Cipriano S C, Chen L, Kumar T R, Matzuk M M
Department of Pathology, Baylor College of Medicine, Houston, Texas 77030, USA.
Endocrinology. 2000 Jul;141(7):2319-27. doi: 10.1210/endo.141.7.7535.
Inhibins and activins are dimeric proteins belonging to the transforming growth factor-beta superfamily. Follistatin is an activin-binding protein that antagonizes the function of activin via binding to its beta-subunits. Previously, we demonstrated that mice deficient in inhibin develop ovarian and testicular sex cord-stromal tumors of granulosa and Sertoli cell origin, with 100% penetrance as early as 4 weeks of age. Overproduction of activins in the serum directly causes a cachexia-like wasting syndrome that results in lethality of these mice at an early stage after the onset of the tumors. In an independent set of studies, overexpression of mouse follistatin using the mouse metallothionein I promoter in transgenic mice led to gonadal defects and eventual infertility, primarily due to local effects of follistatin in these tissues. Activin has a positive growth effect on gonadal tumor cells in culture and directly causes the cancer cachexia-like syndrome in inhibin-deficient mice via interaction with activin receptor type IIA in livers and stomachs. We therefore hypothesized that an activin antagonist such as follistatin can act as a physiological modifier, either locally or via the serum, to block the activin-mediated cancer cachexia-like syndrome in inhibin-deficient mice and/or slow the progression of gonadal cancers in these mice. To test this hypothesis, we generated mice that are homozygous mutant for the inhibin alpha null allele (i.e. inham1/inham1) and carry the mouse metallothionein I follistatin (MT-FS) transgene. Our results show that gonadal tumors that are histologically similar in most, but not all, cases to the tumors in inhibin-deficient mice develop in these inham1/inham1, MT-FS+ mice. However, inham1/inham1, MT-FS+ mice exhibit a less severe wasting syndrome, lower serum activin levels, and a statistically significant prolonged survival in a number of cases compared with mice deficient in inhibin alone. Thus, follistatin can act as a modulator of tumor growth and the activin-induced cancer cachexia-like syndrome in inhibin-deficient mice.
抑制素和激活素是属于转化生长因子-β超家族的二聚体蛋白。卵泡抑素是一种激活素结合蛋白，通过与激活素的β亚基结合来拮抗激活素的功能。此前，我们证明，抑制素缺陷的小鼠会发生起源于颗粒细胞和支持细胞的卵巢和睾丸性索间质肿瘤，早在4周龄时肿瘤发生率就达到100%。血清中激活素的过量产生直接导致一种恶病质样消瘦综合征，导致这些小鼠在肿瘤发生后的早期死亡。在另一组独立研究中，使用小鼠金属硫蛋白I启动子在转基因小鼠中过表达小鼠卵泡抑素导致性腺缺陷并最终导致不育，这主要是由于卵泡抑素在这些组织中的局部作用。激活素对培养中的性腺肿瘤细胞具有正向生长作用，并通过与肝脏和胃中的IIA型激活素受体相互作用，直接在抑制素缺陷的小鼠中导致癌症恶病质样综合征。因此，我们推测，诸如卵泡抑素之类的激活素拮抗剂可以作为一种生理调节剂，通过局部作用或通过血清作用，来阻断抑制素缺陷小鼠中激活素介导的癌症恶病质样综合征和/或减缓这些小鼠中性腺癌症的进展。为了验证这一假设，我们培育了抑制素α无效等位基因纯合突变（即inham1/inham1）并携带小鼠金属硫蛋白I卵泡抑素（MT-FS）转基因的小鼠。我们的结果表明，在这些inham1/inham1、MT-FS+小鼠中发生了性腺肿瘤，在大多数（但不是所有）情况下，这些肿瘤在组织学上与抑制素缺陷小鼠中的肿瘤相似。然而，与仅缺乏抑制素的小鼠相比，inham1/inham1、MT-FS+小鼠表现出较轻的消瘦综合征、较低的血清激活素水平，并且在一些情况下生存期在统计学上显著延长。因此，卵泡抑素可以作为抑制素缺陷小鼠中肿瘤生长和激活素诱导的癌症恶病质样综合征的调节剂。
