Growth advantage of human leiomyoma cells compared to normal smooth-muscle cells due to enhanced sensitivity toward insulin-like growth factor I.
Human uterine leiomyomas exhibit increased IGF-I binding compared to myometrium, while both tissues show IGF-I gene expression. In this study we have examined the functional importance of these findings by testing the presence of IGF-I in 15 leiomyoma biopsies and in 18 myometrium biopsies and the capacity of smooth-muscle cells cultured from these tissues to react to IGF-I. The mean IGF-I peptide concentration in leiomyomas was 3 times higher than in myometrium. This resulted from increased IGF-I uptake in leiomyomas rather than from increased synthesis, as these tissues contain higher concentrations of type-I IGF receptors, as detected by immunohistochemistry, and equal levels of IGF-I mRNA. Blocking IGF-I transport with cytochalasin-B and with the type-I IGF receptor blocking antibody alpha IR3 in cultured cells induced decreased immunostaining intensity for IGF-I in most myometrium and leiomyoma cultures, indicating that the detected IGF-I is internalized. Depending on the culture conditions, IGF-I administration yielded increased survival or a higher proliferation rate in leiomyoma cultures than in myometrium cultures, indicating the increased importance of exogenous IGF-I for the growth of transformed smooth-muscle cells. We conclude that the increased concentrations of type-I IGF receptors in leiomyoma compared to myometrial smooth-muscle cells are functional with respect to the enhanced internalization of IGF-I and that they provide these tumor cells with a growth advantage compared to their normal counterparts.
van der Ven
L T
LT
Department of Pathology, University Hospital Utrecht, The Netherlands.
Gloudemans
T
T
Roholl
P J
PJ
van Buul-Offers
S C
SC
Bladergroen
B A
BA
Welters
M J
MJ
Sussenbach
J S
JS
den Otter
W
W
D000328:Adult; D001692:Biological Transport / Q000187:drug effects; D003571:Cytochalasin B / Q000494:pharmacology; D005260:Female; D006801:Humans; D007124:Immunoenzyme Techniques; D007334:Insulin-Like Growth Factor I / Q000032:analysis / Q000494:pharmacology*; D007889:Leiomyoma / Q000378:metabolism / Q000473:pathology*; D008875:Middle Aged; D009130:Muscle, Smooth / Q000166:cytology* / Q000378:metabolism; D009215:Myometrium / Q000166:cytology; D011863:Radioimmunoassay; D017526:Receptor, IGF Type 1 / Q000378:metabolism; D014407:Tumor Cells, Cultured; D014594:Uterine Neoplasms / Q000378:metabolism / Q000473:pathology*
D003571:Cytochalasin B; D007334:Insulin-Like Growth Factor I; D017526:Receptor, IGF Type 1