. 13.
    Grigorian M, Ambartsumian N, Lukanidin E (2008) Metastasis-inducing S100A4 protein: implication in non-malignant human pathologies. Curr Mol Med 8(6):492–496CrossRefGoogle Scholar
  14. 14.
    Bertheloot D, Latz E (2017) HMGB1, IL-1alpha, IL-33 and S100 proteins: dual-function alarmins. Cell Mol Immunol 14(1):43–64. Scholar
  15. 15.
    Austermann J, Zenker S, Roth J (2017) S100-alarmins: potential therapeutic targets for arthritis. Expert Opin Ther Targets 21(7):739–751. Scholar
  16. 16.
    Chan JK, Roth J, Oppenheim JJ, Tracey KJ, Vogl T, Feldmann M, Horwood N, Nanchahal J (2012) Alarmins: awaiting a clinical response. J Clin Invest 122(8):2711–2719. Scholar
  17. 17.
    Boteanu RM, Suica VI, Uyy E, Ivan L, Dima SO, Popescu I, Simionescu M, Antohe F (2017) Alarmins in chronic noncommunicable diseases: atherosclerosis, diabetes and cancer. J Proteome 153:21–29. Scholar
  18. 18.
    Raposo TP, Beirao BC, Pang LY, Queiroga FL, Argyle DJ (2015) Inflammation and cancer: till death tears them apart. Vet J 205(2):161–174. Scholar
  19. 19.
    Hanahan D, Weinberg RA (2011) Hallmarks of cancer: the next generation. Cell 144(5):646–674. Scholar
  20. 20.
    Wu Y, Zhou BP (2009) Inflammation: a driving force speeds cancer metastasis. Cell Cycle 8(20):3267–3273. Scholar
  21. 21.
    Hansen MT, Forst B, Cremers N, Quagliata L, Ambartsumian N, Grum-Schwensen B, Klingelhofer J, Abdul-Al A, Herrmann P, Osterland M, Stein U, Nielsen GH, Scherer PE, Lukanidin E, Sleeman JP, Grigorian M (2015) A link between inflammation and metastasis: serum amyloid A1 and A3 induce metastasis, and are targets of metastasis-inducing S100A4. Oncogene 34(4):424–435. Scholar
  22. 22.
    Ebralidze A, Tulchinsky E, Grigorian M, Afanasyeva A, Senin V, Revazova E, Lukanidin E (1989) Isolation and characterization of a gene specifically expressed in different metastatic cells and whose deduced gene product has a high degree of homology to a Ca2+-binding protein family. Genes Dev 3(7):1086–1093CrossRefGoogle Scholar
  23. 23.
    Takenaga K, Nakamura Y, Endo H, Sakiyama S (1994) Involvement of S100-related calcium-binding protein pEL98 (or mts1) in cell motility and tumor cell invasion. Jpn J Cancer Res 85(8):831–839CrossRefGoogle Scholar
  24. 24.
    Grigorian M, Ambartsumian N, Lykkesfeldt AE, Bastholm L, Elling F, Georgiev G, Lukanidin E (1996) Effect of mts1 (S100A4) expression on the progression of human breast cancer cells. Int J Cancer 67(6):831–841.<831::AID-IJC13>3.0.CO;2-4CrossRefPubMedGoogle Scholar
  25. 25.
    Davies BR, Davies MP, Gibbs FE, Barraclough R, Rudland PS (1993) Induction of the metastatic phenotype by transfection of a benign rat mammary epithelial cell line with the gene for p9Ka, a rat calcium-binding protein, but not with the oncogene EJ-ras-1. Oncogene 8(4):999–1008PubMedGoogle Scholar
  26. 26.
    Maelandsmo GM, Hovig E, Skrede M, Engebraaten O, Florenes VA, Myklebost O, Grigorian M, Lukanidin E, Scanlon KJ, Fodstad O (1996) Reversal of the in vivo metastatic phenotype of human tumor cells by an anti-CAPL (mts1) ribozyme. Cancer Res 56(23):5490–5498PubMedGoogle Scholar
  27. 27.
    Ambartsumian NS, Grigorian MS, Larsen IF, Karlstrom O, Sidenius N, Rygaard J, Georgiev G, Lukanidin E (1996) Metastasis of mammary carcinomas in GRS/A hybrid mice transgenic for the mts1 gene. Oncogene 13(8):1621–1630PubMedGoogle Scholar
  28. 28.
    Davies MP, Rudland PS, Robertson L, Parry EW, Jolicoeur P, Barraclough R (1996) Expression of the calcium-binding protein S100A4 (p9Ka) in MMTV-neu transgenic mice induces metastasis of mammary tumours. Oncogene 13(8):1631–1637PubMedGoogle Scholar
  29. 29.
    Grum-Schwensen B, Klingelhofer J, Berg CH, El-Naaman C, Grigorian M, Lukanidin E, Ambartsumian N (2005) Suppression of tumor development and metastasis formation in mice lacking the S100A4(mts1) gene. Cancer Res 65(9):3772–3780. Scholar
  30. 30.
    Grum-Schwensen B, Klingelhofer J, Grigorian M, Almholt K, Nielsen BS, Lukanidin E, Ambartsumian N (2010) Lung metastasis fails in MMTV-PyMT oncomice lacking S100A4 due to a T-cell deficiency in primary tumors. Cancer Res 70(3):936–947. Scholar
  31. 31.
    Xue C, Plieth D, Venkov C, Xu C, Neilson EG (2003) The gatekeeper effect of epithelial-mesenchymal transition regulates the frequency of breast cancer metastasis. Cancer Res 63(12):3386–3394PubMedGoogle Scholar
  32. 32.
    Grum-Schwensen B, Klingelhofer J, Beck M, Bonefeld CM, Hamerlik P, Guldberg P, Grigorian M, Lukanidin E, Ambartsumian N (2015) S100A4-neutralizing antibody suppresses spontaneous tumor progression, pre-metastatic niche formation and alters T-cell polarization balance. BMC Cancer 15:44. Scholar
  33. 33.
