Synergistic effects of inhibins and müllerian-inhibiting substance on testicular tumorigenesis.
Members of the transforming growth factor-beta (TGF-beta) superfamily regulate diverse physiological processes in multiple tissues. In particular, important roles for the inhibins and müllerian-inhibiting substance (MIS) have been demonstrated in the regulation of cell growth control both in vitro and in vivo. Inhibin-deficient male and female mice develop mixed granulosa/Sertoli cell tumors with nearly 100% penetrance. MIS-deficient male mice develop as pseudohermaphrodites with oviducts and uteri. In addition, MIS-deficient males have Leydig cell hyperplasia and, in one case, a Leydig cell tumor. To determine whether MIS could modify the development of the granulosa/Sertoli cell tumors in inhibin-deficient mice or whether inhibin could alter the development of the Leydig cell hyperplasia of MIS-deficient mice, animals deficient for both inhibins and MIS were generated. Adult inhibin/MIS-deficient male mice developed testicular tumors and large fluid-filled uteri. The accumulation of uterine fluid was due in part to an increase in estradiol secretion from the tumors and was blocked by a pure estrogen antagonist, ICI 182,780. The testes of the inhibin/MIS-deficient males developed granulosa/Sertoli cell tumors and Leydig cell neoplasia earlier, grew faster, were less hemorrhagic, and produced less estradiol than the testes of inhibin-deficient controls. These results demonstrate that inhibin and MIS synergize to influence testicular tumor development.
Matzuk
M M
MM
Department of Pathology, Baylor College of Medicine, Houston, Texas 77030, USA.
Finegold
M J
MJ
Mishina
Y
Y
Bradley
A
A
Behringer
R R
RR
D000818:Animals; D054304:Anti-Mullerian Hormone; D005260:Female; D006023:Glycoproteins; D006131:Growth Inhibitors / Q000172:deficiency*; D007265:Inhibins / Q000172:deficiency*; D008297:Male; D051379:Mice; D012737:Sex Factors; D013735:Testicular Hormones / Q000172:deficiency*; D013736:Testicular Neoplasms / Q000209:etiology* / Q000378:metabolism / Q000473:pathology
D006023:Glycoproteins; D006131:Growth Inhibitors; D013735:Testicular Hormones; D007265:Inhibins; D054304:Anti-Mullerian Hormone