Ho S M, Leav I, Merk F B, Yu M, Kwan P W, Ziar J
Department of Biology, Tufts University, Medford, Massachusetts, USA.
Lab Invest. 1995 Sep;73(3):356-65.
We have previously shown that combined administration of testosterone (T) and a low dose of estradiol 17 beta (T+LDE2) for 16 weeks induces an atypical proliferative lesion, termed dysplasia, in the dorsolateral prostates of intact Noble rats (1, 2). The lesion was accompanied by increases in the levels of a moderate affinity, high capacity, estrogen-binding site (type II sites) found exclusively in dorsolateral prostates of these animals (1, 3). In contrast, a proliferative response and type II sites were not observed in the ventral prostates (VP) of the same rats treated with this hormonal regimen. In the current study, rats were treated with a higher dose of E2 (4 x LDE2) but the same dose of T (T+HDE2) for 16 weeks. Our aims were to determine how the VP would respond to the T+HDE2 treatment.
Intact Noble rats were treated with T+HDE2 for 16 weeks. Prostatic tissues were removed for histology, electronmicroscopy, and type II site measurements. Proliferating cells were identified by the histochemical detection of proliferating cell nuclear antigen and colcemid-arrested mitotic figures. Apoptotic cells were recognized by their characteristic histologic and ultrastructural features and by in situ detection of nuclear DNA fragmentation. Data were compared with results previously obtained from VP of rats treated with T+LDE2.
The VP of T+HDE2-treated animals contained focal atypical hyperplasia and wide-spread apoptosis. Proliferating cell nuclear Ag-positive-stained epithelial cells and mitotic figures were only present in foci of atypical hyperplasia. Total DNA content of the VP was significantly increased, but the tissue wet weight was not augmented. Nuclear type II sites, never observed in untreated or T+LDE2-treated rats, were detected in the VP of the majority of T+HDE2-treated animals.
The administration of a high dose of E2 with T produced a unique lesion in the VP, characterized by simultaneous occurrence of apoptosis and proliferation. The synergy between androgens and estrogens, via type II site induction, likely produces the proliferative response. On the other hand, inhibition of intracellular androgen activation pathways, leading to reduction in cell survival factors, may be the cause for the apoptotic development. Our model, thus, provides a unique opportunity to further study the balance/switch between cell proliferation and apoptosis that is often disturbed during cancer development.
我们之前已经表明，对完整的诺布尔大鼠的背外侧前列腺联合给予睾酮（T）和低剂量的17β-雌二醇（T + LDE2）16周会诱导一种非典型增生性病变，称为发育异常（1,2）。该病变伴随着仅在这些动物的背外侧前列腺中发现的中等亲和力、高容量雌激素结合位点（II型位点）水平的增加（1,3）。相比之下，用这种激素方案治疗的相同大鼠的腹侧前列腺（VP）中未观察到增殖反应和II型位点。在本研究中，大鼠用更高剂量的E2（4×LDE2）但相同剂量的T（T + HDE2）治疗16周。我们的目的是确定VP对T + HDE2治疗的反应。
对完整的诺布尔大鼠用T + HDE2治疗16周。取出前列腺组织进行组织学、电子显微镜检查和II型位点测量。通过增殖细胞核抗原的组织化学检测和秋水仙酰胺阻断的有丝分裂图像鉴定增殖细胞。通过其特征性的组织学和超微结构特征以及核DNA片段化的原位检测识别凋亡细胞。将数据与先前从用T + LDE2治疗的大鼠的VP获得的结果进行比较。
用T + HDE2治疗的动物的VP含有局灶性非典型增生和广泛的凋亡。增殖细胞核Ag阳性染色的上皮细胞和有丝分裂图像仅存在于非典型增生灶中。VP的总DNA含量显著增加，但组织湿重未增加。在大多数用T + HDE2治疗的动物的VP中检测到未处理或用T + LDE2治疗的大鼠中从未观察到的核II型位点。
高剂量的E2与T联合给药在VP中产生了一种独特的病变，其特征是凋亡和增殖同时发生。雄激素和雌激素之间通过II型位点诱导的协同作用可能产生增殖反应。另一方面，细胞内雄激素激活途径的抑制导致细胞存活因子的减少，可能是凋亡发生的原因。因此，我们的模型为进一步研究细胞增殖和凋亡之间的平衡/转换提供了独特的机会，这种平衡/转换在癌症发展过程中经常受到干扰。
