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Nerve growth factor stimulates clonal growth of human lung cancer cell lines and a human glioblastoma cell line expressing high-affinity nerve growth factor binding sites involving tyrosine kinase signaling.

Abstract
The growth of a panel of 22 different human tumor, leukemia, and lymphoma cell lines was examined in a human tumor cloning assay in agar or methylcellulose and a tritiated thymidine uptake assay. The cultures were performed in the absence or presence of increasing concentrations (0.5-500 ng/ml) of nerve growth factor (NGF). The growth of 17 of the 22 cell lines was not significantly and reproducibly affected by NGF. There was minor (1.2-fold) but reproducible stimulation of clonal growth in one glioblastoma cell line (86-HG-39) by NGF, but in this cell line NGF induced no growth modulation in a tritiated thymidine uptake assay. However, clonal growth of another glioblastoma cell line (87-HG-31) and all three lung cancer cell lines tested (HTB 119, HTB 120, CCL 185) could be stimulated up to 3-fold by NGF with a dose-response relationship for the growth factor. Growth stimulation by NGF could be completely reversed by neutralizing anti-NGF antibody and by the tyrosine kinase inhibitor genistein. Evaluation of secondary plating efficiency revealed the stimulation of colony formation as representing self-renewal and not terminal differentiation. Reverse transcriptase-PCR experiments in the five responding cell lines showed expression of both low-affinity NGF receptor (glycoprotein 75) and c-trk transcripts on the mRNA level. Of the five responding cell lines, only 86-HG-39, the cell line with the lowest responsiveness, revealed low-affinity NGF receptor on the protein level; the other four cell lines with high responsiveness, including the three lung cancer cell lines, expressed no low-affinity NGF receptor as shown by fluorescence-activated cell sorter analysis and immunoprecipitation using the ME 20.4 antibody. Immunoprecipitation using anti-trk antibodies was negative in all five responding cell lines. However, binding studies with iodinated NGF showed only low-affinity binding on the 86-HG-39 cell line and only high-affinity binding on the high-responder cell lines CCL 185 and 87-HG-31. In summary, our data suggest that NGF can be operative in stimulation of clonal growth of malignant tumor cells. High-affinity but not low-affinity binding sites mediate signal transduction for clonal growth and signaling involves tyrosine kinase activity.
AuthorsE Oelmann, L Sreter, I Schuller, H Serve, M Koenigsmann, B Wiedenmann, D Oberberg, B Reufi, E Thiel, W E Berdel
JournalCancer research (Cancer Res) Vol. 55 Issue 10 Pg. 2212-9 (May 15 1995) ISSN: 0008-5472 [Print] United States
PMID7538048 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Isoflavones
  • Nerve Growth Factors
  • Proto-Oncogene Proteins
  • Receptors, Nerve Growth Factor
  • Genistein
  • Protein-Tyrosine Kinases
  • Receptor Protein-Tyrosine Kinases
  • Receptor, trkA
  • RNA-Directed DNA Polymerase
Topics
  • Base Sequence
  • Brain Neoplasms (metabolism, pathology)
  • Carcinoma, Non-Small-Cell Lung (metabolism, pathology)
  • Carcinoma, Small Cell (metabolism, pathology)
  • Cell Differentiation (drug effects)
  • Cell Division (drug effects)
  • Dose-Response Relationship, Drug
  • Genistein
  • Glioblastoma (metabolism, pathology)
  • Humans
  • Isoflavones (pharmacology)
  • Lung Neoplasms (metabolism, pathology)
  • Molecular Sequence Data
  • Nerve Growth Factors (pharmacology)
  • Polymerase Chain Reaction
  • Protein-Tyrosine Kinases (antagonists & inhibitors, physiology)
  • Proto-Oncogene Proteins (metabolism)
  • RNA-Directed DNA Polymerase
  • Receptor Protein-Tyrosine Kinases (metabolism)
  • Receptor, trkA
  • Receptors, Nerve Growth Factor (metabolism)
  • Tumor Cells, Cultured

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