IGFBPs are involved in xenograft development in nude mice.
BACKGROUND
The insulin-like growth factors (IGFs) are involved in the growth and differentiation of neuroblastoma cells. In all biological fluids, they are non-covalently bound to high-affinity binding proteins (IGFBP-1 to -6) which modulate their bioavailability. We previously showed that IGFBP-6 expression is linked to the arrest of growth in neuroblastoma cells, whereas IGFBP-2 is associated with proliferation.


METHODS
To study the role of IGFBP-6 in cell growth, we stably IGR-N-91 neuroblastoma cells with a plasmid containing sequences coding for IGFBP-6 under the control of the cytomegalovirus (CMV) promoter.


RESULTS
The incidence and size of tumors generated by injecting IGFBP-6-expressing cells into nude mice were reduced by factors of 2 and 5, respectively, as compared with those generated by injection by control cells. Northern blot analyses if xenografts revealed weaker expression of IGF-II, type 2 IGF receptor and IGFBP-2 mRNAs in IGFBP-6-expressing cthan in control xenografts. IGFBP-6 may therefore reduce the expression of IGF-II (which induces tumour development) at a transcriptional level. Conversely, containing IGFBP-2 cDNA under the control of CMV promoter grew three to four times as fast as normal control xenografts. Northern blot analyses revealed weaker expression of intact IGFBP-3 and IGFBP-1 in IGFBP-2-expressing than in control xenografts.


CONCLUSIONS
IGFBP-1 and intact IGFBP-3 expression both enhance IGF bioavailability which promotes tumour growth. Although the mechanisms of action of IGFBP-2 and IGFBP-6 remain to be elucidated, an inverse relationship appears to exist between the two binding proteins, IGFBP-2 being involved in proliferation and IGFBP-6 in its arrest.
Babajko
S
S
INSERM U.515, Hĵpital Saint Antoine, Paris, France. babajko@st-antoine.inserm.fr
Grellier
P
P
de Gallé
B
B
Menouny
M
M
Binoux
M
M
D000818:Animals; D001682:Biological Availability; D003587:Cytomegalovirus / Q000235:genetics; D005813:Genes, Synthetic; D006085:Graft Survival; D006801:Humans; D018971:Insulin-Like Growth Factor Binding Protein 2 / Q000235:genetics / Q000502:physiology; D018976:Insulin-Like Growth Factor Binding Protein 6 / Q000235:genetics / Q000502:physiology; D018969:Insulin-Like Growth Factor Binding Proteins / Q000502:physiology*; D007334:Insulin-Like Growth Factor I / Q000502:physiology; D007335:Insulin-Like Growth Factor II / Q000502:physiology; D007624:KB Cells / Q000378:metabolism / Q000637:transplantation; D051379:Mice; D008819:Mice, Nude; D008938:Mitosis; D009368:Neoplasm Transplantation / Q000502:physiology*; D009447:Neuroblastoma / Q000473:pathology*; D011401:Promoter Regions, Genetic; D011993:Recombinant Fusion Proteins / Q000502:physiology; D014162:Transfection; D019076:Transgenes; D014183:Transplantation, Heterologous / Q000502:physiology*; D014407:Tumor Cells, Cultured / Q000378:metabolism / Q000637:transplantation
D018971:Insulin-Like Growth Factor Binding Protein 2; D018976:Insulin-Like Growth Factor Binding Protein 6; D018969:Insulin-Like Growth Factor Binding Proteins; D011993:Recombinant Fusion Proteins; D007334:Insulin-Like Growth Factor I; D007335:Insulin-Like Growth Factor II