The RET and TRKA pathways collaborate to regulate neuroblastoma differentiation.
Neuroblastoma (NB) is a childhood cancer that arises in the adrenal gland and often shows differentiated neuronal and glial elements. The RET receptor signal pathway is functional in most NB, while loss of nerve growth factor (NGF) receptor (trkA) gene expression correlates with an aggressive phenotype. Thus, we hypothesized that the RET and TRKA signal pathways collaborate to instruct NB differentiation, reminiscent of normal neuronal maturation. Here, we demonstrate that activation of the RET receptor by glial cell line-derived neurotrophic factor (GDNF) increases expression of the RET receptor complex in a panel of malignant human NB cell lines, indicative of a positive feedback mechanism. GDNF also induces growth cessation concomitant with an arrest of cells in the G(0)/G(1) phase of the cell cycle. Furthermore, GDNF synergizes with ciliary neurotrophic factor (CNTF) to enhance TRKA receptor expression, thereby strengthening the NGF-mediated differentiation signal. Differentiated NB cells downregulate expression of the amplified N-myc gene, concurrent with the arrest of cell proliferation, while expressing neuron-specific markers (i.e., SCG10). Interestingly, maintenance of differentiated NB cells in culture is independent of the trophic activity of GDNF, but depends on TRKA signaling, thereby re-enacting the differentiation of normal sympathoadrenal (SA) progenitor cells.
Peterson
Suzanne
S
Childrens Hospital Los Angeles, Division of Hematology Oncology, 4650 Sunset Boulevard, Los Angeles, CA 90027, USA.
Bogenmann
Emil
E
D002454:Cell Differentiation; D045744:Cell Line, Tumor; D020934:Ciliary Neurotrophic Factor / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D051100:Glial Cell Line-Derived Neurotrophic Factor; D051097:Glial Cell Line-Derived Neurotrophic Factor Receptors; D006801:Humans; D020932:Nerve Growth Factor / Q000494:pharmacology; D009414:Nerve Growth Factors / Q000494:pharmacology; D009447:Neuroblastoma / Q000473:pathology*; D011518:Proto-Oncogene Proteins / Q000502:physiology*; D016271:Proto-Oncogene Proteins c-myc / Q000032:analysis; D051096:Proto-Oncogene Proteins c-ret; D020794:Receptor Protein-Tyrosine Kinases / Q000502:physiology*; D020917:Receptor, trkA / Q000502:physiology*; D015398:Signal Transduction
D020934:Ciliary Neurotrophic Factor; C495039:GDNF protein, human; D051100:Glial Cell Line-Derived Neurotrophic Factor; D051097:Glial Cell Line-Derived Neurotrophic Factor Receptors; D009414:Nerve Growth Factors; D011518:Proto-Oncogene Proteins; D016271:Proto-Oncogene Proteins c-myc; D020932:Nerve Growth Factor; D051096:Proto-Oncogene Proteins c-ret; D020794:Receptor Protein-Tyrosine Kinases; D020917:Receptor, trkA