Skip to main content

Advertisement

SpringerLink
Log in

The CXCR4-SDF1α axis is a critical mediator of rhabdomyosarcoma metastatic signaling induced by bone marrow stroma

  • Research paper
  • Published:
Clinical & Experimental Metastasis Aims and scope Submit manuscript

Abstract

Rhabdomyosarcoma (RMS) is the most common malignant soft-tissue tumor of childhood. Nearly 15% of children present with metastatic disease, frequently involving the lungs and bone marrow. The prognosis for patients with metastatic RMS is dismal, with an estimated 3-year overall survival of 30%. Stromal-cell derived factor 1-α (SDF1α, CXCL12) is a chemokine that plays a crucial role in the metastatic attraction of tumor cells expressing its receptor, CXCR4. We investigated the role of the bone marrow microenvironment on RMS signaling through the CXCR4/SDF1α pathway in cell lines and primary tumors. Conditioned media (CM) isolated from cultured patient-derived bone marrow stromal cells (BMS) induced migration and proliferation in multiple RMS cell lines. CXCR4 was expressed in RMS cell lines and primary tumors, with higher expression in alveolar subtype RMS. Further, SDF1α was secreted by all BMS cultures and potently induced the migration and proliferation of RMS cells. Small molecule or blocking antibody-mediated inhibition of CXCR4 or SDF1α suppressed RMS cell migration towards BMS-CM, confirming the activity of this axis. Our study provides strong evidence for the involvement of the bone marrow microenvironment and CXCR4/SDF1α signaling in metastasis of RMS. These results form the basis for future studies to delineate the mechanisms of bone marrow metastasis in RMS.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

References

  1. Gurney JG, Young JL Jr, Roffers SD (1999) Soft tissue sarcomas. In Ries LAG, Smith MA, Gurney JG (eds) Cancer incidence and survival among children and adolescents: United States seer program 1975–1995, vol 99. National Cancer Insitute, NIH Publication, Bethesda, pp 4649

  2. Breneman JC, Lyden E, Pappo AS, Link MP, Anderson JR, Parham DM, Qualman SJ, Wharam MD, Donaldson SS, Maurer HM, Meyer WH, Baker KS, Paidas CN, Crist WM (2003) Prognostic factors and clinical outcomes in children and adolescents with metastatic rhabdomyosarcoma – a report from the Intergroup Rhabdomyosarcoma Study IV. J Clin Oncol 21:78–84

    Article  PubMed  Google Scholar 

  3. Koscielniak E, Klingebiel TH, Peters C, Hermann J, Burdach ST, Bender-Gotze C, Muller-Weihrich ST, Treuner J (1997) Do patients with metastatic and recurrent rhabdomyosarcoma benefit from high-dose therapy with hematopoietic rescue? Report of the German/Austrian Pediatric Bone Marrow Transplantation Group. Bone Marrow Transplant 19:227–231

    Article  PubMed  CAS  Google Scholar 

  4. Pappo AS, Bowman LC, Furman WL, Rao BN, Kun LE, Jenkins JJ, Crom WR, Luo X, Kaste SC, Avery L, Meyer WH, Shapiro DN, Crist WM (1997) A phase II trial of high-dose methotrexate in previously untreated children and adolescents with high-risk unresectable or metastatic rhabdomyosarcoma. J Pediatr Hematol Oncol 19:438–442

    Article  PubMed  CAS  Google Scholar 

  5. Pappo AS, Lyden E, Breneman J, Wiener E, Teot L, Meza J, Crist W, Vietti T (2001) Up-front window trial of topotecan in previously untreated children and adolescents with metastatic rhabdomyosarcoma: an intergroup rhabdomyosarcoma study. J Clin Oncol 19:213–219

    PubMed  CAS  Google Scholar 

  6. Galili N, Davis RJ, Fredericks WJ, Mukhopadhyay S, Rauscher FJ 3rd, Emanuel BS, Rovera G, Barr FG (1993) Fusion of a fork head domain gene to PAX3 in the solid tumour alveolar rhabdomyosarcoma. Nat Genet 5:230–235

    Article  PubMed  CAS  Google Scholar 

  7. Davis RJ, D’Cruz CM, Lovell MA, Biegel JA, Barr FG (1994) Fusion of PAX7 to FKHR by the variant t(1;13)(p36;q14) translocation in alveolar rhabdomyosarcoma. Cancer Res 54:2869–2872

