Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Article
  • Published:

Graft-Versus-Tumor Effects

Graft-versus-tumor effects on murine mammary carcinoma in a model of nonmyeloablative haploidentical stem cell transplantation

Abstract

Despite a slight decrease in mortality over the last decade, breast cancer still remains a leading cause of cancer-related death in women. Although anti-tumor effects have been observed after allogeneic stem cell transplantation (SCT), this treatment is not standard care owing to graft-versus-host disease (GVHD) and scarcity of suitable donors. With the aim of reducing treatment-related mortality and increasing donor availability in clinical situations, we developed a preclinical mouse model that combines nonmyeloablative conditioning with the use of haploidentical donor–recipient pairs. To mimic active disease, CB6F1 mice were inoculated with 5 × 104 4T1 mammary carcinoma cells 10 days before transplantation. Keratinocyte growth factor (KGF) was used as GVHD prophylaxis. Syngeneic (CB6F1) SCT did not cure any of the mice and KGF treatment did not influence tumor development. After transplantation with haploidentical (B6CBAF1) bone marrow and splenocytes, however, tumor outgrowth was reduced and long-term disease-free survival (>3 months) was observed in 9/18 (50%) (P=0.0011) of the animals. We conclude that in a model of murine breast cancer, a graft-versus-tumor effect can be induced by a nonmyeloablative haploidentical SCT procedure.

This is a preview of subscription content, access via your institution

Access options

Buy this article

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2

Similar content being viewed by others

References

  1. Jemal A, Murray T, Ward E, Samuels A, Tiwari RC, Ghafoor A et al. Cancer statistics, 2005. Can Cancer J Clin 2005; 55: 10–30.

    Article  Google Scholar 

  2. Bray F, Sankila R, Ferlay J, Parkin DM . Estimates of cancer incidence and mortality in Europe in 1995. Eur J Cancer 2002; 38: 99–166.

    Article  CAS  Google Scholar 

  3. Parkin DM, Bray F, Ferlay J, Pisani P . Global cancer statistics, 2002. Can Cancer J Clin 2005; 55: 74–108.

    Article  Google Scholar 

  4. Levi F, Lucchini F, Negri E, La Vecchia C . Trends in mortality from major cancers in the European Union, including acceding countries, in 2004. Cancer 2004; 101: 2843–2850.

    Article  Google Scholar 

  5. Stewart SL, King JB, Thompson TD, Friedman C, Wingo PA . Cancer mortality surveillance – United States, 1990–2000. MMWR Surveillance Summ 2004; 53: 1–108.

    Google Scholar 

  6. Nieto Y, Jones RB, Shpall EJ . Stem-cell transplantation for the treatment of advanced solid tumors. Springer Semin Immunopathol 2004; 26: 31–56.

    Article  Google Scholar 

  7. Appelbaum FR . Haematopoietic cell transplantation as immunotherapy. Nature 2001; 411: 385–389.

    Article  CAS  Google Scholar 

  8. Eibl B, Schwaighofer H, Nachbaur D, Marth C, Gachter A, Knapp R et al. Evidence for a graft-versus-tumor effect in a patient treated with marrow ablative chemotherapy and allogeneic bone marrow transplantation for breast cancer. Blood 1996; 88: 1501–1508.

    CAS  Google Scholar 

  9. Ueno NT, Rondón G, Mirza NQ, Geisler DK, Anderlini P, Giralt SA et al. Allogeneic peripheral-blood progenitor-cell transplantation for poor-risk patients with metastatic breast cancer. J Clin Oncol 1998; 16: 986–993.

    Article  CAS  Google Scholar 

  10. Ben-Yosef R, Or R, Nagler A, Slavin S . Graft-versus-tumour and graft-versus-leukaemia effect in patient with concurrent breast cancer and acute myelocytic leukaemia. Lancet 1996; 348: 1242–1243.

