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 clinic al use in a setting of residual disease, it is not known whether mobilizati on 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 th e 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 vasculogene sis due to differentiation of the hemangioblast along the endothelial linea ge [in addition to VEGFR-2 expression, angiopoietin-2 (ANG-2) expression ca n also be found in this stage]. New vessel formation in the tumor is critic al 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 n onobese diabetic/severe combined immunodeficient (NOD/SCID) mice, who were sublethally irradiated with 2 Gy. At day 10 after tumor inoculation, half o f 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 leukaphe resis samples of myeloma patients undergoing autologous peripheral blood st em cell mobilization. We compared tumor growth and human-specific VEGFR-2 a nd ANG-2 expression in the two groups. Tumor growth is enhanced 2-fold when mobilized hematopoietic human CD34+ cells are given compared with PBS cont rols (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 wi th human CD34+ cells. This indicates that the injected human CD34+ cells ho me to the tumors and differentiate along the endothelial lineage. In the pr esent study, we demonstrate that mobilized human CD34+ hematopoietic cells injected i.v. might facilitate the outgrowth of tumors in the setting of mi nimal residual disease. Malignant tumors are capable of incorporating human CD34+ hematopoietic cells. This study questions the safety of leukapheresi s in patients with (residual) tumor and has important implications for furt her development of intensive chemotherapy protocols with autologous stem ce ll rescue.