    Klingelhofer J, Grum-Schwensen B, Beck MK, Knudsen RS, Grigorian M, Lukanidin E, Ambartsumian N (2012) Anti-S100A4 antibody suppresses metastasis formation by blocking stroma cell invasion. Neoplasia 14(12):1260–1268CrossRefGoogle Scholar
  34. 34.
    Chen H, Xu C, Jin Q, Liu Z (2014) S100 protein family in human cancer. Am J Cancer Res 4(2):89–115PubMedPubMedCentralGoogle Scholar
  35. 35.
    Sherbet GV (2009) Metastasis promoter S100A4 is a potentially valuable molecular target for cancer therapy. Cancer Lett 280(1):15–30. Scholar
  36. 36.
    Rudland PS, Platt-Higgins A, Renshaw C, West CR, Winstanley JH, Robertson L, Barraclough R (2000) Prognostic significance of the metastasis-inducing protein S100A4 (p9Ka) in human breast cancer. Cancer Res 60(6):1595–1603PubMedGoogle Scholar
  37. 37.
    Gongoll S, Peters G, Mengel M, Piso P, Klempnauer J, Kreipe H, von Wasielewski R (2002) Prognostic significance of calcium-binding protein S100A4 in colorectal cancer. Gastroenterology 123(5):1478–1484CrossRefGoogle Scholar
  38. 38.
    Joyce JA, Pollard JW (2009) Microenvironmental regulation of metastasis. Nat Rev Cancer 9(4):239–252. Scholar
  39. 39.
    Peinado H, Zhang H, Matei IR, Costa-Silva B, Hoshino A, Rodrigues G, Psaila B, Kaplan RN, Bromberg JF, Kang Y, Bissell MJ, Cox TR, Giaccia AJ, Erler JT, Hiratsuka S, Ghajar CM, Lyden D (2017) Pre-metastatic niches: organ-specific homes for metastases. Nat Rev Cancer 17(5):302–317. Scholar
  40. 40.
    Schmidt-Hansen B, Klingelhofer J, Grum-Schwensen B, Christensen A, Andresen S, Kruse C, Hansen T, Ambartsumian N, Lukanidin E, Grigorian M (2004) Functional significance of metastasis-inducing S100A4(Mts1) in tumor-stroma interplay. J Biol Chem 279(23):24498–24504. Scholar
  41. 41.
    Ambartsumian N, Klingelhofer J, Grigorian M, Christensen C, Kriajevska M, Tulchinsky E, Georgiev G, Berezin V, Bock E, Rygaard J, Cao R, Cao Y, Lukanidin E (2001) The metastasis-associated Mts1(S100A4) protein could act as an angiogenic factor. Oncogene 20(34):4685–4695. Scholar
  42. 42.
    Cabezon T, Celis JE, Skibshoj I, Klingelhofer J, Grigorian M, Gromov P, Rank F, Myklebust JH, Maelandsmo GM, Lukanidin E, Ambartsumian N (2007) Expression of S100A4 by a variety of cell types present in the tumor microenvironment of human breast cancer. Int J Cancer 121(7):1433–1444. Scholar
  43. 43.
    Schmidt-Hansen B, Ornas D, Grigorian M, Klingelhofer J, Tulchinsky E, Lukanidin E, Ambartsumian N (2004) Extracellular S100A4(mts1) stimulates invasive growth of mouse endothelial cells and modulates MMP-13 matrix metalloproteinase activity. Oncogene 23(32):5487–5495. Scholar
  44. 44.
    Pedersen KB, Andersen K, Fodstad O, Maelandsmo GM (2004) Sensitization of interferon-gamma induced apoptosis in human osteosarcoma cells by extracellular S100A4. BMC Cancer 4:52. Scholar
  45. 45.
    O’Connell JT, Sugimoto H, Cooke VG, MacDonald BA, Mehta AI, LeBleu VS, Dewar R, Rocha RM, Brentani RR, Resnick MB, Neilson EG, Zeisberg M, Kalluri R (2011) VEGF-A and Tenascin-C produced by S100A4+ stromal cells are important for metastatic colonization. Proc Natl Acad Sci U S A 108(38):16002–16007. Scholar
  46. 46.
    Masuda K, Masuda R, Neidhart M, Simmen BR, Michel BA, Muller-Ladner U, Gay RE, Gay S (2002) Molecular profile of synovial fibroblasts in rheumatoid arthritis depends on the stage of proliferation. Arthritis Res 4(5):R8. Scholar
  47. 47.
    Klingelhofer J, Senolt L, Baslund B, Nielsen GH, Skibshoj I, Pavelka K, Neidhart M, Gay S, Ambartsumian N, Hansen BS, Petersen J, Lukanidin E, Grigorian M (2007) Up-regulation of metastasis-promoting S100A4 (Mts-1) in rheumatoid arthritis: putative involvement in the pathogenesis of rheumatoid arthritis. Arthritis Rheum 56(3):779–789. Scholar
  48. 48.
    Oslejskova L, Grigorian M, Hulejova H, Vencovsky J, Pavelka K, Klingelhofer J, Gay S, Neidhart M, Brabcova H, Suchy D, Senolt L (2009) Metastasis-inducing S100A4 protein is associated with the disease activity of rheumatoid arthritis. Rheumatology (Oxford) 48(12):1590–1594. Scholar
  49. 49.
    Erlandsson MC, Forslind K, Andersson SE, Lund A, Bokarewa MI (2012) Metastasin S100A4 is increased in proportion to radiographic damage in patients with RA. Rheumatology (Oxford) 51(5):932–940. Scholar
  50. 50.