    Article  CAS  Google Scholar 

  11. Martino R, Caballero MD, Canals C, San Miguel J, Sierra J, Rovira M et al. Reduced-intensity conditioning reduces the risk of severe infections after allogeneic peripheral blood stem cell transplantation. Bone Marrow Transplant 2001; 28: 341–347.

    Article  CAS  Google Scholar 

  12. Mielcarek M, Martin PJ, Leisenring W, Flowers ME, Maloney DG, Sandmaier BM et al. Graft-versus-host disease after nonmyeloablative versus conventional hematopoietic stem cell transplantation. Blood 2003; 102: 756–762.

    Article  CAS  Google Scholar 

  13. Ueno NT, Cheng YC, Rondón G, Tannir NM, Gajewski JL, Couriel DR et al. Rapid induction of complete donor chimerism by the use of a reduced-intensity conditioning regimen composed of fludarabine and melphalan in allogeneic stem cell transplantation for metastatic solid tumors. Blood 2003; 102: 3829–3836.

    Article  CAS  Google Scholar 

  14. Bregni M, Dodero A, Peccatori J, Pescarollo A, Bernardi M, Sassi I et al. Nonmyeloablative conditioning followed by hematopoietic cell allografting and donor lymphocyte infusions for patients with metastatic renal and breast cancer. Blood 2002; 99: 4234–4236.

    Article  CAS  Google Scholar 

  15. Childs R, Chernoff A, Contentin N, Bahceci E, Schrump D, Leitman S et al. Regression of metastatic renal-cell carcinoma after nonmyeloablative allogeneic peripheral-blood stem-cell transplantation. N Engl J Med 2000; 343: 750–758.

    Article  CAS  Google Scholar 

  16. Blaise D, Bay JO, Faucher C, Michallet M, Boiron JM, Choufi B et al. Reduced-intensity preparative regimen and allogeneic stem cell transplantation for advanced solid tumors. Blood 2004; 103: 435–441.

    Article  CAS  Google Scholar 

  17. Bregni M, Bernardi M, Ciceri F, Peccatori J . Allogeneic stem cell transplantation for the treatment of advanced solid tumors. Springer Semin Immunopathol 2004; 26: 95–108.

    Article  Google Scholar 

  18. Toh HC, Spitzer TR, Preffer F, Alexander SI, McAfee S, Dombkowski D et al. Fluctuating lymphocyte chimerism, tolerance and anti-tumor response in a patient with refractory lymphoma receiving nonmyeloablative conditioning and a haploidentical related allogeneic bone marrow transplant. Cytokines Cell Mol Ther 2002; 7: 43–47.

    Article  Google Scholar 

  19. Satoh M, Miyamura K, Yamada M, Ishidoya S, Childs RW, Arai Y . Haploidentical, nonmyeloablative stem-cell transplantation for advanced renal-cell carcinoma. Lancet Oncol 2004; 5: 125–126.

    Article  Google Scholar 

  20. Ikegame K, Kawakami M, Yamagami T, Maeda H, Onishi K, Taniguchi Y et al. HLA-haploidentical nonmyeloablative stem cell transplantation: induction to tolerance without passing through mixed chimaerism. Clin Lab Haematol 2005; 27: 139–141.

    Article  CAS  Google Scholar 

  21. Sykes M, Preffer F, McAfee S, Saidman SL, Weymouth D, Andrews DM et al. Mixed lymphohaemopoietic chimerism and graft-versus-lymphoma effects after nonmyeloablative therapy and HLA-mismatched bone-marrow transplantation. Lancet 1999; 353: 1755–1759.

    Article  CAS  Google Scholar 

  22. O’Donnell PV, Luznik L, Jones RJ, Vogelsang GB, Leffell MS, Phelps M et al. Nonmyeloablative bone marrow transplantation from partially HLA-mismatched related donors using posttransplantation cyclophosphamide. Biol Blood Marrow Transplant 2002; 8: 377–386.