    PubMed  CAS  Google Scholar 

  8. Crist W, Gehan EA, Ragab AH, Dickman PS, Donaldson SS, Fryer C, Hammond D, Hays DM, Herrmann J, Heyn R et al (1995) The Third Intergroup Rhabdomyosarcoma Study. J Clin Oncol 13:610–630

    PubMed  CAS  Google Scholar 

  9. Maurer HM, Beltangady M, Gehan EA, Crist W, Hammond D, Hays DM, Heyn R, Lawrence W, Newton W, Ortega J et al (1988) The Intergroup Rhabdomyosarcoma Study-I. A final report. Cancer 61:209–220

    Article  PubMed  CAS  Google Scholar 

  10. Maurer HM, Gehan EA, Beltangady M, Crist W, Dickman PS, Donaldson SS, Fryer C, Hammond D, Hays DM, Herrmann J et al (1993) The Intergroup Rhabdomyosarcoma Study-II. Cancer 71:1904–1922

    Article  PubMed  CAS  Google Scholar 

  11. Paget S (1889) The distribution of secondary growths in cancer of the breast. Lancet 1:571–573

    Article  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  13. Rossi D, Zlotnik A (2000) The biology of chemokines and their receptors. Annu Rev Immunol 18:217–242

    Article  PubMed  CAS  Google Scholar 

  14. Burger JA, Kipps TJ (2006) CXCR4: a key receptor in the crosstalk between tumor cells and their microenvironment. Blood 107:1761–1767

    Article  PubMed  CAS  Google Scholar 

  15. Alsayed Y, Ngo H, Runnels J, Leleu X, Singha UK, Pitsillides CM, Spencer JA, Kimlinger T, Ghobrial JM, Jia X, Lu G, Timm M, Kumar A, Cote D, Veilleux I, Hedin KE, Roodman GD, Witzig TE, Kung AL, Hideshima T, Anderson KC, Lin CP, Ghobrial IM (2007) Mechanisms of regulation of CXCR4/SDF-1 (CXCL12)-dependent migration and homing in multiple myeloma. Blood 109:2708–2717

    PubMed  CAS  Google Scholar 

  16. Juarez J, Bradstock KF, Gottlieb DJ, Bendall LJ (2003) Effects of inhibitors of the chemokine receptor CXCR4 on acute lymphoblastic leukemia cells in vitro. Leukemia 17:1294–1300

    Article  PubMed  CAS  Google Scholar 

  17. Marchesi F, Monti P, Leone BE, Zerbi A, Vecchi A, Piemonti L, Mantovani A, Allavena P (2004) Increased survival, proliferation, and migration in metastatic human pancreatic tumor cells expressing functional CXCR4. Cancer Res 64:8420–8427

    Article  PubMed  CAS  Google Scholar 

  18. Rubin JB, Kung AL, Klein RS, Chan JA, Sun Y, Schmidt K, Kieran MW, Luster AD, Segal RA (2003) A small-molecule antagonist of CXCR4 inhibits intracranial growth of primary brain tumors. Proc Natl Acad Sci USA 100:13513–13518

    Article  PubMed  CAS  Google Scholar 

  19. Serini G, Gabbiani G (1999) Mechanisms of myofibroblast activity and phenotypic modulation. Exp Cell Res 250:273–283

    Article  PubMed  CAS  Google Scholar 

  20. Bhowmick NA, Neilson EG, Moses HL (2004) Stromal fibroblasts in cancer initiation and progression. Nature 432:332–337

    Article  PubMed  CAS  Google Scholar 

  21. Olumi AF, Grossfeld GD, Hayward SW, Carroll PR, Tlsty TD, Cunha GR (1999) Carcinoma-associated fibroblasts direct tumor progression of initiated human prostatic epithelium. Cancer Res 59:5002–5011

    PubMed  CAS  Google Scholar 

  22. 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 

  23. Kurose K, Gilley K, Matsumoto S, Watson PH, Zhou XP, Eng C (2002) Frequent somatic mutations in PTEN and TP53 are mutually exclusive in the stroma of breast carcinomas. Nat Genet 32:355–357

    Article  PubMed  CAS  Google Scholar 

  24. Moinfar F, Man YG, Arnould L, Bratthauer GL, Ratschek M, Tavassoli FA (2000) Concurrent and independent genetic alterations in the stromal and epithelial cells of mammary carcinoma: implications for tumorigenesis. Cancer Res 60:2562–2566

