Senior Scientist, Diagnostic and Translational Research Center, Henry Jackson Foundation, Gaithersburg, MD 20879, USA.
Cancer Genomics Proteomics. 2011 Sep-Oct;8(5):235-44.
Our recent studies have suggested that prostate tumor invasion is triggered by autoimmunoreactions induced focal basal cell layer disruptions (FBCLD) that selectively favor monoclonal proliferation of the overlying progenitors or of a biologically more aggressive cell clone. As circulating chromogranin-A (CgA) levels are found to correlate with tumor progression and the status of hormone refractoriness, our current study attempted to assess whether CgA-positive cells would be preferentially distributed in epithelial structures with FBCLD. Paraffin-embedded specimens from 50 patients with organ-confined prostate cancer were subjected to double immunohistochemical analysis with monoclonal antibodies to basal cells and CgA. From each case, 3-5 randomly selected fields were digitally photographed and the photos were magnified 400% and the numbers of CgA-positive cells in epithelial structures with non-disrupted, focally disrupted, and lost basal cell layer were separately counted. The averaged number of cell for each category was statistically compared with the Pearson's Chi-square test. In addition, morphologically similar structures with and without CgA-positive cell clusters were microdissected from four selected cases and subjected to a comparison of differential micro-RNA expression levels. Our study revealed that, although isolated CgA-positive cells were seen in both the basal cell layer and the luminal cell population in all cases, only 8 cases (16%) harbored large clusters of CgA-positive cells that were concentrated in a given area, in which all or nearly all cells appeared to share a similar morphological and immunohistochemical profile. Microdissected epithelial structures with CgA-positive cell clusters exhibited a more than 5- and 7-fold lower expression of miR-146a and miR-146b-5p than their CgA-negative counterparts. As focal basal cell layer disruptions and the reduction or loss of miR-146a and miR-146b-5p has been documented to correlate with prostate tumor invasion and hormone refractoriness, our findings suggest that aberrant CgA expression in epithelial structures with FBCLD may represent an early sign of these events.
我们最近的研究表明，前列腺肿瘤的侵袭是由自身免疫反应引发的，这种反应导致局灶性基底细胞层破坏（FBCLD），从而选择性地促进覆盖的前体细胞或生物学上更具侵袭性的细胞克隆的单克隆增殖。由于循环嗜铬粒蛋白 A（CgA）水平与肿瘤进展和激素抵抗状态相关，我们目前的研究试图评估 CgA 阳性细胞是否会优先分布在具有 FBCLD 的上皮结构中。对 50 例局限性前列腺癌患者的石蜡包埋标本进行了基底细胞和 CgA 的双重免疫组织化学分析。从每个病例中，随机选择 3-5 个视野进行数字摄影，并将照片放大 400%，分别计数上皮结构中无破坏、局灶性破坏和基底细胞层丢失的 CgA 阳性细胞数量。使用 Pearson's Chi-square 检验对每个类别的平均细胞数进行统计学比较。此外，从 4 例选定病例中分离出具有和不具有 CgA 阳性细胞簇的形态相似结构，并进行差异 microRNA 表达水平的比较。我们的研究表明，尽管在所有病例中，CgA 阳性细胞不仅存在于基底细胞层中，也存在于腔细胞群体中，但只有 8 例（16%）存在大量聚集的 CgA 阳性细胞，这些细胞集中在特定区域，其中所有或几乎所有细胞似乎具有相似的形态和免疫组织化学特征。具有 CgA 阳性细胞簇的微分离上皮结构的 miR-146a 和 miR-146b-5p 的表达水平比其 CgA 阴性对应物低 5 倍以上。由于局灶性基底细胞层破坏以及 miR-146a 和 miR-146b-5p 的减少或丢失与前列腺肿瘤侵袭和激素抵抗相关，我们的发现表明，FBCLD 上皮结构中异常的 CgA 表达可能代表这些事件的早期迹象。
