In the present study, we performed a comparative stage-specific pathological and molecular marker evaluation of TMPRSS2-ERG fusion and PTEN loss-driven (TMPRSS2-ERG. Pten^flox/flox) versus non-fusion-driven prostate tumorigenesis (Hi-Myc) in mice. Anterior, ventral, and dorsolateral prostates were collected from mice at different ages (or time points post-Cre induction). Results indicated that growth and progression of prostatic intraepithelial lesions to adenocarcinoma stages occurred in both mice models albeit at different rates. In the TMPRSS2-ERG. Pten^flox/flox mice, the initiation of tumorigenesis was slow, but subsequent progression through different stages became increasingly faster. Adenocarcinoma stage was reached early on; however, no high-grade undifferentiated tumors were observed. Conversely, in the Hi-Myc^+/− mice, tumorigenesis initiation was rapid; however, progression through different stages was relatively slower and it took a while to reach the more aggressive phenotype stage. Nevertheless, at the advanced stages in the Hi-Myc^+/− mice, high-grade undifferentiated tumors were observed compared to the later stage tumors observed in the fusion-driven TMPRSS2-ERG. Pten^flox/flox mice. These results were corroborated by the stage specific-pattern in the molecular expression of proliferation markers (PCNA and c-Myc); androgen receptor (AR); fusion-resultant overexpression of ERG; Prostein (SLC45-A3); and angiogenesis marker (CD-31). Importantly, there was a significant increase in immune cell infiltrations, which increased with the stage of tumorigenesis, in the TMPRSS2-ERG fusion-positive tumors relative to fusion negative tumors. Together, these findings are both novel and highly significant in establishing a working preclinical model for evaluating the efficacy of interventions during different stages of tumorigenesis in TMPRSS2-ERG fusion-driven PCa.

中文翻译：

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GEM 模型中 TMPRSS2-ERG（融合）驱动和非融合驱动的前列腺癌阶段特异性肿瘤进展的表征

在本研究中，我们对TMPRSS2-ERG融合和PTEN丢失驱动 ( TMPRSS2-ERG. Pten ^flox/flox ) 与非融合驱动的前列腺肿瘤发生 ( Hi-Myc )进行了阶段特异性病理学和分子标记物比较评估在小鼠中。从不同年龄（或Cre诱导后时间点）的小鼠收集前部、腹侧和背外侧前列腺。结果表明，两种小鼠模型中都发生了前列腺上皮内病变的生长和进展至腺癌阶段，尽管速度不同。在TMPRSS2-ERG 中。Pten ^{flox/弗洛克斯}在小鼠中，肿瘤发生的起始速度很慢，但随后不同阶段的进展变得越来越快。早期已达到腺癌阶段；然而，没有观察到高级别未分化肿瘤。相反，在 Hi-Myc ^+/-小鼠中，肿瘤发生迅速^；然而，不同阶段的进展相对较慢，需要一段时间才能达到更具攻击性的表型阶段。然而，与融合驱动的TMPRSS2-ERG中观察到的晚期肿瘤相比，在 Hi-Myc ^{+/-小鼠的晚期阶段，观察到了高级未分化肿瘤。}Pten ^{flox/弗洛克斯}老鼠。增殖标志物（PCNA 和 c-Myc）分子表达的阶段特异性模式证实了这些结果；雄激素受体（AR）；融合导致的 ERG 过度表达；前列腺蛋白 (SLC45-A3)；和血管生成标记物（CD-31）。重要的是，相对于融合阴性肿瘤， TMPRSS2-ERG融合阳性肿瘤中的免疫细胞浸润显着增加，且随着肿瘤发生阶段的增加而增加。总之，这些发现对于建立一个临床前工作模型来评估TMPRSS2-ERG融合驱动的 PCa肿瘤发生不同阶段干预措施的效果来说既新颖又非常重要。