    PubMed  CAS  Google Scholar 

  25. Narendran A, Ganjavi H, Morson N, Connor A, Barlow JW, Keystone E, Malkin D, Freedman MH (2003) Mutant p53 in bone marrow stromal cells increases VEGF expression and supports leukemia cell growth. Exp Hematol 31:693–701

    Article  PubMed  CAS  Google Scholar 

  26. Nicola MH, Bizon R, Machado JJ, Sollero T, Rodarte RS, Nobre JS, Magalhaes MM, Takiya CM, Borojevic R (2003) Breast cancer micrometastases: different interactions of carcinoma cells with normal and cancer patients’ bone marrow stromata. Clin Exp Metastasis 20:471–479

    Article  PubMed  Google Scholar 

  27. Jarvis LJ, Maguire JE, LeBien TW (1997) Contact between human bone marrow stromal cells and B lymphocytes enhances very late antigen-4/vascular cell adhesion molecule-1-independent tyrosine phosphorylation of focal adhesion kinase, paxillin, and ERK2 in stromal cells. Blood 90:1626–1635

    PubMed  CAS  Google Scholar 

  28. Yun HJ, Jo DY (2003) Production of stromal cell-derived factor-1 (SDF-1) and expression of CXCR4 in human bone marrow endothelial cells. J Korean Med Sci 18:679–685

    PubMed  CAS  Google Scholar 

  29. Rosenkilde MM, Gerlach LO, Jakobsen JS, Skerlj RT, Bridger GJ, Schwartz TW (2004) Molecular mechanism of AMD3100 antagonism in the CXCR4 receptor: transfer of binding site to the CXCR3 receptor. J Biol Chem 279:3033–3041

    Article  PubMed  CAS  Google Scholar 

  30. Fricker SP, Anastassov V, Cox J, Darkes MC, Grujic O, Idzan SR, Labrecque J, Lau G, Mosi RM, Nelson KL, Qin L, Santucci Z, Wong RS (2006) Characterization of the molecular pharmacology of AMD3100: a specific antagonist of the G-protein coupled chemokine receptor, CXCR4. Biochem Pharmacol 72:588–596

    Article  PubMed  CAS  Google Scholar 

  31. Fidler IJ (2002) The organ microenvironment and cancer metastasis. Differentiation 70:498–505

    Article  PubMed  Google Scholar 

  32. Fidler IJ (2002) Critical determinants of metastasis. Semin Cancer Biol 12:89–96

    Article  PubMed  Google Scholar 

  33. Liotta LA, Kohn EC (2001) The microenvironment of the tumour-host interface. Nature 411:375–379

    Article  PubMed  CAS  Google Scholar 

  34. Yoneda T, Hiraga T (2005) Crosstalk between cancer cells and bone microenvironment in bone metastasis. Biochem Biophys Res Commun 328:679–687

    Article  PubMed  CAS  Google Scholar 

  35. Jankowski K, Kucia M, Wysoczynski M, Reca R, Zhao D, Trzyna E, Trent J, Peiper S, Zembala M, Ratajczak J, Houghton P, Janowska-Wieczorek A, Ratajczak MZ (2003) Both hepatocyte growth factor (HGF) and stromal-derived factor-1 regulate the metastatic behavior of human rhabdomyosarcoma cells, but only HGF enhances their resistance to radiochemotherapy. Cancer Res 63:7926–7935

    PubMed  CAS  Google Scholar 

  36. Honegger AE, Hofer EL, Baranao RI, Mackinlay TA, Mackinlay DA, Bullorsky EO, Bordenave RH, Chasseing NA (2002) Interleukin-1 beta, transforming growth factor beta 1, prostaglandin E2, and fibronectin levels in the conditioned mediums of bone marrow fibroblast cultures from lung and breast cancer patients. Ann Hematol 81:80–85

    Article  PubMed  CAS  Google Scholar 

  37. Libura J, Drukala J, Majka M, Tomescu O, Navenot JM, Kucia M, Marquez L, Peiper SC, Barr FG, Janowska-Wieczorek A, Ratajczak MZ (2002) CXCR4-SDF-1 signaling is active in rhabdomyosarcoma cells and regulates locomotion, chemotaxis, and adhesion. Blood 100:2597–2606

    Article  PubMed  CAS  Google Scholar 

  38. Wysoczynski M, Miekus K, Jankowski K, Wanzeck J, Bertolone S, Janowska-Wieczorek A, Ratajczak J, Ratajczak MZ (2007) Leukemia inhibitory factor: a newly identified metastatic factor in rhabdomyosarcomas. Cancer Res 67:2131–2140

