Beamer W G, Shultz K L, Tennent B J, Shultz L D
Jackson Laboratory, Bar Harbor, Maine 04609.
Cancer Res. 1993 Aug 15;53(16):3741-6.
The SWR and SWXJ recombinant inbred strains of mice develop heritable, pubertal onset ovarian granulosa cell (GC) tumors with characteristics similar to those observed for human juvenile GC tumors. We utilized this murine model to determine: (a) whether spontaneous tumorigenesis is an intrinsic property of the susceptible ovary; (b) whether pubertal developmental stage affects tumorigenesis; and (c) whether tumorigenesis depends on extraovarian regulation provided by an immune system or a hypothalamic-pituitary gonadotropin system. To test these questions, ovaries from tumor-susceptible donors were grafted beneath the kidney capsules of hosts with differing immunological and hormonal capabilities. Hosts for these ovarian grafts were: (a) immunologically intact, syngeneic mice; (b) immune-deficient, allogeneic mice homozygous for the severe combined immune deficiency (scid/scid) mutation; and (c) scid/scid mice segregating for the hypogonadal (hpg) mutation, yielding gonadotropin-deficient hpg/hpg scid/scid and gonadotropin replete +/? (hpg/+ or +/+) scid/scid littermates. Donors and hosts of differing ages were used to address questions of developmental effects on tumorigenesis. Grafts were examined 6 to 10 wk after implantation for ovarian morphology and tumor incidence. Results showed that ovary grafts from susceptible female mice formed spontaneous GC tumors equally well in both syngeneic and immune-deficient scid/scid hosts. In each type of host, the incidence of grafts exhibiting spontaneous tumor development declined significantly with increasing age of both donor and host. In addition, prepubertal ovary grafts formed spontaneous tumors in hormonally normal +/? scid/scid but not in hormonally deficient hpg/hpg scid/scid hosts. Finally, treatment of hpg/hpg scid/scid host mice with the androgenic steroid hormone precursor, dehydroepiandrosterone, resulted in GC tumor formation in the tumor-susceptible ovary grafts. We conclude that pubertal onset, spontaneous tumorigenesis in the susceptible ovaries is: (a) independent of an intact immune system; (b) terminated by completion of ovarian maturation as a cyclic organ; (c) not dependent on extraovarian factors unique to the genetically susceptible host; and (d) potentially initiated by androgenic steroids in the absence of an intact hypothalamic-pituitary gonadotropin axis. We hypothesize that ovarian androgens synthesized in response to normal gonadotropin stimulation initiate spontaneous tumorigenesis in the genetically susceptible ovary.
SWR和SWXJ重组近交系小鼠会发生遗传性的青春期起始卵巢颗粒细胞瘤（GC），其特征与人类青少年GC肿瘤相似。我们利用这个小鼠模型来确定：（a）自发肿瘤形成是否是易感卵巢的固有特性；（b）青春期发育阶段是否影响肿瘤形成；以及（c）肿瘤形成是否依赖于免疫系统或下丘脑 - 垂体促性腺激素系统提供的卵巢外调节。为了测试这些问题，将来自肿瘤易感供体的卵巢移植到具有不同免疫和激素功能的宿主的肾包膜下。这些卵巢移植的宿主包括：（a）免疫健全的同基因小鼠；（b）严重联合免疫缺陷（scid/scid）突变纯合的免疫缺陷异基因小鼠；以及（c）分离性腺功能减退（hpg）突变的scid/scid小鼠，产生促性腺激素缺乏的hpg/hpg scid/scid和促性腺激素充足的 +/?（hpg/+ 或 +/+）scid/scid同窝小鼠。使用不同年龄的供体和宿主来解决发育对肿瘤形成影响的问题。移植后6至10周检查移植物的卵巢形态和肿瘤发生率。结果表明，来自易感雌性小鼠的卵巢移植物在同基因和免疫缺陷的scid/scid宿主中形成自发GC肿瘤的情况相同。在每种类型的宿主中，表现出自发肿瘤发展的移植物发生率随着供体和宿主年龄的增加而显著下降。此外，青春期前的卵巢移植物在激素正常的 +/? scid/scid宿主中形成自发肿瘤，但在激素缺乏的hpg/hpg scid/scid宿主中则不会。最后，用雄激素类固醇前体脱氢表雄酮治疗hpg/hpg scid/scid宿主小鼠，导致肿瘤易感卵巢移植物中形成GC肿瘤。我们得出结论，易感卵巢中青春期起始的自发肿瘤形成：（a）独立于完整的免疫系统；（b）随着卵巢作为周期性器官成熟的完成而终止；（c）不依赖于遗传易感宿主特有的卵巢外因素；以及（d）在没有完整的下丘脑 - 垂体促性腺激素轴的情况下可能由雄激素类固醇引发。我们假设，响应正常促性腺激素刺激合成的卵巢雄激素会引发遗传易感卵巢中的自发肿瘤形成。
