The IGF system in neuroblastoma xenografts: focus on IGF-binding protein-6

Abstract

With a view to investigating the implication of IGFbinding 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 antiapoptotic 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.

Influence of energy balance on the somatotrophic axis and matrix metalloproteinase expression in the endometrium of the postpartum dairy cow

“…2008). IGFBP6 has a much higher affinity for IGF2, generally inhibiting IGF2 activity (Bach 1999, Grellier et al . 2002, Bach 2005).…”

Insulin-like growth factor binding protein-6 inhibits prostate cancer cell proliferation: implication for anticancer effect of diethylstilbestrol in hormone refractory prostate cancer

“…IGF-II is an autocrine growth factor that affects neuroblastoma (Grellier et al, 2002) and rhabdomyosarcoma (Gallicchio et al, 2001) cells. In vivo, Grellier et al reported on the transplantation of human IGFBP-6-expressing neuroblastoma cells in nude mice, and their results showed a lower incidence of xenografts, which also exhibited slower growth than those obtained using control cells (1998).…”

IGFBP-6 five years on; not so ‘forgotten’?

“…Neuroblastoma is an IGF-II-dependent tumour [3] and IGFBP-6 overexpression inhibited neuroblastoma xenograft growth in vivo [10], an effect that may be attributable to increased apoptosis [11]. Further, infusion of IGFBP-6 also delayed neuroblastoma xenograft growth in vivo, probably by inhibiting IGF-II actions [12].…”