With a view to investigating the implication of IGF-binding protein-6 (IGFBP-6) in the growth of neuroblastomas, nude mice were injected with IGFBP-6-expressing or control IGR-N-91 human neuroblastoma cells and the resulting xenografts examined. Expression of IGFBP-3, IGFBP-4 and type 1 and type 2 IGF receptor messengers was similar in control tumours and equal-sized IGFBP-6-expressing tumours that had developed. IGF-II was more strongly expressed in control tumours, and IGFBP-6-expressing tumours contained less IGFBP-2 than controls. In both populations, there was a significant positive correlation between IGF-II and IGFBP-2 expression. In small IGFBP-6-expressing xenografts where tumour development had apparently been arrested, haematoxylin--eosin and TUNEL staining revealed numerous apoptotic cells. In situ hybridization indicated homogeneous distribution of the IGFBP-6 signal in test tumours. In cell culture, IGFBP-6-expressing cells expressed similar amounts of IGFBP-2, IGF-II and N-myc mRNAs as control cells; but media conditioned by IGFBP-6-expressing cells contained less intact IGFBP-2 protein, with no increase in its proteolytic fragment. In media treated with plasminogen, in which IGFBP-2 was proteolysed, IGFBP-6 was increased. With its especially strong affinity for IGF-II and its resistance to proteolysis, IGFBP-6 would act by sequestering IGF-II, hence inhibiting its mitogenic and anti-apoptotic effects. In excess, IGFBP-6 would displace IGF-II from IGFBP-2 whose potentiation of IGF-II action would cease and whose susceptibility to degradation would be increased. This study therefore shows that IGFBP-6 plays a role in neuroblastoma cell growth in vivo and in vitro and that stable overexpression of IGFBP-6 leads to alteration of the initial balance between the IGFBPs.

This article has been cited by other articles:

				C. Iosef, T. Gkourasas, C. Y. H. Jia, S. S.-C. Li, and V. K. M. Han A Functional Nuclear Localization Signal in Insulin-Like Growth Factor Binding Protein-6 Mediates Its Nuclear Import Endocrinology, March 1, 2008; 149(3): 1214 - 1226. [Abstract] [Full Text] [PDF]

				M A Fenwick, S Llewellyn, R Fitzpatrick, D A Kenny, J J Murphy, J Patton, and D C Wathes Negative energy balance in dairy cows is associated with specific changes in IGF-binding protein expression in the oviduct Reproduction, January 1, 2008; 135(1): 63 - 75. [Abstract] [Full Text] [PDF]

				B. L. Dake, M. Boes, L. A. Bach, and R. S. Bar Effect of an Insulin-Like Growth Factor Binding Protein Fusion Protein on Thymidine Incorporation in Neuroblastoma and Rhabdomyosarcoma Cell Lines Endocrinology, July 1, 2004; 145(7): 3369 - 3374. [Abstract] [Full Text] [PDF]