    Senolt L, Cerezo LA, Sumova B, Pecha O, Plestilova L, Forejtova S, Ruzickova O, Husakova M, Zavada J, Pavelka K, Vencovsky J, Mann H (2015) High levels of metastasis-inducing S100A4 protein and treatment outcome in early rheumatoid arthritis: data from the PERAC cohort. Biomarkers 20(1):47–51. Scholar
  51. 51.
    Zibert JR, Skov L, Thyssen JP, Jacobsen GK, Grigorian M (2010) Significance of the S100A4 protein in psoriasis. J Invest Dermatol 130(1):150–160. Scholar
  52. 52.
    Tomcik M, Palumbo-Zerr K, Zerr P, Avouac J, Dees C, Sumova B, Distler A, Beyer C, Cerezo LA, Becvar R, Distler O, Grigorian M, Schett G, Senolt L, Distler JH (2015) S100A4 amplifies TGF-beta-induced fibroblast activation in systemic sclerosis. Ann Rheum Dis 74(9):1748–1755. Scholar
  53. 53.
    Cutolo M, Ruaro B, Montagna P, Brizzolara R, Stratta E, Trombetta AC, Scabini S, Tavilla PP, Parodi A, Corallo C, Giordano N, Paolino S, Pizzorni C, Sulli A, Smith V, Soldano S (2018) Effects of selexipag and its active metabolite in contrasting the profibrotic myofibroblast activity in cultured scleroderma skin fibroblasts. Arthritis Res Ther 20(1):77. Scholar
  54. 54.
    Janson C, Anto J, Burney P, Chinn S, de Marco R, Heinrich J, Jarvis D, Kuenzli N, Leynaert B, Luczynska C, Neukirch F, Svanes C, Sunyer J, Wjst M, European Community Respiratory Health Survey II (2001) The European Community Respiratory Health Survey: what are the main results so far? European Community Respiratory Health Survey II. Eur Respir J 18(3):598–611CrossRefGoogle Scholar
  55. 55.
    Bruhn S, Fang Y, Barrenas F, Gustafsson M, Zhang H, Konstantinell A, Kronke A, Sonnichsen B, Bresnick A, Dulyaninova N, Wang H, Zhao Y, Klingelhofer J, Ambartsumian N, Beck MK, Nestor C, Bona E, Xiang Z, Benson M (2014) A generally applicable translational strategy identifies S100A4 as a candidate gene in allergy. Sci Transl Med 6(218):218ra214. Scholar
  56. 56.
    Kriajevska MV, Cardenas MN, Grigorian MS, Ambartsumian NS, Georgiev GP, Lukanidin EM (1994) Non-muscle myosin heavy chain as a possible target for protein encoded by metastasis-related mts-1 gene. J Biol Chem 269(31):19679–19682PubMedGoogle Scholar
  57. 57.
    Ismail TM, Fernig DG, Rudland PS, Terry CJ, Wang G, Barraclough R (2008) The basic C-terminal amino acids of calcium-binding protein S100A4 promote metastasis. Carcinogenesis 29(12):2259–2266. Scholar
  58. 58.
    Naiya G, Kaypee S, Kundu TK, Roy S (2015) A constrained helical peptide against S100A4 inhibits cell motility in tumor cells. Chem Biol Drug Des 86(4):945–950. Scholar
  59. 59.
    Li ZH, Dulyaninova NG, House RP, Almo SC, Bresnick AR (2010) S100A4 regulates macrophage chemotaxis. Mol Biol Cell 21(15):2598–2610. Scholar
  60. 60.
    Fernandez-Fernandez MR, Veprintsev DB, Fersht AR (2005) Proteins of the S100 family regulate the oligomerization of p53 tumor suppressor. Proc Natl Acad Sci U S A 102(13):4735–4740. Scholar
  61. 61.
    Orre LM, Panizza E, Kaminskyy VO, Vernet E, Graslund T, Zhivotovsky B, Lehtio J (2013) S100A4 interacts with p53 in the nucleus and promotes p53 degradation. Oncogene 32(49):5531–5540. Scholar
  62. 62.
    Tamaki Y, Iwanaga Y, Niizuma S, Kawashima T, Kato T, Inuzuka Y, Horie T, Morooka H, Takase T, Akahashi Y, Kobuke K, Ono K, Shioi T, Sheikh SP, Ambartsumian N, Lukanidin E, Koshimizu TA, Miyazaki S, Kimura T (2013) Metastasis-associated protein, S100A4 mediates cardiac fibrosis potentially through the modulation of p53 in cardiac fibroblasts. J Mol Cell Cardiol 57:72–81. Scholar
  63. 63.
    Xu Y, Rong LJ, Meng SL, Hou FL, Zhang JH, Pan G (2016) PRAME promotes in vitro leukemia cells death by regulating S100A4/p53 signaling. Eur Rev Med Pharmacol Sci 20(6):1057–1063PubMedGoogle Scholar
  64. 64.
    Kriajevska M, Fischer-Larsen M, Moertz E, Vorm O, Tulchinsky E, Grigorian M, Ambartsumian N, Lukanidin E (2002) Liprin beta 1, a member of the family of LAR transmembrane tyrosine phosphatase-interacting proteins, is a new target for the metastasis-associated protein S100A4 (Mts1). J Biol Chem 277(7):5229–5235. Scholar
  65. 65.
    Serra-Pages C, Medley QG, Tang M, Hart A, Streuli M (1998) Liprins, a family of LAR transmembrane protein-tyrosine phosphatase-interacting proteins. J Biol Chem 273(25):15611–15620CrossRefGoogle Scholar
  66. 66.
    Grigorian M, Tulchinsky E, Burrone O, Tarabykina S, Georgiev G, Lukanidin E (1994) Modulation of mts1 expression in mouse and human normal and tumor cells. Electrophoresis 15(3-4):463–468CrossRefGoogle Scholar
  67. 67.
    Kalluri R, Zeisberg M (2006) Fibroblasts in cancer. Nat Rev Cancer 6(5):392–401. Scholar
  68. 68.
