Shou W, Woodruff T K, Matzuk M M
Department of Pathology, Baylor College of Medicine, Houston, Texas 77030, USA.
Endocrinology. 1997 Nov;138(11):5000-5. doi: 10.1210/endo.138.11.5499.
To understand gonadal tumor development, we have previously created a mouse model in which mice deficient in the inhibins develop gonadal sex cord-stromal tumors with essentially 100% penetrance. These tumors develop as early as 4 weeks of age and cause cancer cachexia-like symptoms and subsequent death in the inhibin-deficient mice. Gonadectomized inhibin-deficient mice eventually develop adrenal cortical tumors with nearly 100% penetrance. These studies have identified inhibin as a novel secreted tumor suppressor protein with specificity for the gonads and adrenal glands. Sex steroids have been implicated to influence gonadal tumor development in humans and mice. To determine the role of androgens in gonadal tumorigenesis in inhibin-deficient male mice, we have used a genetic intercross strategy, breeding inhibin alpha mutant mice with tfm (testicular feminization, a naturally occurring androgen receptor mutant) carrying females to eventually generate compound mutant male mice that lack inhibins and carry the tfm mutation. These compound mutant mice, like inhibin-deficient mice, continue to develop testicular tumors and the accompanying cancer cachexia-like wasting syndrome. Consistent with these findings, elevated levels of activins A and B secreted from the gonadal tumors are seen in the adult compound mutant mice as well as the secondary pathological consequences of these high activin levels in the livers and glandular stomachs. However, in contrast to male mice lacking only inhibin, in which essentially 100% of the testicular tumors are hemorrhagic, 65% of the tumors in these compound mutant male mice are less hemorrhagic, and approximately 50% of the compound mutants live longer than 17 weeks of age (95% of the male mice lacking only inhibin die by 12 weeks). These results suggest that androgens are not required for testicular tumor development in inhibin-deficient mice, but may play a regulatory role in testicular tumor progression.
为了解性腺肿瘤的发生发展，我们之前构建了一个小鼠模型，其中缺乏抑制素的小鼠会发展为性腺性索间质肿瘤，其发生率基本为100%。这些肿瘤早在4周龄时就会出现，导致抑制素缺陷小鼠出现癌性恶病质样症状并随后死亡。切除性腺的抑制素缺陷小鼠最终会发展为肾上腺皮质肿瘤，发生率近100%。这些研究已确定抑制素是一种新型的分泌型肿瘤抑制蛋白，对性腺和肾上腺具有特异性。性类固醇被认为会影响人类和小鼠性腺肿瘤的发生发展。为了确定雄激素在抑制素缺陷雄性小鼠性腺肿瘤发生中的作用，我们采用了遗传杂交策略，将抑制素α突变小鼠与携带tfm（睾丸雌性化，一种天然存在的雄激素受体突变体）的雌性小鼠杂交，最终产生缺乏抑制素并携带tfm突变的复合突变雄性小鼠。这些复合突变小鼠与抑制素缺陷小鼠一样，继续发展为睾丸肿瘤以及伴随的癌性恶病质样消瘦综合征。与这些发现一致，在成年复合突变小鼠中，性腺肿瘤分泌的激活素A和B水平升高，同时在肝脏和腺胃中也出现了这些高激活素水平的继发性病理后果。然而，与仅缺乏抑制素的雄性小鼠不同，仅缺乏抑制素的雄性小鼠中基本上100%的睾丸肿瘤是出血性的，而这些复合突变雄性小鼠中65%的肿瘤出血较少，约50%的复合突变体存活时间超过17周龄（仅缺乏抑制素的雄性小鼠95%在12周龄前死亡）。这些结果表明，雄激素对于抑制素缺陷小鼠的睾丸肿瘤发生不是必需的，但可能在睾丸肿瘤进展中起调节作用。
