Conversion from a paracrine to an autocrine mechanism of androgen-stimulated growth during malignant transformation of prostatic epithelial cells.
Conversion from a paracrine to an autocrine mechanism of androgen-stimulated growth during malignant transformation of prostatic epithelial cells.
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发表时间：
2001-07
期刊：
影响因子：
11.2
通讯作者：
Jin Gao;J. Arnold;J. Isaacs
中科院分区：
文献类型：
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作者：
Jin Gao;J. Arnold;J. Isaacs
将人和大鼠来源的正常成年前列腺上皮与基质胶一起移植到完整的或雄激素消融的（即，去势的）裸鼠。在这些移植物中，小鼠间充质细胞的流入是最早发生的事件之一，导致移植上皮周围的平滑肌细胞和成纤维细胞形成项圈。这些周围的基质细胞的一个子集表达雄激素受体（AR）。周围移植上皮最初表达前列腺基底细胞和AR特征性的高分子量细胞角蛋白。在完整的和雄激素消融的宿主中，该上皮随后发展出一个开放的管腔，产生一个不发育的腺泡。然而，只有在未消融的宿主中，这些原始腺泡才经历进一步的增殖生长期，如通过Ki 67免疫细胞化学染色和管腔的低分子量细胞角蛋白阳性层（即，分泌）上皮细胞。由于AR在供体上皮和宿主中均表达（即，小鼠）基质细胞，这种雄激素刺激的生长反应可能涉及供体正常成体上皮细胞自身内起始的自分泌途径或小鼠基质细胞的AR表达亚群内起始的旁分泌途径。为了解决这个问题，将携带X连锁AR基因中的睾丸雌性化突变的小鼠与AR-wt裸鼠杂交以产生AR无效的裸鼠雄性小鼠。在这些AR基因敲除的雄性裸鼠中没有细胞表达功能性AR蛋白。因此，这些动物可用于防止任何可能性的宿主基质细胞旁分泌参与启动雄激素刺激的生长反应时，正常成人或恶性前列腺上皮细胞移植到这些空主机。在这些无AR基因的裸雄性小鼠中，正常成年前列腺上皮细胞的雄激素刺激的生长没有发生（即，正常前列腺上皮细胞的雄激素诱导的生长反应需要基质细胞旁分泌参与）。相比之下，使用四种不同的前列腺癌模型（即，人PC-82、人LNCaP、人LAPC-4和大鼠R3327 G），雄激素刺激的前列腺癌细胞生长在AR-无效和AR-wt裸雄性小鼠中相同地发生（即，直接自分泌机制负责雄激素刺激的恶性前列腺上皮细胞生长）。总之，雄激素刺激生长的机制发生了根本性的变化，从正常到恶性前列腺上皮细胞的转化。
Normal adult prostate epithelium of both human and rat origin was transplanted with Matrigel into intact or androgen-ablated (i.e., castrated) nude mice. Within these transplants, an influx of mouse mesenchymal cells was one of the earliest events to occur resulting in the development of a collar of smooth muscle cells and fibroblasts surrounding the transplanted epithelium. A subset of these surrounding stromal cells express androgen receptor (AR). The surrounded transplanted epithelium initially expresses high molecular weight cytokeratins characteristic of prostatic basal cells and AR. In both intact and androgen-ablated hosts, this epithelium subsequently develops a patent lumen producing a rudimentary glandular acini. Only in the nonablated hosts, however, do these rudimentary acini undergo a further proliferative growth phase, as determined by Ki67 immunocytochemical stainings and the development of a low molecular weight cytokeratin positive layer of luminal (i.e., secretory) epithelial cells. Because AR is expressed in both the donor epithelium and host (i.e., mouse) stromal cells, this androgen-stimulated growth response could involve either autocrine pathways initiated within donor normal adult epithelial cells themselves or paracrine pathways initiated within the AR-expressing subset of mouse stromal cells. To resolve this issue, mice carrying the testicular feminized mutation in the X-linked AR gene were cross-bred to AR-wt nude mice to produce AR-null nude male mice. None of the cells in these AR-null nude male mice express functional AR protein. Therefore, these animals can be used to prevent any possibility of host stromal cell paracrine involvement in initiating an androgen-stimulated growth response when normal adult or malignant prostatic epithelial cells are transplanted into these null hosts. In these AR-null nude male mice, the androgen-stimulated growth of normal adult prostatic epithelial cells did not occur (i.e., androgen-induced growth response of normal prostatic epithelial cells requires stromal cell paracrine involvement). In contrast, using four different prostatic cancer models (i.e., human PC-82, human LNCaP, human LAPC-4, and rat R3327G), the androgen-stimulated growth of prostatic cancer cells occurred identically in both AR-null and AR-wt nude male mice (i.e., a direct autocrine mechanism is responsible for androgen-stimulated growth of malignant prostatic epithelial cells). In summary, a fundamental change in the mechanism for androgen-stimulated growth occurs during the transformation from normal to malignant prostatic epithelial cells.