    Weatherly K, Bettonville M, Torres D, Kohler A, Goriely S, Braun MY (2015) Functional profile of S100A4-deficient T cells. Immun Inflamm Dis 3(4):431–444. Scholar
  69. 69.
    Greene WA, Burke TA, Por ED, Kaini RR, Wang HC (2016) Secretion profile of induced pluripotent stem cell-derived retinal pigment epithelium during wound healing. Invest Ophthalmol Vis Sci 57(10):4428–4441. Scholar
  70. 70.
    Herwig N, Belter B, Pietzsch J (2016) Extracellular S100A4 affects endothelial cell integrity and stimulates transmigration of A375 melanoma cells. Biochem Biophys Res Commun 477(4):963–969. Scholar
  71. 71.
    Rasanen K, Sriswasdi S, Valiga A, Tang HY, Zhang G, Perego M, Somasundaram R, Li L, Speicher K, Klein-Szanto AJ, Basu D, Rustgi AK, Speicher DW, Herlyn M (2013) Comparative secretome analysis of epithelial and mesenchymal subpopulations of head and neck squamous cell carcinoma identifies S100A4 as a potential therapeutic target. Mol Cell Proteomics 12(12):3778–3792. Scholar
  72. 72.
    Gong XJ, Song XY, Wei H, Wang J, Niu M (2015) Serum S100A4 levels as a novel biomarker for detection of acute myocardial infarction. Eur Rev Med Pharmacol Sci 19(12):2221–2225PubMedGoogle Scholar
  73. 73.
    Abu El-Asrar AM, Nawaz MI, De Hertogh G, Alam K, Siddiquei MM, Van den Eynde K, Mousa A, Mohammad G, Geboes K, Opdenakker G (2014) S100A4 is upregulated in proliferative diabetic retinopathy and correlates with markers of angiogenesis and fibrogenesis. Mol Vis 20:1209–1224PubMedPubMedCentralGoogle Scholar
  74. 74.
    Christensen MH, Fenne IS, Nordbo Y, Varhaug JE, Nygard KO, Lien EA, Mellgren G (2015) Novel inflammatory biomarkers in primary hyperparathyroidism. Eur J Endocrinol 173(1):9–17. Scholar
  75. 75.
    Donato R, Cannon BR, Sorci G, Riuzzi F, Hsu K, Weber DJ, Geczy CL (2013) Functions of S100 proteins. Curr Mol Med 13(1):24–57CrossRefGoogle Scholar
  76. 76.
    Forst B, Hansen MT, Klingelhofer J, Moller HD, Nielsen GH, Grum-Schwensen B, Ambartsumian N, Lukanidin E, Grigorian M (2010) Metastasis-inducing S100A4 and RANTES cooperate in promoting tumor progression in mice. PLoS One 5(4):e10374. Scholar
  77. 77.
    Yammani RR, Long D, Loeser RF (2009) Interleukin-7 stimulates secretion of S100A4 by activating the JAK/STAT signaling pathway in human articular chondrocytes. Arthritis Rheum 60(3):792–800. Scholar
  78. 78.
    Dukhanina EA, Portseva TN, Pankratova EV, Soshnikova NV, Stepchenko AG, Dukhanin AS, Georgieva SG (2016) Oct-1 modifies S100A4 exchange between intra- and extracellular compartments in Namalwa cells and increases their sensitivity to glucocorticoids. Cell Cycle 15(11):1471–1478. Scholar
  79. 79.
    Novitskaya V, Grigorian M, Kriajevska M, Tarabykina S, Bronstein I, Berezin V, Bock E, Lukanidin E (2000) Oligomeric forms of the metastasis-related Mts1 (S100A4) protein stimulate neuronal differentiation in cultures of rat hippocampal neurons. J Biol Chem 275(52):41278–41286. Scholar
  80. 80.
    Pedersen MV, Kohler LB, Grigorian M, Novitskaya V, Bock E, Lukanidin E, Berezin V (2004) The Mts1/S100A4 protein is a neuroprotectant. J Neurosci Res 77(6):777–786. Scholar
  81. 81.
    Beutler B, Jiang Z, Georgel P, Crozat K, Croker B, Rutschmann S, Du X, Hoebe K (2006) Genetic analysis of host resistance: Toll-like receptor signaling and immunity at large. Annu Rev Immunol 24:353–389. Scholar
  82. 82.
    Pusterla T, Nemeth J, Stein I, Wiechert L, Knigin D, Marhenke S, Longerich T, Kumar V, Arnold B, Vogel A, Bierhaus A, Pikarsky E, Hess J, Angel P (2013) Receptor for advanced glycation endproducts (RAGE) is a key regulator of oval cell activation and inflammation-associated liver carcinogenesis in mice. Hepatology 58(1):363–373. Scholar
  83. 83.
    Riehl A, Nemeth J, Angel P, Hess J (2009) The receptor RAGE: bridging inflammation and cancer. Cell Commun Signal 7:12. Scholar
  84. 84.
    Dahlmann M, Okhrimenko A, Marcinkowski P, Osterland M, Herrmann P, Smith J, Heizmann CW, Schlag PM, Stein U (2014) RAGE mediates S100A4-induced cell motility via MAPK/ERK and hypoxia signaling and is a prognostic biomarker for human colorectal cancer metastasis. Oncotarget 5(10):3220–3233. Scholar
  85. 85.
    Siddique HR, Adhami VM, Parray A, Johnson JJ, Siddiqui IA, Shekhani MT, Murtaza I, Ambartsumian N, Konety BR, Mukhtar H, Saleem M (2013) The S100A4 oncoprotein promotes prostate tumorigenesis in a transgenic mouse model: regulating NFkappaB through the RAGE receptor. Genes Cancer 4(5–6):224–234. Scholar
  86. 86.
    Yammani RR, Carlson CS, Bresnick AR, Loeser RF (2006) Increase in production of matrix metalloproteinase 13 by human articular chondrocytes due to stimulation with S100A4: role of the receptor for advanced glycation end products. Arthritis Rheum 54(9):2901–2911. Scholar
  87. 87.
