Summary The expression of mRNA for the epidermal growth factor (EGF) receptor, EGF and transforming growth factor a (TGF-a) was determined in 76 malignant, six borderline and 15 benign primary ovarian tumours using the reverse transcriptase-polymerase chain reaction and related to clinical and pathological parameters. Of the malignant tumours, 70% (53/76) expressed EGF receptor mRNA, 31% (23/75) expressed EGF mRNA and 35% (26/75) expressed TGF-a mRNA. For the borderline tumours, four of six (67%) expressed EGF receptor mRNA, 1/6 (17%) expressed TGF-a mRNA and none expressed EGF mRNA. Finally, 33% (5/15) of the benign tumours expressed EGF receptor mRNA, whereas 40% (6/15) expressed EGF mRNA and 7% (1/15) expressed TGF-a mRNA. The presence of the EGF receptor in malignant tumours was associated with that of TGF-a (P = 0.0015) but not with EGF (P = 1.00), whereas there was no relationship between the presence of EGF and TGF-a (P = 1.00). EGF receptor mRNA expression was significantly and positively associated with serous histology (P = 0.006) but not with stage or grade. Neither EGF nor TGF-a showed any link with histological subtype or stage. The survival of patients with malignant tumours possessing EGF receptor mRNA was significantly reduced compared with that of patients whose tumours were negative (P = 0.030 for all malignant tumours; P= 0.007 for malignant epithelial tumours only). In contrast, neither the expression of TGF-a nor EGF was related to survival. These data suggest that the presence of EGF receptor mRNA is associated with poor prognosis in primary ovarian cancer.
Leydig cells were purified on discontinuous Percoll gradients after collagenase digestion of human or rat testes. Leydig cells from both species were found in three bands. As determined by positive staining for 3 beta-hydroxysteroid dehydrogenase, band 1 (lowest density cells) from both species contained only 12-28% Leydig cells. However, while band 3 was the most Leydig cell-enriched fraction in rat cell preparations (70-90% Leydig cells), human band 2 (48-70% Leydig cells) was consistently more Leydig cell enriched than was band 3 (30-56% Leydig cells). Despite their slightly different fractionation pattern, Leydig cells prepared from five men with prostatic carcinoma were similar to those from the rat, both in terms of the amount of testosterone produced basally per 10(6) Leydig cells (80-234 ng/20 h) and in terms of the magnitude of their response to hCG (764-1342 ng/10(6) Leydig cells X 20 h; 5- to 17-fold stimulation above basal). Cells prepared from five other men with prostatic carcinoma produced much lower amounts of testosterone, but still had up to a 6-fold response to hCG. Plasma LH, FSH, and testosterone concentrations in the latter group could not be distinguished from those in the group whose Leydig cells produced large amounts of testosterone in vitro. Morphologically, the testes from the latter group appeared to contain more darkly staining than lightly staining Leydig cells than did the former group. Rat Leydig cells responded in a dose-dependent fashion to hCG over the range 0.03-0.5 mU/mL, whereas human Leydig cells were 10- to 100-fold less sensitive, responding to hCG in the range 0.4-100 mU/mL. The number and affinity of Leydig cell LH (hCG) receptors were assessed from Scatchard analysis of [125I]hCG binding. Compared with rat cells, human Leydig cells contained approximately 20% of the number of LH receptors, while the affinity of the receptors (Kd, approximately 10(-10) M) was similar to that in rats. In conclusion, a method for the isolation of highly responsive human Leydig cells has been developed. The results so far suggest that the function of human Leydig cells may be more similar to that of the rat than thought previously.
Immunohistochemical expression of EGF-R, c-erbB-2 and c-erbB-3, members of the type-1 family of receptor tyrosine kinases, were investigated in 67 primary ovarian-tumour samples (46 malignant, 8 borderline and 13 benign), and related to tumour clinicopathological features. The incidence of all 3 receptor proteins was highest in overtly malignant tumours. No significant correlations were observed between either EGF-R or c-erbB-3 and clinical parameters such as tumour stage, differentiation or extent of debulking surgery, but c-erbB-2 was significantly associated with several indicators of prognosis, including early stage and good/moderate differentiation in optimally debulked tumours. Multiple expression of c-erbB receptor proteins was also significantly higher in malignant tumours compared with borderline and benign tumours. Early-stage tumours were also more likely to express multiple c-erbB-receptor proteins than were late-stage tumours. Co-expression of EGF-R with c-erbB-2, and c-erbB-2 with c-erbB-3 was significantly greater in malignant tumours than in borderline or benign tumours, and within the malignant tumour group, positive associations were observed between EGF-R and c-erbB-3, also between c-erbB-2 and c-erbB-3. Because of the evidence of increased expression of individual c-erbB proteins as well as multiple expression of this family of growth-factor receptors in malignant ovarian tumours, we hypothesize that stimulation by the appropriate ligands may confer a selective advantage to cells expressing more than one receptor. Increased expression of c-erbB growth-factor receptors in malignancy may mediate increased propensity for tumour development.
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