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Inhibition of Hemopoiesis in Vitro by Neuroblastoma-derived Gangliosides¹

Department of Pediatric Oncology, Beatrix Children's Hospital, University Hospital, 9713 GZ Groningen [H. S., W. A. K.]; Department of Physiological Chemistry, University of Groningen, 9713 AV Groningen [H. S., W. N., B. D., J. W. K.]; and Department of Hematology, University Hospital Groningen, 9713 GZ Groningen [E. V.], the Netherlands

Hemopoiesis is disturbed in bone marrow-involving cancers like leukemia and neuroblastoma. Shedding of gangliosides by tumor cells may contribute to this tumor-induced bone marrow suppression. We studied in vitro the inhibitory effects of murine neuroblastoma cells (Neuro-2a and C1300) and their gangliosides on hemopoiesis using normal murine hemopoietic progenitor colony-forming assays. Transwell cultured neuroblastoma cells showed a dose-dependent inhibition on hemopoiesis, indicating that a soluble factor was responsible for this effect. Furthermore, the supernatant of Neuro-2a cultured cells inhibited hemopoietic proliferation and differentiation. To determine whether the inhibitory effect was indeed due to shed gangliosides and not, for instance, caused by cytokines, the effect of DL-threo-1-phenyl-2-decanoylamino-3-morpholino-1-propanol (DL-PDMP) on Neuro-2a cells was studied. DL-PDMP is a potent inhibitor of glucosylceramide synthase, resulting in inhibition of the synthesis and shedding of gangliosides. The initially observed inhibitory effect of supernatant of Neuro-2a cells was abrogated by culturing these cells for 3 days in the presence of 10 µM DL-PDMP. Moreover, gangliosides isolated from Neuro-2a cell membranes inhibited hemopoietic growth. To determine whether the described phenomena in vitro are a reflection of bone marrow suppression occurring in vivo, gangliosides isolated from plasma of neuroblastoma patients were tested for their effects on human hemopoietic progenitor colony-forming assays. These human neuroblastoma-derived gangliosides inhibited normal erythropoiesis (colony-forming unit-erythroid/burst-forming unit-erythroid) and myelopoiesis (colony-forming unit-granulocyte/macrophage) to a higher extent compared with gangliosides isolated from control plasma. Altogether these results suggest that gangliosides shed by neuroblastoma cells inhibit hemopoiesis and may contribute to the observed bone marrow depression in neuroblastoma patients.

¹ This work was supported by Grant KOCG 94-03 from the Groningen Foundation of Pediatric Oncology. J. W. K. was supported by a fellowship of the Royal Netherlands Academy of Arts and Sciences. We thank the Department of Thoracic Surgery of the University Hospital Groningen, the Netherlands, for assistance in obtaining normal human bone marrow samples.

² To whom requests for reprints should be addressed, at Department of Physiological Chemistry, Faculty of Medical Sciences, University of Groningen, A. Deusinglaan 1, 9713 AV Groningen, the Netherlands. Phone: 31-50-3632725/3632727; Fax: 31-50-3632728; E-mail: j.w.kok@med.rug.nl.

Received 5/ 4/98. Accepted 8/27/98.

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