    Hernandez JL, Padilla L, Dakhel S, Coll T, Hervas R, Adan J, Masa M, Mitjans F, Martinez JM, Coma S, Rodriguez L, Noe V, Ciudad CJ, Blasco F, Messeguer R (2013) Therapeutic targeting of tumor growth and angiogenesis with a novel anti-S100A4 monoclonal antibody. PLoS One 8(9):e72480. Scholar
  88. 88.
    Chaabane C, Heizmann CW, Bochaton-Piallat ML (2015) Extracellular S100A4 induces smooth muscle cell phenotypic transition mediated by RAGE. Biochim Biophys Acta 1853(9):2144–2157. Scholar
  89. 89.
    Medapati MR, Dahlmann M, Ghavami S, Pathak KA, Lucman L, Klonisch T, Hoang-Vu C, Stein U, Hombach-Klonisch S (2015) RAGE mediates the pro-migratory response of extracellular S100A4 in human thyroid cancer cells. Thyroid 25(5):514–527. Scholar
  90. 90.
    Kiryushko D, Novitskaya V, Soroka V, Klingelhofer J, Lukanidin E, Berezin V, Bock E (2006) Molecular mechanisms of Ca(2+) signaling in neurons induced by the S100A4 protein. Mol Cell Biol 26(9):3625–3638. Scholar
  91. 91.
    Cerezo LA, Remakova M, Tomcik M, Gay S, Neidhart M, Lukanidin E, Pavelka K, Grigorian M, Vencovsky J, Senolt L (2014) The metastasis-associated protein S100A4 promotes the inflammatory response of mononuclear cells via the TLR4 signalling pathway in rheumatoid arthritis. Rheumatology (Oxford) 53(8):1520–1526. Scholar
  92. 92.
    Grotterod I, Maelandsmo GM, Boye K (2010) Signal transduction mechanisms involved in S100A4-induced activation of the transcription factor NF-kappaB. BMC Cancer 10:241. Scholar
  93. 93.
    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(11):1349–1355. Scholar
  94. 94.
    Vogl T, Tenbrock K, Ludwig S, Leukert N, Ehrhardt C, van Zoelen MA, Nacken W, Foell D, van der Poll T, Sorg C, Roth J (2007) Mrp8 and Mrp14 are endogenous activators of Toll-like receptor 4, promoting lethal, endotoxin-induced shock. Nat Med 13(9):1042–1049. Scholar
  95. 95.
    Li Q, Dai C, Xue R, Wang P, Chen L, Han Y, Erben U, Qin Z (2018) S100A4 protects myeloid-derived suppressor cells from intrinsic apoptosis via TLR4-ERK1/2 signaling. Front Immunol 9:388. Scholar
  96. 96.
    Li J, Yang F, Wei F, Ren X (2017) The role of toll-like receptor 4 in tumor microenvironment. Oncotarget 8(39):66656–66667. Scholar
  97. 97.
    Dmytriyeva O, Pankratova S, Owczarek S, Sonn K, Soroka V, Ridley CM, Marsolais A, Lopez-Hoyos M, Ambartsumian N, Lukanidin E, Bock E, Berezin V, Kiryushko D (2012) The metastasis-promoting S100A4 protein confers neuroprotection in brain injury. Nat Commun 3:1197. Scholar
  98. 98.
    Herbst RS (2004) Review of epidermal growth factor receptor biology. Int J Radiat Oncol Biol Phys 59(2 Suppl):21–26. Scholar
  99. 99.
    Klingelhofer J, Moller HD, Sumer EU, Berg CH, Poulsen M, Kiryushko D, Soroka V, Ambartsumian N, Grigorian M, Lukanidin EM (2009) Epidermal growth factor receptor ligands as new extracellular targets for the metastasis-promoting S100A4 protein. FEBS J 276(20):5936–5948. Scholar
  100. 100.
    Cho CC, Chou RH, Yu C (2016) Amlexanox blocks the interaction between S100A4 and epidermal growth factor and inhibits cell proliferation. PLoS One 11(8):e0161663. Scholar
  101. 101.
    Buetti-Dinh A, Pivkin IV, Friedman R (2015) S100A4 and its role in metastasis - computational integration of data on biological networks. Mol BioSyst 11(8):2238–2246. Scholar
  102. 102.
    Zhang Q, Zhao Z, Ma Y, Wang H, Ma J, He X, Zhang D (2014) Combined expression of S100A4 and Annexin A2 predicts disease progression and overall survival in patients with urothelial carcinoma. Urol Oncol 32(6):798–805. Scholar
  103. 103.
    Boye K, Grotterod I, Aasheim HC, Hovig E, Maelandsmo GM (2008) Activation of NF-kappaB by extracellular S100A4: analysis of signal transduction mechanisms and identification of target genes. Int J Cancer 123(6):1301–1310. Scholar
  104. 104.
    Rojas A, Figueroa H, Morales E (2010) Fueling inflammation at tumor microenvironment: the role of multiligand/RAGE axis. Carcinogenesis 31(3):334–341. Scholar
  105. 105.
    Terzic J, Grivennikov S, Karin E, Karin M (2010) Inflammation and colon cancer. Gastroenterology 138(6):2101–2114 e2105. Scholar
  106. 106.
    Ahmad S, Khan H, Siddiqui Z, Khan MY, Rehman S, Shahab U, Godovikova T, Silnikov V, Moinuddin (2018) AGEs, RAGEs and s-RAGE; friend or foe for cancer. Semin Cancer Biol 49:44–55. Scholar
  107. 107.
    Hou S, Tian T, Qi D, Sun K, Yuan Q, Wang Z, Qin Z, Wu Z, Chen Z, Zhang J (2018) S100A4 promotes lung tumor development through beta-catenin pathway-mediated autophagy inhibition. Cell Death Dis 9(3):277. Scholar
  108. 108.
