Insulin-Like Growth Factor I (IGF-I), IGF-I Receptors, and IGF Binding Proteins 1–4 in Human Uterine Tissue: Tissue Localization and IGF-I Action in Endometrial Stromal and Myometrial Smooth Muscle Cells in Vitro

Abstract

The objective of the present study was to elucidate the presence and cellular distribution of insulin-like growth factor I (IGF-I), IGF-I receptor (IGF-IR), and IGF binding proteins (IGFBPs) in human uterine tissue at various reproductive stages, and to determine the effect of IGF-I and its interaction with epidermal growth factor (EGF) and platelet-derived growth factor (PDGF) in endometrial stromal and myometrial smooth muscle cells in primary culture. Using specific antibodies, immunohistochemical observations indicated that luminal and glandular epithelial cells were the major sites of immunoreactive IGF-I, IGF-IR, and IGFBPs 1-4, followed by myometrial smooth muscle and endometrial stromal cells. The immunostaining intensity of IGF-I, IGF-IR, and IGFBPs in endometrial but not myometrial tissue was cycle-dependent and higher in the late proliferative and early/mid-secretory periods than in the late secretory and postmenopausal periods, with little immunostaining at the early proliferative phase of the menstrual cycle. Stromal and smooth cells in primary cell culture also contained immunoreactive IGF-I, IGF-IR, and IGFBPs. IGF-I at 10-100 ng/ml stimulated 3H-thymidine incorporation in quiescent stromal and smooth muscle cells with maximal effect at 100 ng/ml (p < 0.05). However, in the presence of 2% serum, which induces half-maximal stimulation, IGF-I (100 ng/ml) further increased the rate of 3H-thymidine incorporation in stromal but not smooth muscle cells (p < 0.05). The effect of IGF-I was significantly lower than that induced by EGF (10 ng/ml), PDGF-BB (10 ng/ml) and their combination (p < 0.005), and higher in stromal cells from proliferative, than secretory phase of the cycle in the presence of 2% fetal bovine serum, but not serum-free condition (p < 0.005). The effect of IGF-I on myometrial smooth muscle cells was significantly higher than that induced by EGF, but lower than that induced by PDGF-BB or by EGF+PDGF-BB, without the cycle specificity seen with stromal cells. EGF, PDGF-BB, and their combination with IGF-I, but not IGF-I alone, stimulated stromal and smooth muscle cell growth as determined by a cell proliferation assay. The results indicate that human uterine tissue at various reproductive stages contains immunoreactive IGF-I, IGF-IR, and IGFBPs 1-4. Although IGF-I alone was found to be a weak mitogenic factor for stromal and smooth muscle cells, by interacting with EGF and PDGF-BB in a cycle-dependent manner it may regulate the growth and differentiation of these and other uterine cell types.

Overexpression of the Insulin-Like Growth Factor I Receptor and Activation of the AKT Pathway in Hyperplastic Endometrium

“…In premenopausal or normal cycling endometrium, increased IGF-I has been implicated in normal proliferation of the glandular epithelium and stromal cells (16,19). The IGF-I signaling pathway can also be activated by decreased levels of PTEN expression because PTEN is a phosphatase that normally suppresses the activity of the phosphoinositide-3-kinase pathway (21,26).…”

“…IGF-IR is localized to the luminal and glandular epithelium as well as the stroma, and its expression is down-regulated by progesterone (19,20). In endometrial cells, the activity of the phosphoinositide-3-kinase/Akt pathway is also critically regulated by the activity of phosphatase and tensin homologue deleted on chromosome 10 (PTEN), a lipid phosphatase that negatively regulates phosphoinositide-3-kinase activity by the dephosphorylation of phosphoinositol (3,4,5) triphosphate (21).…”

Insulin-Like Growth Factor-I Stimulated DNA Replication in Mouse Endometrial Stromal Cells

“…In addition to the IGFBP transport functions, IGFBPs are involved in cell cycle, apoptosis, cell adhesion and motility in various tissues [32,33]. IGFBP expression in the uterus is highly associated with IGF-I activity [34][35][36]. In the human endometrium, the expression of mRNAs for the six IGFBPs are detected during the menstrual cycle.…”

Estradiol, Progesterone, and Transforming Growth Factor α Regulate Insulin-Like Growth Factor Binding Protein-3 (IGFBP3) Expression in Mouse Endometrial Cells

“…IGFBP3 is expressed in the mouse uterus, and expression levels change during estrous cycle (Girvigian et al, 1994;Molnar and Murphy, 1994;Tang et al, 1994). These findings suggest that uterine IGFBP3 production is partly regulated by ovarian steroid hormones.…”