Gastrin-releasing peptide is a growth factor for human neuroblastomas

Ann Surg. 2002 May;235(5):621-9; discussion 629-30. doi: 10.1097/00000658-200205000-00003.


Objective: To evaluate whether gastrin-releasing peptide (GRP) and GRP receptor (GRP-R) expression correlate with tumor behavior and to examine the mitogenic actions of GRP on neuroblastomas.

Summary background data: Neuroblastoma is the most common solid tumor of infants and children. Despite recent advances in multimodality treatment regimens, the survival for advanced-stage tumors remains dismal. Neuroblastomas are known to produce GRP; however, the proliferative effects of GRP on neuroblastomas have not been elucidated.

Methods: Sections of paraffin-embedded neuroblastomas from 33 patients were analyzed for GRP and GRP-R protein expression by immunohistochemistry. Functional binding of GRP-R to the Ca2+ signaling pathway was examined. In addition, the proliferative effect of GRP on neuroblastoma cells (SK-N-SH, IMR-32, SH-SY5Y, LAN-1) was determined.

Results: Immunohistochemical analysis showed GRP and GRP-R protein expression in neuroblastomas; an increased expression of GRP-R was noted in a higher percentage of undifferentiated tumors compared with tumors that were benign. GRP-R mRNA was confirmed in neuroblastoma cell lines. GRP treatment resulted in intracellular calcium [Ca2+]i mobilization in two cell lines (SK-N-SH, LAN-1). GRP treatment stimulated growth of all four neuroblastoma cell lines; this effect was inhibited in SK-N-SH cells by pretreatment with GRP antibody.

Conclusions: These findings show increased GRP-R expression in the more aggressive and undifferentiated neuroblastomas. The synchronous expression of GRP and its receptor, GRP-R, suggests a role for these proteins in tumor growth. Moreover, these findings show enhanced proliferation of neuroblastoma cells in vitro after GRP treatment, suggesting that GRP may act as an autocrine and/or paracrine growth factor for neuroblastomas. Treatment with specific GRP-R antagonists may provide novel adjuvant therapy for neuroblastomas in children.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Calcium / metabolism
  • Cell Division
  • Cell Line
  • Child, Preschool
  • Gastrin-Releasing Peptide / metabolism
  • Gastrin-Releasing Peptide / physiology*
  • Growth Substances / physiology*
  • Humans
  • Immunohistochemistry
  • Infant
  • Neuroblastoma / metabolism*
  • RNA, Messenger / biosynthesis
  • Receptors, Bombesin / metabolism
  • Receptors, Bombesin / physiology*
  • Reverse Transcriptase Polymerase Chain Reaction
  • Tumor Cells, Cultured


  • Growth Substances
  • RNA, Messenger
  • Receptors, Bombesin
  • Gastrin-Releasing Peptide
  • Calcium