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Die metastatische Nische

Mechanismen und prognostische Implikationen

The metastatic niche

Mechanisms and prognostic implications

  • Hauptreferate: Metastasierungsmechanismen
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Zusammenfassung

Die prämetastatische Nische ist essentiell für die Ausbildung von Metastasen. Sie wird u. a. durch vaskuläres Remodeling und eingewanderte Knochenmarkszellen charakterisiert. Sowohl die Forschungsarbeit anderer Gruppen als auch unsere Studienergebnisse konnten belegen, dass die Neubildung intranodaler Lymphgefäße in lokoregionären Lymphknoten das Auftreten von Lymphknotenmetastasen fördert und bei neoadjuvant vorbehandelten Rektumkarzinompatienten die Länge des progressionsfreien Überlebens vorhersagt. Dabei sezernieren die neugebildeten Endothelien Substanzen, die Tumorzellen und Knochenmarkszellen anlocken. CXCL12 ist einer dieser Stoffe. CXCL12 aktiviert den Chemokinrezeptor CXCR4 und induziert die gradientenabhängige Migration. Dieser Übersichtsartikel behandelt die Regulation und Funktion der CXCR4/CXCL12-Signalachse während der Metastasierung maligner Erkrankungen sowie therapeutische Blockadeoptionen.

Abstract

Disseminated tumor cells require a special microenvironment to form metastases. This metastatic niche is organ specific and forms prior to the establishment of visible metastases. The niche is characterized by vascular remodeling and bone marrow-derived cells which have migrated into it. Studies by other groups and our own results have already shown that intranodal lymphangiogenesis is an important prerequisite for regional lymph node metastases in rectal cancer patients, and can be used as a prognostic marker for progression-free survival. Niche cells such as endothelia secrete factors that attract tumor and bone marrow-derived cells. CXCL12 is one of these factors. CXCL12 activates the CXCR4 chemokine axis and induces migration along its gradient. Several factors, such as hypoxia, have been described to regulate CXCR4 function and surface expression on tumor cells. Low molecular weight agents have been used to block CXCR4 activation. This review focuses on the function and regulation of CXCR4 and its ligand CXCL12 in metastases formation. It also discusses potential options for therapeutic blockage.

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Literatur

  1. Feng Y, Broder CC, Kennedy PE, Berger EA (1996) HIV-1 entry cofactor: functional cDNA cloning of a seven-transmembrane, G protein-coupled receptor. Science 272(5263):872–877

    Article  CAS  PubMed  Google Scholar 

  2. Bleul CC, Fuhlbrigge RC, Casasnovas JM, Aiuti A, Springer TA (1996) A highly efficacious lymphocyte chemoattractant, stromal cell-derived factor 1 (SDF-1). J Exp Med 184(3):1101–1109

    Article  CAS  PubMed  Google Scholar 

  3. Kucia M, Reca R, Campbell FR, Zuba-Surma E, Majka M, Ratajczak J et al (2006) A population of very small embryonic-like (VSEL) CXCR4(+)SSEA-1(+)Oct-4 + stem cells identified in adult bone marrow. Leukemia 20(5):857–869. doi:10.1038/sj.leu.2404171

    Article  CAS  PubMed  Google Scholar 

  4. Kucia M, Jankowski K, Reca R, Wysoczynski M, Bandura L, Allendorf DJ et al (2004) CXCR4-SDF-1 signalling, locomotion, chemotaxis and adhesion. J Mol Histol 35(3):233–245

    Article  CAS  PubMed  Google Scholar 

  5. Schabath R, Muller G, Schubel A, Kremmer E, Lipp M, Forster R (1999) The murine chemokine receptor CXCR4 is tightly regulated during T cell development and activation. J Leukoc Biol 66(6):996–1004

    CAS  PubMed  Google Scholar 

  6. Bachelerie F (2010) CXCL12/CXCR4-axis dysfunctions: Markers of the rare immunodeficiency disorder WHIM syndrome. Dis Markers 29(3–4):189–198. doi:10.3233/DMA-2010-0736

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  7. Treon SP, Cao Y, Xu L, Yang G, Liu X, Hunter ZR (2014) Somatic mutations in MYD88 and CXCR4 are determinants of clinical presentation and overall survival in Waldenstrom macroglobulinemia. Blood 123(18):2791–2796. doi:10.1182/blood-2014-01-550905

