Beamer W G, Shultz K L, Tennent B J
Jackson Laboratory, Bar Harbor, Maine 04609.
Cancer Res. 1988 May 15;48(10):2788-92.
Spontaneous ovarian granulosa cell (GC) tumors develop in SWXJ-9 inbred mice at approximately the time of puberty. The effect of dehydroepiandrosterone (DHEA), a steroid secreted by the adrenals and reported to have antitumor actions, was examined in this ovarian tumor model. In contrast with expectations, administration of diet supplemented with 0.4% DHEA or Silastic capsules containing 10 mg DHEA resulted in a significant multifold increase in GC tumor incidence. Similar studies with metabolites of DHEA, i.e., testosterone (TESTO), dihydrotestosterone (DHT), and 17 beta-estradiol (E2), revealed that TESTO was as effective as DHEA in increasing GC tumor incidence. DHT was without effect, and E2 suppressed GC tumor incidence. Serum steroid levels and steroid target tissue responses were assessed to determine if a correlation between a change in level or response to specific steroids and GC tumorigenesis existed. In both tumor-free and GC tumor host mice, dietary or capsular treatment with DHEA, TESTO, or DHT resulted in substantial alteration in one or more of serum steroids, DHEA, androstenedione, TESTO, and DHT, in addition to the administered steroid. No consistent correlation was observed between changes in a single steroid or pattern of steroids and GC tumorigenesis. Although significant increases in serum estrogens could be detected in GC tumor hosts treated with DHEA but not TESTO, estrogens did not induce these tumors. Treatment with E2 increased only serum E2 levels. In tumor-free mice, DHEA and E2 treatments were associated with vaginal cytological evidence of estrogen action, whereas the androgens induced a leukocytic pattern. Eighty-eight % of GC tumor host mice, regardless of steroid treatment, showed a vaginal cytology pattern that included cornified cells. The evidence presented in this report leads us to hypothesize that (a) spontaneous and steroid-induced GC tumorigenesis in these mice have the same mechanism, and (b) subtle increases in DHEA or a closely related metabolite during the peripubertal period may initiate GC tumors in these genetically susceptible mice. The mechanism whereby these steroids initiate GC tumorigenesis remains to be determined.
自发性卵巢颗粒细胞瘤（GC）在SWXJ - 9近交系小鼠青春期前后发生。本研究在该卵巢肿瘤模型中检测了脱氢表雄酮（DHEA）的作用，DHEA是一种由肾上腺分泌的类固醇，据报道具有抗肿瘤作用。与预期相反，给予添加0.4% DHEA的饮食或含10 mg DHEA的硅橡胶胶囊导致GC肿瘤发生率显著增加数倍。对DHEA的代谢产物，即睾酮（TESTO）、双氢睾酮（DHT）和17β - 雌二醇（E2）进行的类似研究表明，TESTO在增加GC肿瘤发生率方面与DHEA同样有效。DHT无作用，而E2抑制GC肿瘤发生率。评估血清类固醇水平和类固醇靶组织反应，以确定特定类固醇水平或反应的变化与GC肿瘤发生之间是否存在相关性。在无肿瘤和GC肿瘤宿主小鼠中，用DHEA、TESTO或DHT进行饮食或胶囊治疗除了导致所给予的类固醇外，还使血清类固醇、DHEA、雄烯二酮、TESTO和DHT中的一种或多种发生了显著改变。在单一类固醇的变化或类固醇模式与GC肿瘤发生之间未观察到一致的相关性。虽然在用DHEA而非TESTO治疗的GC肿瘤宿主中可检测到血清雌激素显著增加，但雌激素并未诱发这些肿瘤。用E2治疗仅增加了血清E2水平。在无肿瘤小鼠中，DHEA和E2治疗与雌激素作用的阴道细胞学证据相关，而雄激素诱导了白细胞模式。88%的GC肿瘤宿主小鼠，无论类固醇治疗如何，均表现出包括角化细胞的阴道细胞学模式。本报告中提供的证据使我们推测：（a）这些小鼠中自发性和类固醇诱导的GC肿瘤发生具有相同机制；（b）青春期前后DHEA或密切相关代谢产物的细微增加可能在这些遗传易感小鼠中引发GC肿瘤。这些类固醇引发GC肿瘤发生的机制仍有待确定。
