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  • Author: MC Vacher-Lavenu x
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I Eude, E Dallot, MC Vacher-Lavenu, C Chapron, F Ferre and M Breuiller-Fouche

OBJECTIVE: Factors responsible for the abnormal proliferation of myometrial cells that accompanies leiomyoma formation are unknown, although steroid hormones and peptide growth factors have been implicated. We hypothesized that endothelin-1 (ET-1) is a physiological regulator of tumor growth. DESIGN: In this study, we investigated the role of ET-1 on growth of human leiomyoma cells and its synergistic effect with growth factors, as well as the signaling pathway involved in this interaction. METHODS: Leiomyoma cell proliferation was assayed by [H]thymidine incorporation and cell number. Protein kinase C (PKC) isoforms were analyzed by Western blot using specific antibodies. RESULTS: ET-1 on its own was unable to stimulate DNA synthesis but potentiated the leiomyoma cell growth effects of basic fibroblast growth factor (bFGF), epidermal growth factor (EGF), IGF-I and IGF-II. The failure of a protein tyrosine kinase (PTK) inhibitor, tyrphostin 51, to affect the potentiating effect of ET-1, supports the hypothesis of non-involvement of PTK in this process. The inhibition of PKC by calphostin C or its down-regulation by phorbol 12,13-dibutyrate (PDB) eliminated the potentiating effect of ET-1, but did not block cell proliferation induced by the growth factors alone. Five PKC isoforms (alpha, beta1, epsilon, delta and zeta) were detected in leiomyoma cells, but only phorbol ester-sensitive PKC isoforms (PKCalpha, epsilon and delta) contribute to the potentiating effect of leiomyoma cell growth by ET-1. CONCLUSIONS: We have demonstrated that ET-1 potentiates leiomyoma cell proliferation to growth factors through a PKC-dependent pathway. These findings suggest a possible involvement of ET-1 in the pathogenesis of leiomyomas.

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F Tissier, A Louvel, S Grabar, AM Hagnere, J Bertherat, MC Vacher-Lavenu, B Dousset, Y Chapuis, X Bertagna and C Gicquel

OBJECTIVE: In many cases, the prognosis of an adrenocortical tumor cannot be determined from pathologic findings alone. We investigated cyclin E levels as a potential marker. METHODS: We studied 57 tumors by immunohistochemical staining with an anticyclin E antibody. We also evaluated clinical and pathologic factors (McFarlane staging and Weiss score) and previously validated genetic markers (17p13 loss of heterozygosity, 11p15 uniparental disomy, and overexpression of the IGF-II gene) for these tumors. Disease-free survival was estimated in 49 patients who underwent curative surgery. RESULTS: Cyclin E overproduction (> or =5%) was associated with the malignant phenotype and was strongly correlated with tumor size (P<0.0001), Weiss score (P<0.0001) and the presence of genetic abnormalities in tumors (P<0.001) (nonparametric Wilcoxon test and Fisher's exact test). Within a median follow-up of 44.1 months, seven patients exhibited a recurrence and two patients died from other causes. Cyclin E overproduction was significantly associated with shorter disease-free survival in univariate analysis (P=0.016; RR: 7.6), as were histologic grade (Weiss score > or =4; P=0.0006; RR: 18), 17p13 LOH (P=0.014, RR: 14.9), 11p15 UPD (P=0.003, RR: 11.8) and overexpression of the IGF-II gene (P=0.015, RR: 13.8). CONCLUSION: This study shows that cyclin E overproduction is of adverse prognostic significance in adrenocortical tumors.