    Article  Google Scholar 

  23. Tamaki H, Ikegame K, Kawakami M, Fujioka T, Tsuboi A, Oji Y et al. Successful engraftment of HLA-haploidentical related transplants using nonmyeloablative conditioning with fludarabine, busulfan and anti-T-lymphocyte globulin. Leukemia 2003; 17: 2052–2054.

    Article  CAS  Google Scholar 

  24. Koenecke C, Shaffer J, Alexander SI, Preffer F, Dombkowski D, Siadman SL et al. NK cell recovery, chimerism, function, and recognition in recipients of haploidentical hematopoietic cell transplantation following nonmyeloablative conditioning using a humanized anti-CD2 mAb, Medi-507. Exp Hematol 2003; 31: 911–923.

    Article  CAS  Google Scholar 

  25. Morecki S, Yacovlev E, Diab A, Slavin S . Allogeneic cell therapy for a murine mammary carcinoma. Cancer Res 1998; 58: 3891–3895.

    CAS  PubMed  Google Scholar 

  26. Prigozhina TB, Gurevitch O, Morecki S, Yakovlev E, Elkin G, Slavin S . Nonmyeloablative allogeneic bone marrow transplantation as immunotherapy for hematologic malignancies and metastatic solid tumors in preclinical models. Exp Hematol 2002; 30: 89–96.

    Article  Google Scholar 

  27. Panigrahi S, Morecki S, Yacovlev E, Gelfand Y, Kassir J, Slavin S . A novel approach for prevention of lethal GVHD by selective elimination of alloreactive donor lymphocytes prior to stem cell transplantation. Exp Hematol 2004; 32: 756–764.

    Article  CAS  Google Scholar 

  28. Panoskaltsis-Mortari A, Lacey DL, Vallera DA, Blazar BR . Keratinocyte growth factor administered before conditioning ameliorates graft-versus-host disease after allogeneic bone marrow transplantation in mice. Blood 1998; 92: 3960–3967.

    CAS  Google Scholar 

  29. Krijanovski OI, Hill GR, Cooke KR, Teshima T, Crawford JM, Brinson YS et al. Keratinocyte growth factor separates graft- versus-leukemia effects from graft-versus-host disease. Blood 1999; 94: 825–831.

    CAS  Google Scholar 

  30. Vanclée A, Lutgens LC, Oving EB, Deutz NE, Gijbels MJ, Schouten HC et al. Keratinocyte growth factor ameliorates acute graft-versus-host disease in a novel nonmyeloablative haploidentical transplantation model. Bone Marrow Transplant 2005; 36: 907–915.

    Article  Google Scholar 

  31. Dexter DL, Kowalski HM, Blazar BA, Fligiel Z, Vogel R, Heppner GH . Heterogeneity of tumor cells from a single mouse mammary tumor. Cancer Res 1978; 38: 3174–3181.

    CAS  PubMed  Google Scholar 

  32. Or R, Ackerstein A, Nagler A, Amar A, Naparstek E, Varadi G et al. Allogeneic cell-mediated immunotherapy for breast cancer after autologous stem cell transplantation: a clinical pilot study. Cytokines Cell Mol Ther 1998; 4: 1–6.

    CAS  PubMed  Google Scholar 

  33. Bishop MR, Fowler DH, Marchigiani D, Castro K, Kasten-Sportes C, Steinberg SM et al. Allogeneic lymphocytes induce tumor regression of advanced metastatic breast cancer. J Clin Oncol 2004; 22: 3886–3892.

    Article  Google Scholar 

  34. Glass B, Nickelsen M, Dreger P, Claviez A, Hasenkamp J, Wulf G et al. Reduced-intensity conditioning prior to allogeneic transplantation of hematopoietic stem cells: the need for T cells early after transplantation to induce a graft-versus-lymphoma effect. Bone Marrow Transplant 2004; 34: 391–397.

