Immunohistochemical localization of growth factors and their receptors in uterine leiomyomas and matched myometrium.
Immunolocalization of transforming growth factor alpha (TGF-Alpha), epidermal growth factor (EGF), insulinlike growth factor (IGF)-I, vascular endothelial growth factor (VEGF(165,189,121)), basic fibroblast growth factor (FGF)-2, EGF receptor (R), IGF-IRbeta, and FGFR-1 was studied in uterine leiomyomas and matched myometrial samples taken from seven women (42-47 years of age) in the proliferative phase of the menstrual cycle. Immunolocalization of growth factor peptides was accomplished with either monoclonal or polyclonal antibodies to the amino or carboxy terminus of growth factor peptides or their respective receptors, or against full-length recombinant growth factor. All reactions were conducted using the avidin-biotin complex method. Immunolocalization of TGF-alpha, EGF, EGF-R, IGF-I, IGF-IRbeta, FGF-2, FGFR-1, and VEGF was observed in the cytoplasm of smooth-muscle cells of leiomyomas and matched myometrium. The cytoplasm of vascular smooth-muscle cells expressed TGF-alpha, EGF, EGF-R, IGF-I, IGF-IRbeta, FGF-2, FGFR-1, and VEGF, whereas the vascular endothelium was positive for TGF-alpha, EGF, EGF-R, FGF-2, and FGFR-1 in both leiomyomas and matched myometria. Fibroblasts within the fibrous component of some leiomyomas were positive for IGF-I and FGF-2 and minimally positive for FGFR-1. In addition, the extracellular matrix of leiomyomas showed focal localization of FGF-2 and IGF-I in some tumors. When scores of intensity and percent positive staining were compared, IGF-IRbeta was significantly increased in the leiomyomas compared to matched myometria, whereas EGF was significantly decreased in the uterine leiomyomas compared to matched myometria. In summary, these data revealed growth factors to be expressed differentially in smooth muscle, vascular and fibroblastic cell types of leiomyomas and matched myometria. Specifically, IGF-IRbeta was significantly increased in leiomyomas; although a similar increase was seen with IGF-I peptide, statistical significance was not achieved. The EGF peptide was significantly decreased in the leiomyomas compared to matched myometrium. These data suggest that IGF-IRbeta and IGF-I peptide may be one of several growth factor/receptor pathways important in uterine leiomyoma growth during the proliferative phase of the menstrual cycle. In addition, decreased EGF may be secondary to the predominant estrogenic milieu present at time of sampling, as it has been proposed that progesterone, and not estrogen, may regulate EGF.
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Laboratory of Experimental Pathology, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina 27709, USA. dixon@niehs.nih.gov
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D000328:Adult; D016022:Case-Control Studies; D016228:Endothelial Growth Factors / Q000032:analysis; D004815:Epidermal Growth Factor / Q000032:analysis; D066246:ErbB Receptors / Q000032:analysis; D005260:Female; D016222:Fibroblast Growth Factor 2 / Q000032:analysis; D006133:Growth Substances / Q000032:analysis*; D006801:Humans; D007150:Immunohistochemistry; D007889:Leiomyoma / Q000473:pathology*; D008222:Lymphokines / Q000032:analysis; D008597:Menstrual Cycle / Q000502:physiology; D008875:Middle Aged; D020794:Receptor Protein-Tyrosine Kinases / Q000032:analysis; D051496:Receptor, Fibroblast Growth Factor, Type 1; D017527:Receptor, IGF Type 2 / Q000032:analysis; D017468:Receptors, Fibroblast Growth Factor / Q000032:analysis; D017978:Receptors, Growth Factor / Q000032:analysis*; D013002:Somatomedins / Q000032:analysis; D016211:Transforming Growth Factor alpha / Q000032:analysis; D014594:Uterine Neoplasms / Q000473:pathology*; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors
D016228:Endothelial Growth Factors; D006133:Growth Substances; D008222:Lymphokines; D017527:Receptor, IGF Type 2; D017468:Receptors, Fibroblast Growth Factor; D017978:Receptors, Growth Factor; D013002:Somatomedins; D016211:Transforming Growth Factor alpha; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D016222:Fibroblast Growth Factor 2; D004815:Epidermal Growth Factor; D066246:ErbB Receptors; C496348:FGFR1 protein, human; D020794:Receptor Protein-Tyrosine Kinases; D051496:Receptor, Fibroblast Growth Factor, Type 1