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Glial Cell Line-derived Neurotrophic Factor/Neurturin-induced Differentiation and Its Enhancement by Retinoic Acid in Primary Human Neuroblastomas Expressing c-Ret, GFR-1, and GFR-2¹

Divisions of Biochemistry [T. H., Y. Ni., E. I., K. K., S. I., Y. Na., T. O., S. S., A. N.] and Clinical Examination [M. H.], Chiba Cancer Center Research Institute, Chiba 260-8717; Laboratory of Gene Structure I, Kazusa DNA Research Institute, Chiba 292-0812 [N. S.]; and Department of Pediatric Surgery, Chiba University School of Medicine, Chiba 260-8670 [T. H., H. T., N. O., M. T.], Japan

Neuroblastomas often undergo spontaneous differentiation and/or regression in vivo, which is at least partly regulated by the signals through neurotrophins and their receptors. Recently, glial cell line-derived neurotrophic factor (GDNF) and a second family member, neurturin (NTN), have been found to mediate their signals by binding to a heterotetrameric complex of c-Ret tyrosine kinase receptors and glycosylphosphatidylinositol-linked proteins, GFR-1 (GDNFR-) or GFR-2 (TrnR2/GDNFR-ß/NTNR-/RETL2). Here, we studied the effect of GDNF and NTN on human neuroblastomas in the short-term primary culture system, as well as the expression of c-Ret, GFR-1, GFR-2, GDNF, and NTN. GDNF (1–100 ng/ml) induced morphological differentiation in 34 of 38 primary neuroblastomas and an accompanying increase in c-Fos induction. These effects were markedly enhanced by treatment with 5 µM all-trans-retinoic acid. Although GDNF alone induced a rather weak differentiation independent of the disease stages, the enhancement of neurite outgrowth induced by treatment with both GDNF and all-trans-retinoic acid was significantly correlated with younger age (less than 1 year; P = 0.0039), non-stage 4 diseases (P = 0.0023), a single copy of N-myc (P = 0.027), and high levels of TRK-A expression (P = 0.0062). To examine the expression levels of GFR-1, we cloned a short form of the human GFR-1 gene with a 15-bp deletion by screening a human adult substantia nigra cDNA library. Many primary neuroblastomas expressed c-Ret, GFR-1, and GFR-2 as well as their ligands, GDNF and NTN, suggesting the presence of a paracrine or autocrine signaling system within the tumor tissue. The effect of NTN on primary culture cells of neuroblastoma was similar to that of GDNF. These imply that the GDNF(NTN)/c-Ret/GFR-1(GFR-2) signaling may have an important role in regulating the growth, differentiation, and cell death of neuroblastomas.

¹ Supported in part by a grant-in-aid from the Ministry of Health and Welfare for a New Comprehensive 10-Year Strategy for Cancer Control, Japan.

² To whom requests for reprints should be addressed, at Division of Biochemistry, Chiba Cancer Center Research Institute, 666-2 Nitona, Chuoh-ku, Chiba 260-8717, Japan. Phone: 81-43-264-5431; Fax: 81-43-265-4459; E-mail: akiranak@biolab.kazusa.or.jp.

Received 10/29/97. Accepted 3/18/98.

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