Mobilized human CD34+ hematopoietic stem cells enhance tumor growth in a nonobese diabetic/severe combined immunodeficient mouse model of human non-Hodgkin's lymphoma.
Autologous peripheral blood stem cell mobilization is increasingly applied in the treatment of hematological malignancies. Despite the frequent clinical use in a setting of residual disease, it is not known whether mobilization of hematopoietic stem cells might facilitate tumor outgrowth in vivo. In the bone marrow, a bipotential precursor for hematopoietic and endothelial cells called hemangioblast exists. This hemangioblast, characterized by the expression of CD34 and vascular endothelial growth factor receptor (VEGFR)-2, is released from the bone marrow by mobilization and might be able to result in not only the generation of peripheral blood cells but vasculogenesis due to differentiation of the hemangioblast along the endothelial lineage [in addition to VEGFR-2 expression, angiopoietin-2 (ANG-2) expression can also be found in this stage]. New vessel formation in the tumor is critical for tumor growth. A xenotransplant model was established with 10 x 10(6) Daudi cells (non-Hodgkin's lymphoma) s.c. injected in the neck region of nonobese diabetic/severe combined immunodeficient (NOD/SCID) mice, who were sublethally irradiated with 2 Gy. At day 10 after tumor inoculation, half of the mice were given 0.5 x 10(6) human CD34+ cells i.v., whereas the other half were given PBS i.v. The human CD34+ cells were obtained from leukapheresis samples of myeloma patients undergoing autologous peripheral blood stem cell mobilization. We compared tumor growth and human-specific VEGFR-2 and ANG-2 expression in the two groups. Tumor growth is enhanced 2-fold when mobilized hematopoietic human CD34+ cells are given compared with PBS controls (P = 0.004). In addition, the human-specific VEGFR-2 and ANG-2 reverse transcription-PCR was only positive in the tumors of mice i.v. injected with human CD34+ cells. This indicates that the injected human CD34+ cells home to the tumors and differentiate along the endothelial lineage. In the present study, we demonstrate that mobilized human CD34+ hematopoietic cells injected i.v. might facilitate the outgrowth of tumors in the setting of minimal residual disease. Malignant tumors are capable of incorporating human CD34+ hematopoietic cells. This study questions the safety of leukapheresis in patients with (residual) tumor and has important implications for further development of intensive chemotherapy protocols with autologous stem cell rescue.
de Bont
E S
ES
Division of Pediatric Oncology, Department of Pediatrics, University Hospital Groningen, 9700RB Groningen, The Netherlands. e.de.bont@bkk.azg.nl
Guikema
J E
JE
Scherpen
F
F
Meeuwsen
T
T
Kamps
W A
WA
Vellenga
E
E
Bos
N A
NA
D042702:Angiopoietin-2; D000818:Animals; D018952:Antigens, CD34 / Q000096:biosynthesis*; D002455:Cell Division; D016228:Endothelial Growth Factors / Q000096:biosynthesis; D016222:Fibroblast Growth Factor 2 / Q000096:biosynthesis; D019650:Hematopoietic Stem Cell Mobilization / Q000009:adverse effects*; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D006801:Humans; D007937:Leukapheresis; D008222:Lymphokines / Q000096:biosynthesis; D008228:Lymphoma, Non-Hodgkin / Q000378:metabolism / Q000473:pathology*; D020778:Matrix Metalloproteinase 2 / Q000096:biosynthesis; D020780:Matrix Metalloproteinase 9 / Q000096:biosynthesis; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D014176:Protein Biosynthesis; D020794:Receptor Protein-Tyrosine Kinases / Q000096:biosynthesis; D017978:Receptors, Growth Factor / Q000096:biosynthesis; D040262:Receptors, Vascular Endothelial Growth Factor; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D023041:Xenograft Model Antitumor Assays
D042702:Angiopoietin-2; D018952:Antigens, CD34; D016228:Endothelial Growth Factors; D008222:Lymphokines; D017978:Receptors, Growth Factor; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D016222:Fibroblast Growth Factor 2; D020794:Receptor Protein-Tyrosine Kinases; D040262:Receptors, Vascular Endothelial Growth Factor; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9