    Article  PubMed  CAS  Google Scholar 

  39. Zhang L, Yeger H, Das B, Irwin MS, Baruchel S (2007) Tissue microenvironment modulates CXCR4 expression and tumor metastasis in neuroblastoma. Neoplasia 9:36–46

    Article  PubMed  CAS  Google Scholar 

  40. Balkwill F (2004) Cancer and the chemokine network. Nat Rev Cancer 4:540–550

    Article  PubMed  CAS  Google Scholar 

  41. Liang Z, Yoon Y, Votaw J, Goodman MM, Williams L, Shim H (2005) Silencing of CXCR4 blocks breast cancer metastasis. Cancer Res 65:967–971

    Article  PubMed  CAS  Google Scholar 

  42. Tomescu O, Xia SJ, Strezlecki D, Bennicelli JL, Ginsberg J, Pawel B, Barr FG (2004) Inducible short-term and stable long-term cell culture systems reveal that the PAX3-FKHR fusion oncoprotein regulates CXCR4, PAX3, and PAX7 expression. Lab Invest 84:1060–1070

    Article  PubMed  CAS  Google Scholar 

  43. Corcoran KE, Patel N, Rameshwar P (2007) Stromal derived growth factor-1alpha: another mediator in neural-emerging immune system through Tac1 expression in bone marrow stromal cells. J Immunol 178:2075–2082

    PubMed  CAS  Google Scholar 

  44. Scala S, Giuliano P, Ascierto PA, Ierano C, Franco R, Napolitano M, Ottaiano A, Lombardi ML, Luongo M, Simeone E, Castiglia D, Mauro F, De Michele I, Calemma R, Botti G, Caraco C, Nicoletti G, Satriano RA, Castello G (2006) Human melanoma metastases express functional CXCR4. Clin Cancer Res 12:2427–2433

    Article  PubMed  CAS  Google Scholar 

  45. Chinni SR, Sivalogan S, Dong Z, Filho JC, Deng X, Bonfil RD, Cher ML (2006) CXCL12/CXCR4 signaling activates Akt-1 and MMP-9 expression in prostate cancer cells: the role of bone microenvironment-associated CXCL12. Prostate 66:32–48

    Article  PubMed  CAS  Google Scholar 

  46. Tabe Y, Jin L, Tsutsumi-Ishii Y, Xu Y, McQueen T, Priebe W, Mills GB, Ohsaka A, Nagaoka I, Andreeff M, Konopleva M (2007) Activation of integrin-linked kinase is a critical prosurvival pathway induced in leukemic cells by bone marrow-derived stromal cells. Cancer Res 67:684–694

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgements

AD is a recipient of a Canadian Institute for Health Research MD/PhD Scholarship and a University of Toronto Open Fellowship. This work was supported in part by funds from the Andrew Mizzoni Cancer Research Fund.

We thank Dr. Maria Zielenska (The Hospital for Sick Children, Toronto, ON) for the kind gift of primary rhabdomyosarcoma RNA.

Author information

Authors and Affiliations

  1. Division of Haematology and Oncology, Department of Paediatrics, The Hospital for Sick Children, University of Toronto, 555 University Avenue, Toronto, ON, Canada, M5G 1X8

    Brigitte Strahm, Adam D. Durbin, Elizabeth Sexsmith & David Malkin

  2. Programme in Genetics and Genome Biology, The Hospital for Sick Children, University of Toronto, Toronto, Canada

    Brigitte Strahm, Adam D. Durbin & David Malkin

  3. Department of Paediatric Haematology and Oncology, Centre for Paediatric and Adolescent Medicine, University of Freiburg, Freiburg, Germany

    Brigitte Strahm

  4. Department of Medical Biophysics, University of Toronto, Toronto, Canada

    Adam D. Durbin & David Malkin

Authors
  1. Brigitte Strahm
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Adam D. Durbin
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Elizabeth Sexsmith
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. David Malkin
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to David Malkin.

Additional information

Brigitte Strahm and Adam D. Durbin contributed equally to this work.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Strahm, B., Durbin, A.D., Sexsmith, E. et al. The CXCR4-SDF1α axis is a critical mediator of rhabdomyosarcoma metastatic signaling induced by bone marrow stroma. Clin Exp Metastasis 25, 1–10 (2008). https://doi.org/10.1007/s10585-007-9094-6

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10585-007-9094-6

Keywords

Search

Navigation