    Article  CAS  PubMed  Google Scholar 

  8. Muller A, Homey B, Soto H, Ge N, Catron D, Buchanan ME et al (2001) Involvement of chemokine receptors in breast cancer metastasis. Nature 410(6824):50–56. doi:10.1038/35065016

    Article  CAS  PubMed  Google Scholar 

  9. Zeelenberg IS, Ruuls-Van Stalle L, Roos E (2003) The chemokine receptor CXCR4 is required for outgrowth of colon carcinoma micrometastases. Cancer Res 63(13):3833–3839

    CAS  PubMed  Google Scholar 

  10. Jakob C, Aust DE, Liebscher B, Baretton GB, Datta K, Muders MH (2011) Lymphangiogenesis in regional lymph nodes is an independent prognostic marker in rectal cancer patients after neoadjuvant treatment. PloS One 6(11):e27402. doi:10.1371/journal.pone.0027402

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  11. Hirakawa S, Brown LF, Kodama S, Paavonen K, Alitalo K, Detmar M (2007) VEGF-C-induced lymphangiogenesis in sentinel lymph nodes promotes tumor metastasis to distant sites. Blood 109(3):1010–1017. doi:10.1182/blood-2006-05-021758

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  12. Hirakawa S, Kodama S, Kunstfeld R, Kajiya K, Brown LF, Detmar M (2005) VEGF-A induces tumor and sentinel lymph node lymphangiogenesis and promotes lymphatic metastasis. J Exp Med 201(7):1089–1099. doi:10.1084/jem.20041896

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  13. Schimanski CC, Schwald S, Simiantonaki N, Jayasinghe C, Gonner U, Wilsberg V et al (2005) Effect of chemokine receptors CXCR4 and CCR7 on the metastatic behavior of human colorectal cancer. Clinical cancer research: an official journal of the American Association for Cancer Res 11(5):1743–1750. doi:10.1158/1078-0432.CCR-04-1195

    CAS  Google Scholar 

  14. Romain B, Hachet-Haas M, Rohr S, Brigand C, Galzi JL, Gaub MP et al (2014) Hypoxia differentially regulated CXCR4 and CXCR7 signaling in colon cancer. Mol Cancer 13:58. doi:10.1186/1476-4598-13-58

    Article  PubMed Central  PubMed  Google Scholar 

  15. Feng YF, Yuan F, Guo H, Wu WZ (2014) TGF-beta1 enhances SDF-1-induced migration and tube formation of choroid-retinal endothelial cells by up-regulating CXCR4 and CXCR7 expression. Mol Cell Biochem 397(1–2):131–138. doi:10.1007/s11010-014-2180-6

    Article  CAS  PubMed  Google Scholar 

  16. Zhi Y, Duan Y, Zhou X, Yin X, Guan G, Zhang H et al (2014) NF-kappaB signaling pathway confers neuroblastoma cells migration and invasion ability via the regulation of CXCR4. Med Sci Monit 20:2746–2752. doi:10.12659/MSM.892597

    Article  PubMed Central  PubMed  Google Scholar 

  17. Phillips RJ, Mestas J, Gharaee-Kermani M, Burdick MD, Sica A, Belperio JA et al (2005) Epidermal growth factor and hypoxia-induced expression of CXC chemokine receptor 4 on non-small cell lung cancer cells is regulated by the phosphatidylinositol 3-kinase/PTEN/AKT/mammalian target of rapamycin signaling pathway and activation of hypoxia inducible factor-1alpha. J Biol Chem 280(23):22473–22481. doi:10.1074/jbc.M500963200

    Article  CAS  PubMed  Google Scholar 

  18. Bamidele AO, Kremer KN, Hirsova P, Clift IC, Gores GJ, Billadeau DD et al (2015) IQGAP1 promotes CXCR4 chemokine receptor function and trafficking via EEA-1 + endosomes. J Cell Biol 210(2):257–272. doi:10.1083/jcb.201411045

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  19. Stanton MJ, Dutta S, Polavaram NS, Roy S, Muders MH, Datta K (2013) Angiogenic growth factor axis in autophagy regulation. Autophagy 9(5):789–790. doi:10.4161/auto.23783

