Shibata M A, Ward J M, Devor D E, Liu M L, Green J E
Veterinary and Tumor Pathology Section, Office of Laboratory Animal Science, National Cancer Institute, Frederick, Maryland 21702-1201, USA.
Cancer Res. 1996 Nov 1;56(21):4894-903.
The progression of prostatic intraepithelial neoplasia (PIN) to invasive prostate carcinoma has been analyzed in the C3(1)/T(AG) transgenic mouse model and appears very similar to the process proposed to occur in humans. PIN lesions in these transgenic mice histologically resemble those found in human PIN. Low-grade PIN was observed in the ventral and dorsolateral lobes at 2 months of age, whereas high-grade PIN was found in both lobes by 5 months of age. A progressive increase in the number of PIN lesions was observed with age. Prostate carcinomas, which appeared to arise from PIN lesions, were found by 7 months of age in the ventral lobe and 11 months of age in the dorsolateral lobe. Expression of T(AG) mRNA and protein in these lesions correlated with the development of PIN and carcinomas, as did the overexpression of p53 protein. Apoptosis levels were quite low in normal epithelial cells, moderate in low-grade PIN, and high in high-grade PIN and carcinomas. Levels of expression of proliferating cell nuclear antigen correlated with the degree of severity of the prostate lesions. Eighteen % of PIN lesions were found to already harbor Ha-ras mutations, whereas 33% of carcinomas showed various mutations in Ha-ras, Ki-ras, and/or p53. Mutations in Ha-ras may, therefore, be an early event in a significant portion of PIN lesions. Because high-grade PIN showed many characteristics similar to those observed in carcinomas and high-grade PIN was often found contiguous to carcinomas, we conclude that high-grade PIN is a precursor lesion of prostate carcinoma in this transgenic model. These transgenic mice will be useful to study mechanisms responsible for the progression of invasive carcinomas from PIN precursor lesions, as may occur during the development of prostate cancer in humans.
在C3(1)/T(AG)转基因小鼠模型中，已对前列腺上皮内瘤变（PIN）向浸润性前列腺癌的进展进行了分析，其过程似乎与人类中推测发生的过程非常相似。这些转基因小鼠中的PIN病变在组织学上类似于人类PIN中发现的病变。在2月龄时，在腹侧叶和背外侧叶观察到低级别PIN，而到5月龄时，在两个叶中均发现了高级别PIN。随着年龄的增长，PIN病变数量逐渐增加。在7月龄时，在腹侧叶发现了似乎由PIN病变引发的前列腺癌，在11月龄时，在背外侧叶发现了此类癌症。这些病变中T(AG) mRNA和蛋白的表达与PIN和癌的发展相关，p53蛋白的过表达也是如此。正常上皮细胞中的凋亡水平相当低，低级别PIN中为中度，高级别PIN和癌中为高水平。增殖细胞核抗原的表达水平与前列腺病变的严重程度相关。发现18%的PIN病变已存在Ha-ras突变，而33%的癌在Ha-ras、Ki-ras和/或p53中显示出各种突变。因此，Ha-ras突变可能是相当一部分PIN病变中的早期事件。由于高级别PIN表现出许多与癌中观察到的特征相似的特征，并且高级别PIN经常与癌相邻发现，我们得出结论，在该转基因模型中，高级别PIN是前列腺癌的前驱病变。这些转基因小鼠将有助于研究PIN前驱病变发展为浸润性癌的机制，这在人类前列腺癌的发生过程中可能会出现。