    Wolf S, Haase-Kohn C, Lenk J, Hoppmann S, Bergmann R, Steinbach J, Pietzsch J (2011) Expression, purification and fluorine-18 radiolabeling of recombinant S100A4: a potential probe for molecular imaging of receptor for advanced glycation endproducts in vivo? Amino Acids 41(4):809–820. Scholar
  109. 109.
    Haase-Kohn C, Wolf S, Herwig N, Mosch B, Pietzsch J (2014) Metastatic potential of B16-F10 melanoma cells is enhanced by extracellular S100A4 derived from RAW264.7 macrophages. Biochem Biophys Res Commun 446(1):143–148. Scholar
  110. 110.
    Ambartsumian N, Grigorian M (2016) [S100A4, a link between metastasis and inflammation]. Mol Biol (Mosk) 50(4):577–588. Scholar
  111. 111.
    Seif F, Khoshmirsafa M, Aazami H, Mohsenzadegan M, Sedighi G, Bahar M (2017) The role of JAK-STAT signaling pathway and its regulators in the fate of T helper cells. Cell Commun Signal 15(1):23. Scholar
  112. 112.
    Smith BN, Bhowmick NA (2016) Role of EMT in metastasis and therapy resistance. J Clin Med 5(2). Scholar
  113. 113.
    Bowers RR, Manevich Y, Townsend DM, Tew KD (2012) Sulfiredoxin redox-sensitive interaction with S100A4 and non-muscle myosin IIA regulates cancer cell motility. Biochemistry 51(39):7740–7754. Scholar
  114. 114.
    Chen M, Bresnick AR, O'Connor KL (2013) Coupling S100A4 to Rhotekin alters Rho signaling output in breast cancer cells. Oncogene 32(32):3754–3764. Scholar
  115. 115.
    Spiekerkoetter E, Guignabert C, de Jesus Perez V, Alastalo TP, Powers JM, Wang L, Lawrie A, Ambartsumian N, Schmidt AM, Berryman M, Ashley RH, Rabinovitch M (2009) S100A4 and bone morphogenetic protein-2 codependently induce vascular smooth muscle cell migration via phospho-extracellular signal-regulated kinase and chloride intracellular channel 4. Circ Res 105(7):639–647, 613 p following 647. Scholar
  116. 116.
    Talbot LJ, Bhattacharya SD, Kuo PC (2012) Epithelial-mesenchymal transition, the tumor microenvironment, and metastatic behavior of epithelial malignancies. Int J Biochem Mol Biol 3(2):117–136PubMedPubMedCentralGoogle Scholar
  117. 117.
    Pradella D, Naro C, Sette C, Ghigna C (2017) EMT and stemness: flexible processes tuned by alternative splicing in development and cancer progression. Mol Cancer 16(1):8. Scholar
  118. 118.
    Harris MA, Yang H, Low BE, Mukherjee J, Guha A, Bronson RT, Shultz LD, Israel MA, Yun K (2008) Cancer stem cells are enriched in the side population cells in a mouse model of glioma. Cancer Res 68(24):10051–10059. Scholar
  119. 119.
    Ren D, Zhu X, Kong R, Zhao Z, Sheng J, Wang J, Xu X, Liu J, Cui K, Zhang XH, Zhao H, Wong STC (2018) Targeting brain-adaptive cancer stem cells prohibits brain metastatic colonization of triple-negative breast cancer. Cancer Res 78(8):2052–2064. Scholar
  120. 120.
    Cheng LH, Hung KF, Huang TF, Hsieh HP, Wang SY, Huang CY, Lo JF (2016) Attenuation of cancer-initiating cells stemness properties by abrogating S100A4 calcium binding ability in head and neck cancers. Oncotarget 7(48):78946–78957. Scholar
  121. 121.
    Lo JF, Yu CC, Chiou SH, Huang CY, Jan CI, Lin SC, Liu CJ, Hu WY, Yu YH (2011) The epithelial-mesenchymal transition mediator S100A4 maintains cancer-initiating cells in head and neck cancers. Cancer Res 71(5):1912–1923. Scholar
  122. 122.
    Xia H, Gilbertsen A, Herrera J, Racila E, Smith K, Peterson M, Griffin T, Benyumov A, Yang L, Bitterman PB, Henke CA (2017) Calcium-binding protein S100A4 confers mesenchymal progenitor cell fibrogenicity in idiopathic pulmonary fibrosis. J Clin Invest 127(7):2586–2597. Scholar
  123. 123.
    Jiao J, Gonzalez A, Stevenson HL, Gagea M, Sugimoto H, Kalluri R, Beretta L (2018) Depletion of S100A4(+) stromal cells does not prevent HCC development but reduces the stem cell-like phenotype of the tumors. Exp Mol Med 50(1):e422. Scholar
  124. 124.
    Powell E, Piwnica-Worms D, Piwnica-Worms H (2014) Contribution of p53 to metastasis. Cancer Discov 4(4):405–414. Scholar
  125. 125.
    Shen W, Chen D, Liu S, Chen L, Yu A, Fu H, Sun X (2015) S100A4 interacts with mutant p53 and affects gastric cancer MKN1 cell autophagy and differentiation. Int J Oncol 47(6):2123–2130. Scholar
  126. 126.
    van Dieck J, Teufel DP, Jaulent AM, Fernandez-Fernandez MR, Rutherford TJ, Wyslouch-Cieszynska A, Fersht AR (2009) Posttranslational modifications affect the interaction of S100 proteins with tumor suppressor p53. J Mol Biol 394(5):922–930. Scholar
  127. 127.
    Sun Z, Wu Z, Zhang F, Guo Q, Li L, Li K, Chen H, Zhao J, Song D, Huang Q, Li L, Xiao J (2016) PRAME is critical for breast cancer growth and metastasis. Gene 594(1):160–164. Scholar
  128. 128.
