Greenberg N M, DeMayo F, Finegold M J, Medina D, Tilley W D, Aspinall J O, Cunha G R, Donjacour A A, Matusik R J, Rosen J M
Department of Cell Biology, Baylor College of Medicine, Houston, TX 77030, USA.
Proc Natl Acad Sci U S A. 1995 Apr 11;92(8):3439-43. doi: 10.1073/pnas.92.8.3439.
Progress toward understanding the biology of prostate cancer has been slow due to the few animal research models available to study the spectrum of this uniquely human disease. To develop an animal model for prostate cancer, several lines of transgenic mice were generated by using the prostate-specific rat probasin promoter to derive expression of the simian virus 40 large tumor antigen-coding region. Mice expressing high levels of the transgene display progressive forms of prostatic disease that histologically resemble human prostate cancer, ranging from mild intraepithelial hyperplasia to large multinodular malignant neoplasia. Prostate tumors have been detected specifically in the prostate as early as 10 weeks of age. Immunohistochemical analysis of tumor tissue has demonstrated that dorsolateral prostate-specific secretory proteins were confined to well-differentiated ductal epithelial cells adjacent to, or within, the poorly differentiated tumor mass. Prostate tumors in the mice also display elevated levels of nuclear p53 and a decreased heterogeneous pattern of androgen-receptor expression, as observed in advanced human prostate cancer. The establishment of breeding lines of transgenic mice that reproducibly develop prostate cancer provides an animal model system to study the molecular basis of transformation of normal prostatic cells and the factors influencing the progression to metastatic prostate cancer.
由于可用于研究这种独特人类疾病谱系的动物研究模型较少，对前列腺癌生物学的理解进展缓慢。为了开发一种前列腺癌动物模型，通过使用前列腺特异性大鼠前列腺素启动子来驱动猿猴病毒40大肿瘤抗原编码区的表达，培育了几条转基因小鼠品系。表达高水平转基因的小鼠表现出前列腺疾病的进展形式，其组织学特征类似于人类前列腺癌，从轻度上皮内增生到大型多结节恶性肿瘤。早在10周龄时就在前列腺中特异性检测到前列腺肿瘤。对肿瘤组织的免疫组织化学分析表明，背外侧前列腺特异性分泌蛋白局限于低分化肿瘤块附近或内部的高分化导管上皮细胞。正如在晚期人类前列腺癌中观察到的那样，小鼠前列腺肿瘤还表现出核p53水平升高以及雄激素受体表达的异质性模式降低。可重复性发生前列腺癌的转基因小鼠育种系的建立提供了一个动物模型系统，用于研究正常前列腺细胞转化的分子基础以及影响向转移性前列腺癌进展的因素。
