Matzuk M M, Finegold M J, Mather J P, Krummen L, Lu H, Bradley A
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030.
Proc Natl Acad Sci U S A. 1994 Sep 13;91(19):8817-21. doi: 10.1073/pnas.91.19.8817.
Activins and inhibins, members of the type beta transforming growth factor superfamily of growth regulatory proteins, are produced in multiple tissues and affect diverse physiologic processes. Using embryonic stem cell technology, we previously demonstrated that inhibin can function as a gonadal tumor suppressor. In this study, we show that development of gonadal tumors is rapidly followed by a cancer cachexia-like wasting syndrome. Cachectic inhibin-deficient mice develop hepatocellular necrosis around the central vein and parietal cell depletion and mucosal atrophy in the glandular stomach, are anemic, and demonstrate severe weight loss. The liver pathology is consistent with studies demonstrating an effect of elevated activins on rat hepatocytes. In inhibin-deficient mice with tumors, activins are > 10-fold elevated in the serum and are likely causing some of the cachexia symptoms. In contrast, inhibin-deficient mice gonadectomized at an early age do not develop this wasting syndrome. However, these gonadectomized, inhibin-deficient mice eventually develop adrenal cortical sex steroidogenic tumors with nearly 100% penetrance, demonstrating that inhibin is also a tumor suppressor for the adrenal gland.
激活素和抑制素是生长调节蛋白β型转化生长因子超家族的成员，在多种组织中产生，并影响多种生理过程。利用胚胎干细胞技术，我们先前证明抑制素可作为性腺肿瘤抑制因子。在本研究中，我们发现性腺肿瘤发生后迅速出现类似癌症恶病质的消瘦综合征。恶病质的抑制素缺陷小鼠在中央静脉周围出现肝细胞坏死，腺胃壁细胞减少和黏膜萎缩，出现贫血，并表现出严重体重减轻。肝脏病理学与证明激活素升高对大鼠肝细胞有影响的研究一致。在患有肿瘤的抑制素缺陷小鼠中，血清中激活素升高超过10倍，可能是导致一些恶病质症状的原因。相比之下，幼年时切除性腺的抑制素缺陷小鼠不会出现这种消瘦综合征。然而，这些切除性腺的抑制素缺陷小鼠最终会发展出肾上腺皮质性类固醇生成肿瘤，外显率近100%，表明抑制素也是肾上腺的肿瘤抑制因子。