    EL naaman C, Grum-Schwensen B, Mansouri A, Grigorian M, Santoni-Rugiu E, Hansen T, Kriajevska M, Schafer BW, Heizmann CW, Lukanidin E, Ambartsumian N (2004) Cancer predisposition in mice deficient for the metastasis-associated Mts1(S100A4) gene. Oncogene 23(20):3670–3680. Scholar
  129. 129.
    Mrakovcic M, Frohlich LF (2018) p53-mediated molecular control of autophagy in tumor cells. Biomol Ther 8(2).
  130. 130.
    Guo S, Pridham KJ, Virbasius CM, He B, Zhang L, Varmark H, Green MR, Sheng Z (2018) A large-scale RNA interference screen identifies genes that regulate autophagy at different stages. Sci Rep 8(1):2822. Scholar
  131. 131.
    Bian XW, Chen JH, Jiang XF, Bai JS, Wang QL, Zhang X (2004) Angiogenesis as an immunopharmacologic target in inflammation and cancer. Int Immunopharmacol 4(12):1537–1547. Scholar
  132. 132.
    Jackson JR, Seed MP, Kircher CH, Willoughby DA, Winkler JD (1997) The codependence of angiogenesis and chronic inflammation. FASEB J 11(6):457–465CrossRefGoogle Scholar
  133. 133.
    Ono M (2008) Molecular links between tumor angiogenesis and inflammation: inflammatory stimuli of macrophages and cancer cells as targets for therapeutic strategy. Cancer Sci 99(8):1501–1506. Scholar
  134. 134.
    de Silva Rudland S, Martin L, Roshanlall C, Winstanley J, Leinster S, Platt-Higgins A, Carroll J, West C, Barraclough R, Rudland P (2006) Association of S100A4 and osteopontin with specific prognostic factors and survival of patients with minimally invasive breast cancer. Clin Cancer Res 12(4):1192–1200. Scholar
  135. 135.
    Ochiya T, Takenaga K, Asagiri M, Nakano K, Satoh H, Watanabe T, Imajoh-Ohmi S, Endo H (2015) Efficient inhibition of tumor angiogenesis and growth by a synthetic peptide blocking S100A4-methionine aminopeptidase 2 interaction. Mol Ther Methods Clin Dev 2:15008. Scholar
  136. 136.
    Sun JB, Holmgren J, Larena M, Terrinoni M, Fang Y, Bresnick AR, Xiang Z (2017) Deficiency in calcium-binding protein S100A4 impairs the adjuvant action of cholera toxin. Front Immunol 8:1119. Scholar
  137. 137.
    Duguet F, Locard-Paulet M, Marcellin M, Chaoui K, Bernard I, Andreoletti O, Lesourne R, Burlet-Schiltz O, Gonzalez de Peredo A, Saoudi A (2017) Proteomic analysis of regulatory T cells reveals the importance of Themis1 in the control of their suppressive function. Mol Cell Proteomics 16(8):1416–1432. Scholar
  138. 138.
    Pfoertner S, Jeron A, Probst-Kepper M, Guzman CA, Hansen W, Westendorf AM, Toepfer T, Schrader AJ, Franzke A, Buer J, Geffers R (2006) Signatures of human regulatory T cells: an encounter with old friends and new players. Genome Biol 7(7):R54. Scholar
  139. 139.
    Chen L, Li J, Zhang J, Dai C, Liu X, Wang J, Gao Z, Guo H, Wang R, Lu S, Wang F, Zhang H, Chen H, Fan X, Wang S, Qin Z (2015) S100A4 promotes liver fibrosis via activation of hepatic stellate cells. J Hepatol 62(1):156–164. Scholar
  140. 140.
    Osterreicher CH, Penz-Osterreicher M, Grivennikov SI, Guma M, Koltsova EK, Datz C, Sasik R, Hardiman G, Karin M, Brenner DA (2011) Fibroblast-specific protein 1 identifies an inflammatory subpopulation of macrophages in the liver. Proc Natl Acad Sci U S A 108(1):308–313. Scholar
  141. 141.
    Bettum IJ, Vasiliauskaite K, Nygaard V, Clancy T, Pettersen SJ, Tenstad E, Maelandsmo GM, Prasmickaite L (2014) Metastasis-associated protein S100A4 induces a network of inflammatory cytokines that activate stromal cells to acquire pro-tumorigenic properties. Cancer Lett 344(1):28–39. Scholar
  142. 142.
    Prasmickaite L, Tenstad EM, Pettersen S, Jabeen S, Egeland EV, Nord S, Pandya A, Haugen MH, Kristensen VN, Borresen-Dale AL, Oslo Breast Cancer Research Consortium, Engebraten O, Maelandsmo GM (2018) Basal-like breast cancer engages tumor-supportive macrophages via secreted factors induced by extracellular S100A4. Mol Oncol. Scholar
  143. 143.
    Mah SJ, Lee J, Kim H, Kang YG, Baek SH, Kim HH, Lim WH (2015) Induction of S100A4 in periodontal ligament cells enhances osteoclast formation. Arch Oral Biol 60(9):1215–1221. Scholar
  144. 144.
    Kondo N, Ichimiya S, Tamura Y, Tonooka A, Koshiba S, Torigoe T, Kamiguchi K, Takenaga K, Sato N (2005) A calcium binding protein, S100A4, mediates T cell dependent cytotoxicity as a transformation-associated antigen. Microbiol Immunol 49(1):49–56CrossRefGoogle Scholar
  145. 145.
    Lotfi R, Wiegmann D, Asseck L, Nienhaus C, Erle A, Schrezenmeier H (2012) Necrosis-Associated factors (DAMPs) not only promote tumor proliferation per se but also impact adaptive immune response. Impact of S100A4 within tumor microenvironment. Onkologie 35:81–81Google Scholar
  146. 146.