    Article  CAS  Google Scholar 

  35. Foley JE, Jung U, Miera A, Borenstein T, Mariotti J, Echhaus M et al. Ex vivo rapamycin generates donor Th2 cells that potently inhibit graft-versus-host disease and graft-versus-tumor effects via an IL-4-dependent mechanism. J Immunol 2005; 175: 5732–5743.

    Article  CAS  Google Scholar 

  36. Ruggeri L, Capanni M, Urbani E, Perruccio K, Schlomchik WD, Tosti A et al. Effectiveness of donor natural killer cell alloreactivity in mismatched hematopoietic transplants. Science 2002; 295: 2097–2100.

    Article  CAS  Google Scholar 

  37. Rubin JS, Osada H, Finch PW, Taylor WG, Rudikoff S, Aaronson SA . Purification and characterization of a newly identified growth factor specific for epithelial cells. Proc Natl Acad Sci USA 1989; 86: 802–806.

    Article  CAS  Google Scholar 

  38. Farrell CL, Bready JV, Rex KL, Chen JN, DiPalma CR, Whitcomb KL et al. Keratinocyte growth factor protects mice from chemotherapy and radiation-induced gastrointestinal injury and mortality. Cancer Res 1998; 58: 933–939.

    CAS  Google Scholar 

  39. Miki T, Bottaro DP, Fleming TP, Smith CL, Burgess WH, Chan AM et al. Determination of ligand-binding specificity by alternative splicing: two distinct growth factor receptors encoded by a single gene. Proc Natl Acad Sci USA 1992; 89: 246–250.

    Article  CAS  Google Scholar 

  40. Johnson DE, Lu J, Chen H, Werner S, Williams LT . The human fibroblast growth factor receptor genes: a common structural arrangement underlies the mechanisms for generating receptor forms that differ in their third immunoglobulin domain. Mol Cell Biol 1991; 11: 4627–4634.

    Article  CAS  Google Scholar 

  41. Bansal GS, Cox HC, Marsh S, Gomm JJ, Yiangou C, Luqmani Y et al. Expression of keratinocyte growth factor and its receptor in human breast cancer. Br J Cancer 1997; 75: 1567–1574.

    Article  CAS  Google Scholar 

  42. Zang XP, Pento JT . Keratinocyte growth factor-induced motility of breast cancer cells. Clin Exp Metast 2000; 18: 573–580.

    Article  CAS  Google Scholar 

  43. Nguyen TN, Zang XP, Pento JT . Keratinocyte growth factor stimulates the migration and proliferation of breast cancer cells in a culture wounding model. Pharmacol Res 2002; 46: 179–183.

    Article  CAS  Google Scholar 

  44. Oelmann E, Haghgu S, Kulimova E, Mesters RM, Kienast J, Herbst H et al. Influence of keratinocyte growth factor on clonal growth of epithelial tumor cells, lymphoma and leukemia cells and on sensitivity of tumor cells towards 5-fluorouracil in vitro. Int J Oncol 2004; 25: 1001–1012.

    CAS  PubMed  Google Scholar 

  45. Taniguchi F, Harada T, Sakamoto Y, Yamauchi N, Yoshida S, Iwabe T et al. Activation of mitogen-activated protein kinase pathway by keratinocyte growth factor or fibroblast growth factor-10 promotes cell proliferation in human endometrial carcinoma cells. J Clin Endocrinol Metab 2003; 88: 773–780.

    Article  CAS  Google Scholar 

  46. Shan S, Robson ND, Cao Y, Qiao T, Li CY, Kontos CD et al. Responses of vascular endothelial cells to angiogenic signaling are important for tumor cell survival. FASEB J 2004; 18: 326–328.

    Article  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to A Vanclée.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Vanclée, A., van Gelder, M., Schouten, H. et al. Graft-versus-tumor effects on murine mammary carcinoma in a model of nonmyeloablative haploidentical stem cell transplantation. Bone Marrow Transplant 37, 1043–1049 (2006). https://doi.org/10.1038/sj.bmt.1705383

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.bmt.1705383

Keywords

This article is cited by

Search

Quick links