transforming-growth-factor-alpha and Endometrial-Hyperplasia

The biological significance of epidermal growth factor (EGF)-related proteins in the development and progression of endometrioid endometrial carcinoma was studied. Expression of EGF-related proteins including EGF, transforming growth factor-alpha (TGF-alpha), cripto (CR), amphiregulin (AR), and EGF receptor (EGFR) were immunohistochemically examined. Results were then correlated with clinicopathologic findings and steroid receptor status in 12 specimens with normal endometrium, 13 with endometrial hyperplasia, and 40 with endometrioid endometrial carcinoma. EGFR, EGF, TGF-alpha, and CR immunoreactivities were observed in 58.3%, 66.7%, 91.6%, and 66.7% of normal endometrial specimens; 100%, 15.4%, 100%, and 30.8% of endometrial hyperplasia specimens; and 67.5%, 32.5%, 65.0%, and 65.0% of endometrial carcinoma specimens, respectively. AR immunoreactivity was not observed in any of the normal, hyperplastic, or neoplastic endometrium. The presence or absence of EGFR or TGF-alpha in endometrial carcinoma correlated with surgical stage, depth of myometrial invasion, and findings from peritoneal washing cytology. EGF expression significantly correlated with the age of the patients and that of CR with surgical stage and peritoneal washing cytological findings. There was a significant correlation between EGFR and TGF-alpha expression, and between EGF and TGF-alpha. Co-expression of EGFR and TGF-alpha, EGFR and CR, and TGF-alpha and CR in carcinoma specimens significantly correlated with advanced surgical stage, deeper myometrial invasion, and positive peritoneal washing cytology. In normal as well as hyperplastic endometrium, endometrial glands immunohistochemically positive for TGF-alpha were generally positive for ER, but in poorly differentiated endometrial carcinoma, cells positive for TGF-alpha tended to be negative for ER. The results of the present study show that among EGF-related proteins, expression of TGF-alpha and CR seem to be associated with the progression of human endometrioid endometrial carcinoma. Additionally, expression of TGF-alpha became increasingly estrogen independent with increasing histological carcinoma grades.

Topics: Adult; Amphiregulin; Carcinoma, Endometrioid; EGF Family of Proteins; Endometrial Hyperplasia; Endometrial Neoplasms; Endometrium; Epidermal Growth Factor; ErbB Receptors; Female; Glycoproteins; GPI-Linked Proteins; Growth Substances; Humans; Intercellular Signaling Peptides and Proteins; Membrane Glycoproteins; Middle Aged; Neoplasm Proteins; Neoplasm Staging; Receptors, Estrogen; Receptors, Progesterone; Receptors, Steroid; Retrospective Studies; Transforming Growth Factor alpha

Basement membranes (BM) are elements of the extracellular matrix that are essential for growth and differentiation of tissues. Several collagenolytic enzymes of tumor cells are involved in degradation of the extracellular matrix; growth and inhibitor factors [e.g. Epidermal Growth Factor (EGF), Transforming Growth Factors alpha and beta (TGF-alpha, beta)] seem to be involved in the extracellular matrix formation and degradation. To establish a possible association between the presence of collagenase (C), urokinase-type plasminogen activator (uPA) and the neoplastic growth of the endometrium, 44 endometrial specimens (14 proliferative, 11 secretive, 7 adenomatous hyperplasia, 12 adenocarcinoma) were studied using immunohistochemistry with antisera for C, uPA, EGF receptors and TGF-alpha. Immunostaining for collagenase revealed a positive reaction in moderately differentiated adeno-carcinoma without staining the normal and hyperplastic endometrium. A progressive increase in uPA immunostaining was observed in proliferative and neoplastic endometrium. TGF-alpha and its receptor (EGFr) were stained in proliferative and more clearly in hyperplastic and carcinomatous endometrium. In conclusion, BM play an important role in proliferation and differentiation of human endometrium; their degradation influences estrogen transportation from blood to the stroma. Endometrial BM degradation is associated with the presence of collagenolytic enzymes and growth factors.

Topics: Adult; Basement Membrane; Endometrial Hyperplasia; Endometrium; ErbB Receptors; Female; Fibrinolytic Agents; Humans; Microbial Collagenase; Middle Aged; Peptide Hydrolases; Plasminogen Activators; Transforming Growth Factor alpha; Urokinase-Type Plasminogen Activator; Uterine Neoplasms

Progesterone (P) and progestins play an important role in the control of endometrial growth. We have investigated P and progestin effects on endometrial estrogen extraction, on basement membrane (BM) synthesis and on the presence of the epidermal growth factor receptor (EGFr) in normal and pathologic endometrium. E2 uptake, evaluated in human isolated perfused uteri is significantly decreased by P. BMs investigated using immunohistochemistry, with antisera to collagen IV and laminin, were found around stromal cells only in the luteal phase or during P or progestin administration. Glandular BM, discontinuous in hyperplastic and carcinomatous endometria, were restored to integrity only in typical hyperplasia after therapy with progestin. Endometrial EGFr is modified by P: revelation of this antigen is increased in proliferative phase and decreased in secretory phase. Similarly this molecule was present in hyperplastic and carcinomatous endometria. Only in benign hyperplasia did we observe no staining for the same antigen after progestinic therapy. These data suggest that P or progestins may also have an indirect influence through mechanisms such as estrogen uptake and tissue factor activity with important differences between normal and pathologic endometrium.

Topics: Adult; Cell Membrane; Cell Transformation, Neoplastic; Collagen; Endometrial Hyperplasia; Endometrium; ErbB Receptors; Female; Humans; Immunohistochemistry; Laminin; Middle Aged; Neoplasm Invasiveness; Progesterone; Progestins; Transforming Growth Factor alpha; Uterine Neoplasms