    Veglia F, Perego M, Gabrilovich D (2018) Myeloid-derived suppressor cells coming of age. Nat Immunol 19(2):108–119. Scholar
  147. 147.
    Sorokin L (2010) The impact of the extracellular matrix on inflammation. Nat Rev Immunol 10(10):712–723. Scholar
  148. 148.
    Wight TN, Frevert CW, Debley JS, Reeves SR, Parks WC, Ziegler SF (2017) Interplay of extracellular matrix and leukocytes in lung inflammation. Cell Immunol 312:1–14. Scholar
  149. 149.
    Berge G, Pettersen S, Grotterod I, Bettum IJ, Boye K, Maelandsmo GM (2011) Osteopontin – an important downstream effector of S100A4-mediated invasion and metastasis. Int J Cancer 129(4):780–790. Scholar
  150. 150.
    Kahles F, Findeisen HM, Bruemmer D (2014) Osteopontin: a novel regulator at the cross roads of inflammation, obesity and diabetes. Mol Metab 3(4):384–393. Scholar
  151. 151.
    Nissinen L, Kahari VM (2014) Matrix metalloproteinases in inflammation. Biochim Biophys Acta 1840(8):2571–2580. Scholar
  152. 152.
    Bjornland K, Winberg JO, Odegaard OT, Hovig E, Loennechen T, Aasen AO, Fodstad O, Maelandsmo GM (1999) S100A4 involvement in metastasis: deregulation of matrix metalloproteinases and tissue inhibitors of matrix metalloproteinases in osteosarcoma cells transfected with an anti-S100A4 ribozyme. Cancer Res 59(18):4702–4708PubMedGoogle Scholar
  153. 153.
    Saleem M, Kweon MH, Johnson JJ, Adhami VM, Elcheva I, Khan N, Bin Hafeez B, Bhat KM, Sarfaraz S, Reagan-Shaw S, Spiegelman VS, Setaluri V, Mukhtar H (2006) S100A4 accelerates tumorigenesis and invasion of human prostate cancer through the transcriptional regulation of matrix metalloproteinase 9. Proc Natl Acad Sci U S A 103(40):14825–14830. Scholar
  154. 154.
    Zhang J, Zhang DL, Jiao XL, Dong Q (2013) S100A4 regulates migration and invasion in hepatocellular carcinoma HepG2 cells via NF-kappaB-dependent MMP-9 signal. Eur Rev Med Pharmacol Sci 17(17):2372–2382PubMedGoogle Scholar
  155. 155.
    Zhang W, Liu Y, Wang CW (2014) S100A4 promotes squamous cell laryngeal cancer Hep-2 cell invasion via NF-kB/MMP-9 signal. Eur Rev Med Pharmacol Sci 18(9):1361–1367PubMedGoogle Scholar
  156. 156.
    Ismail TM, Bennett D, Platt-Higgins AM, Al-Medhity M, Barraclough R, Rudland PS (2017) S100A4 elevation empowers expression of metastasis effector molecules in human breast cancer. Cancer Res 77(3):780–789. Scholar
  157. 157.
    Xu H, Li M, Zhou Y, Wang F, Li X, Wang L, Fan Q (2016) S100A4 participates in epithelial-mesenchymal transition in breast cancer via targeting MMP2. Tumour Biol 37(3):2925–2932. Scholar
  158. 158.
    Cao J, Geng L, Wu Q, Wang W, Chen Q, Lu L, Shen W, Chen Y (2013) Spatiotemporal expression of matrix metalloproteinases (MMPs) is regulated by the Ca2+-signal transducer S100A4 in the pathogenesis of thoracic aortic aneurysm. PLoS One 8(7):e70057. Scholar
  159. 159.
    Senolt L, Grigorian M, Lukanidin E, Simmen B, Michel BA, Pavelka K, Gay RE, Gay S, Neidhart M (2006) S100A4 is expressed at site of invasion in rheumatoid arthritis synovium and modulates production of matrix metalloproteinases. Ann Rheum Dis 65(12):1645–1648. Scholar
  160. 160.
    Andersen K, Mori H, Fata J, Bascom J, Oyjord T, Maelandsmo GM, Bissell M (2011) The metastasis-promoting protein S100A4 regulates mammary branching morphogenesis. Dev Biol 352(2):181–190. Scholar
  161. 161.
    Schneider M, Kostin S, Strom CC, Aplin M, Lyngbaek S, Theilade J, Grigorian M, Andersen CB, Lukanidin E, Lerche Hansen J, Sheikh SP (2007) S100A4 is upregulated in injured myocardium and promotes growth and survival of cardiac myocytes. Cardiovasc Res 75(1):40–50. Scholar
  162. 162.
    Sack U, Walther W, Scudiero D, Selby M, Kobelt D, Lemm M, Fichtner I, Schlag PM, Shoemaker RH, Stein U (2011) Novel effect of antihelminthic Niclosamide on S100A4-mediated metastatic progression in colon cancer. J Natl Cancer Inst 103(13):1018–1036. Scholar
  163. 163.
    Stein U, Arlt F, Smith J, Sack U, Herrmann P, Walther W, Lemm M, Fichtner I, Shoemaker RH, Schlag PM (2011) Intervening in beta-catenin signaling by sulindac inhibits S100A4-dependent colon cancer metastasis. Neoplasia 13(2):131–144CrossRefGoogle Scholar
  164. 164.
    Burock S, Daum S, Keilholz U, Neumann K, Walther W, Stein U (2018) Phase II trial to investigate the safety and efficacy of orally applied niclosamide in patients with metachronous or synchronous metastases of a colorectal cancer progressing after therapy: the NIKOLO trial. BMC Cancer 18(1):297. Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  • Noona Ambartsumian
    • 1
    Email author
  • Jörg Klingelhöfer
    • 1
  • Mariam Grigorian
    • 1
  1. 1.Faculty of Health, Department of NeuroscienceCopenhagen UniversityCopenhagenDenmark

Personalised recommendations