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  20. Grandclement C, Pallandre JR, Valmary Degano S, Viel E, Bouard A, Balland J et al (2011) Neuropilin-2 expression promotes TGF-beta1-mediated epithelial to mesenchymal transition in colorectal cancer cells. PloS One 6(7):e20444. doi:10.1371/journal.pone.0020444

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  21. Keck B, Wach S, Taubert H, Zeiler S, Ott OJ, Kunath F et al (2014) Neuropilin-2 and its ligand VEGF-C predict treatment response after transurethral resection and radiochemotherapy in bladder cancer patients. Int J Cancer. doi:10.1002/ijc.28987

  22. Stanton MJ, Dutta S, Zhang H, Polavaram NS, Leontovich AA, Honscheid P et al (2013) Autophagy control by the VEGF-C/NRP-2 axis in cancer and its implication for treatment resistance. Cancer Res 73(1):160–171. doi:10.1158/0008-5472.CAN-11-3635

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  23. Muders MH, Zhang H, Wang E, Tindall DJ, Datta K (2009) Vascular endothelial growth factor-C protects prostate cancer cells from oxidative stress by the activation of mammalian target of rapamycin complex-2 and AKT-1. Cancer Res 69(15):6042–6048. doi:10.1158/0008-5472.CAN-09-0552

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  24. Beck B, Driessens G, Goossens S, Youssef KK, Kuchnio A, Caauwe A et al (2011) A vascular niche and a VEGF-Nrp1 loop regulate the initiation and stemness of skin tumours. Nature 478(7369):399–403. doi:10.1038/nature10525

    Article  CAS  PubMed  Google Scholar 

  25. Bachelder RE, Wendt MA, Mercurio AM (2002) Vascular endothelial growth factor promotes breast carcinoma invasion in an autocrine manner by regulating the chemokine receptor CXCR4. Cancer Res 62(24):7203–7206

    CAS  PubMed  Google Scholar 

  26. Yasuoka H, Kodama R, Tsujimoto M, Yoshidome K, Akamatsu H, Nakahara M et al (2009) Neuropilin-2 expression in breast cancer: correlation with lymph node metastasis, poor prognosis, and regulation of CXCR4 expression. BMC Cancer 9:220. doi:10.1186/1471-2407-9-220

    Article  PubMed Central  PubMed  Google Scholar 

  27. Liles WC, Broxmeyer HE, Rodger E, Wood B, Hubel K, Cooper S et al (2003) Mobilization of hematopoietic progenitor cells in healthy volunteers by AMD3100, a CXCR4 antagonist. Blood 102(8):2728–2730. doi:10.1182/blood-2003-02-0663

    Article  CAS  PubMed  Google Scholar 

  28. O’Boyle G, Swidenbank I, Marshall H, Barker CE, Armstrong J, White SA et al (2013) Inhibition of CXCR4-CXCL12 chemotaxis in melanoma by AMD11070. Br J Cancer 108(8):1634–1640. doi:10.1038/bjc.2013.124

    Article  Google Scholar 

  29. Domanska UM, Timmer-Bosscha H, Nagengast WB, Oude Munnink TH, Kruizinga RC, Ananias HJ et al (2012) CXCR4 inhibition with AMD3100 sensitizes prostate cancer to docetaxel chemotherapy. Neoplasia 14(8):709–718

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  30. Scala S (2015) Molecular Pathways: targeting the CXCR4-CXCL12 Axis-Untapped Potential in the Tumor Microenvironment. Clin Cancer Res. doi:10.1158/1078-0432.CCR-14-0914

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Authors and Affiliations

  1. Institut für Pathologie, Universitätsklinikum „Carl Gustav Carus“ an der TU Dresden, Fetscherstraße 74, 01307, Dresden, Deutschland

    M.H. Muders &  G.B. Baretton

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  1. M.H. Muders
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  2. G.B. Baretton
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M.H. Muders und G.B. Baretton geben an, dass kein Interessenkonflikt besteht

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Muders, M., Baretton, G. Die metastatische Nische. Pathologe 36 (Suppl 2), 185–188 (2015). https://doi.org/10.1007/s00292-015-0079-y

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  • DOI: https://doi.org/10.1007/s00292-015-0079-y

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