Department of Pathology, The Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America.
PLoS One. 2010 Feb 25;5(2):e9427. doi: 10.1371/journal.pone.0009427.
Lo-MYC and Hi-MYC mice develop prostatic intraepithelial neoplasia (PIN) and prostatic adenocarcinoma as a result of MYC overexpression in the mouse prostate. However, prior studies have not determined precisely when, and in which cell types, MYC is induced. Using immunohistochemistry (IHC) to localize MYC expression in Lo-MYC transgenic mice, we show that morphological and molecular alterations characteristic of high grade PIN arise in luminal epithelial cells as soon as MYC overexpression is detected. These changes include increased nuclear and nucleolar size and large scale chromatin remodeling. Mouse PIN cells retained a columnar architecture and abundant cytoplasm and appeared as either a single layer of neoplastic cells or as pseudo-stratified/multilayered structures with open glandular lumina-features highly analogous to human high grade PIN. Also using IHC, we show that the onset of MYC overexpression and PIN development coincided precisely with decreased expression of the homeodomain transcription factor and tumor suppressor, Nkx3.1. Virtually all normal appearing prostate luminal cells expressed high levels of Nkx3.1, but all cells expressing MYC in PIN lesions showed marked reductions in Nkx3.1, implicating MYC as a key factor that represses Nkx3.1 in PIN lesions. To determine the effects of less pronounced overexpression of MYC we generated a new line of mice expressing MYC in the prostate under the transcriptional control of the mouse Nkx3.1 control region. These "Super-Lo-MYC" mice also developed PIN, albeit a less aggressive form. We also identified a histologically defined intermediate step in the progression of mouse PIN into invasive adenocarcinoma. These lesions are characterized by a loss of cell polarity, multi-layering, and cribriform formation, and by a "paradoxical" increase in Nkx3.1 protein. Similar histopathological changes occurred in Hi-MYC mice, albeit with accelerated kinetics. Our results using IHC provide novel insights that support the contention that MYC overexpression is sufficient to transform prostate luminal epithelial cells into PIN cells in vivo. We also identified a novel histopathologically identifiable intermediate step prior to invasion that should facilitate studies of molecular pathway alterations occurring during early progression of prostatic adenocarcinomas.
Lo-MYC 和 Hi-MYC 小鼠由于 MYC 在小鼠前列腺中的过度表达而发展为前列腺上皮内瘤形成（PIN）和前列腺腺癌。然而，先前的研究并未确定 MYC 何时以及在何种细胞类型中被诱导。通过免疫组织化学（IHC）定位 Lo-MYC 转基因小鼠中的 MYC 表达，我们表明，一旦检测到 MYC 过度表达，具有高级别 PIN 特征的形态和分子改变就会出现在腔上皮细胞中。这些变化包括核和核仁大小增加以及大规模染色质重塑。小鼠 PIN 细胞保留柱状结构和丰富的细胞质，表现为单层或假分层/多层结构，具有开放的腺体腔-高度类似于人类高级别 PIN 的特征。同样通过 IHC，我们表明 MYC 过度表达和 PIN 发育的开始与同源域转录因子和肿瘤抑制因子 Nkx3.1 的表达下调精确吻合。实际上，所有正常的前列腺腔上皮细胞都表达高水平的 Nkx3.1，但在 PIN 病变中表达 MYC 的所有细胞都表现出 Nkx3.1 的明显减少，这表明 MYC 是一种关键因素，可在 PIN 病变中抑制 Nkx3.1 的表达。为了确定 MYC 表达程度较低的影响，我们生成了一条在前列腺中表达 MYC 的新小鼠系，其表达受小鼠 Nkx3.1 控制区的转录控制。这些“超级 Lo-MYC”小鼠也发展为 PIN，尽管形式不太激进。我们还确定了从小鼠 PIN 进展为浸润性腺癌的一个在组织学上定义的中间步骤。这些病变的特征是失去细胞极性、多层化和筛状形成，以及 Nkx3.1 蛋白的“反常”增加。Hi-MYC 小鼠中也发生了类似的组织病理学变化，尽管动力学加快。我们使用 IHC 的结果提供了新的见解，支持 MYC 过度表达足以将前列腺腔上皮细胞在体内转化为 PIN 细胞的观点。我们还确定了在侵袭前具有独特的可识别的中间步骤，这应该有助于研究前列腺腺癌早期进展过程中发生的分子途径改变。
