Modulation of insulin-like growth factor (IGF) action by IGF-binding proteins in normal, benign, and malignant smooth muscle tissues.
The insulin-like growth factor (IGF) system is involved in the growth of uterine leiomyomas (L), as these tumors have higher IGF-II messenger ribonucleic acid levels, type I IGF receptor levels, and IGF-I peptide concentrations than myometrium (M). Furthermore, cultured L smooth muscle cells (SMC) respond with greater efficiency to IGF-I than M SMC. Here we investigate a possible modulating role of the binding proteins for the IGFs (IGFBPs) on the actions of IGFs. IGFBP-3 is the most predominant IGFBP in conditioned medium from SMC, with levels ranging from 13-288 ng/mL. Incubation of SMC cultures with IGF-I and the IGF-I analogs long-R3IGF-I and des(1-3)-IGF-I, which have decreased affinity for IGFBPs, revealed a facilitating effect of IGFBPs on the growth-stimulating activity of a high concentration of IGF-I in cell lines with high IGFBP-3 levels. Both a decreased level of IGFBP-3 and a low concentration of the growth factors added were a disadvantage for the facilitating effect. In M and L tissue sections, IGFBP-3 was found exclusively bound to the constituting cells, not in the extracellular matrix. This suggests that a negative modulating role of IGFBP-3 due to sequestration of IGF-I, as occurs in culture medium, is less relevant in vivo. In leiomyosarcoma sections, IGFBP-3 levels are decreased, indicating a decreasing, role for this binding protein in malignant smooth muscle tissues.
van der Ven
L T
LT
Department of Pathology, University Hospital Utrecht, The Netherlands. leoven@knoware.nl
Van Buul-Offers
S C
SC
Gloudemans
T
T
Bloemen
R J
RJ
Roholl
P J
PJ
Sussenbach
J S
JS
Den Otter
W
W
D000328:Adult; D000368:Aged; D002455:Cell Division; D002462:Cell Membrane / Q000737:chemistry; D002478:Cells, Cultured; D017077:Culture Media, Conditioned; D003593:Cytoplasm / Q000737:chemistry; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D018972:Insulin-Like Growth Factor Binding Protein 3 / Q000032:analysis / Q000502:physiology; D018969:Insulin-Like Growth Factor Binding Proteins / Q000032:analysis / Q000502:physiology*; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology*; D007889:Leiomyoma / Q000473:pathology*; D008297:Male; D008875:Middle Aged; D009130:Muscle, Smooth / Q000473:pathology*; D014594:Uterine Neoplasms / Q000473:pathology*
D017077:Culture Media, Conditioned; D018972:Insulin-Like Growth Factor Binding Protein 3; D018969:Insulin-Like Growth Factor Binding Proteins; D007334:Insulin-Like Growth Factor I