transforming-growth-factor-alpha and Prostatic-Intraepithelial-Neoplasia

To gain insight into autocrine/paracrine mechanisms that may influence normal and abnormal growth of the human prostate, we studied the immunohistochemical localization of transforming growth factor alpha (TGF-alpha) and epidermal growth factor receptor (EGFr) in fetal, neonatal, prepubertal, and young adult glands. Results were compared with findings in specimens of benign prostatic hyperplasia (BPH), dysplasia (prostatic intraepithelial neoplasia--PIN), and carcinoma. EGFr was strongly and exclusively expressed in fetal basal cells, whereas TGF-alpha was localized in these and secretory cells as well as in differentiating smooth muscle cells. In neonatal and prepubertal glands, EGFr continued to be found only in basal cells, whereas TGF-alpha was now present in smooth muscle and infrequently in secretory cells. In the normal adult prostate, the receptor was strictly localized in basal cells and in the lateral plasma membranes of secretory cells, whereas its ligand was exclusively expressed in smooth muscle. This pattern persisted in PBH, but both EGFr and TGF-alpha staining appeared to be enhanced in their respective cellular compartments. Irrespective of grade, in dysplasia diffuse-moderate EGFr and strong TGF-alpha staining were both present in a majority of secretory cells. Similarly, most cells in Gleason grade 3 and 4 carcinomas expressed both EGFr and TGF-alpha. Our findings suggest that an unregulated paracrine mode of growth attends the development of BPH, whereas malignant transformation and progression involves autocrine/paracrine mechanisms reminiscent of those found in the developing prostate.

Topics: Adult; Aged; Carcinoma; Child; Epithelial Cells; ErbB Receptors; Fetus; Humans; Immunoenzyme Techniques; Infant, Newborn; Male; Middle Aged; Prostate; Prostatic Hyperplasia; Prostatic Intraepithelial Neoplasia; Prostatic Neoplasms; Stromal Cells; Transforming Growth Factor alpha; Up-Regulation

Analysis of growth factors and receptors in putative premalignant lesions of prostatic adenocarcinoma should aid our understanding of their growth pathways. Sixty prostatic TURP (transurethral resection of the prostate) specimens exhibiting atypical adenomatous hyperplasia (AAH) and/or prostatic intraepithelial neoplasia (PIN) lesions were assayed by immunohistochemistry for androgen receptor (AR), epidermal growth factor receptor (EGFR), c-erbB-2, transforming growth factor-alpha (TGF-alpha), vascular endothelial growth factor (VEGF), fibroblast growth factor-2 (FGF-2), MIB-1, E-cadherin, and high molecular weight keratin. Expression of these factors in the lesions was compared with that in the co-existing benign prostatic hyperplasia (BPH) or prostatic adenocarcinoma. Strong AR nuclear staining was observed in the luminal cells, but not the basal cells, of BPH and PIN lesions and in all the carcinomas examined. A similar growth factor and receptor profile was demonstrated in the secretory epithelium of high-grade PIN and carcinoma with a tendency to higher expression of membranous EGFR and c-erbB-2 and cytoplasmic TGF-alpha, and lower levels of FGF-2 than in low-grade PIN or BPH glands. Also, increased rates of proliferation, as estimated by MIB-1 stained cells, were observed in high-grade PIN in comparison with low-grade PIN and BPH and were not confined to the basal layer. AAH lesions resembled neither BPH nor carcinoma. Proliferation was virtually absent (MIB-1 expression); both AR and E-cadherin expression was significantly reduced; and, with the exception of FGF-2, all the other growth factors and receptors studied were absent. The results presented would support a premalignant role for high-grade PIN, whilst AAH would appear to represent a quiescent phenotype unlikely to progress to neoplasia.

Topics: Antigens, Nuclear; Cadherins; Endothelial Growth Factors; ErbB Receptors; Fibroblast Growth Factor 2; Growth Substances; Humans; Ki-67 Antigen; Lymphokines; Male; Nuclear Proteins; Precancerous Conditions; Prostatic Hyperplasia; Prostatic Intraepithelial Neoplasia; Prostatic Neoplasms; Receptor, ErbB-2; Receptors, Androgen; Transforming Growth Factor alpha; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factors