UCD Conway Institute of Biomolecular and Biomedical Research, University College Dublin, Dublin, Ireland.
Center for Molecular Oncologic Pathology, Harvard Medical School, Boston, Massachusetts.
Mol Cancer Res. 2017 Mar;15(3):281-293. doi: 10.1158/1541-7786.MCR-16-0358. Epub 2017 Jan 5.
Prostate cancer is the second most common cancer in men worldwide. Gleason grading is an important predictor of prostate cancer outcomes and is influential in determining patient treatment options. Clinical decisions based on a Gleason score of 7 are difficult as the prognosis for individuals diagnosed with Gleason 4+3 cancer is much worse than for those diagnosed with Gleason 3+4 cancer. Laser capture microdissection (LCM) is a highly precise method to isolate specific cell populations or discrete microregions from tissues. This report undertook a detailed molecular characterization of the tumor microenvironment in prostate cancer to define the proteome in the epithelial and stromal regions from tumor foci of Gleason grades 3 and 4. Tissue regions of interest were isolated from several Gleason 3+3 and Gleason 4+4 tumors using telepathology to leverage specialized pathology expertise to support LCM. Over 2,000 proteins were identified following liquid chromatography tandem mass spectrometry (LC-MS/MS) analysis of all regions of interest. Statistical analysis revealed significant differences in protein expression (>100 proteins) between Gleason 3 and Gleason 4 regions-in both stromal and epithelial compartments. A subset of these proteins has had prior strong association with prostate cancer, thereby providing evidence for the authenticity of the approach. Finally, validation of these proteins by immunohistochemistry has been obtained using an independent cohort of prostate cancer tumor specimens. This unbiased strategy provides a strong foundation for the development of biomarker protein panels with significant diagnostic and prognostic potential. .
前列腺癌是全球男性第二大常见癌症。格里森分级是前列腺癌预后的重要预测指标，对确定患者的治疗选择有影响。基于格里森评分 7 的临床决策具有挑战性，因为诊断为格里森 4+3 癌症的个体的预后比诊断为格里森 3+4 癌症的个体差得多。激光捕获显微切割（LCM）是一种从组织中分离特定细胞群或离散微区的高度精确方法。本报告对前列腺癌肿瘤微环境进行了详细的分子特征分析，以确定格里森 3 级和 4 级肿瘤焦点的上皮和基质区域的蛋白质组。使用远程病理学从几个格里森 3+3 和格里森 4+4 肿瘤中分离出感兴趣的组织区域，以利用专门的病理学专业知识来支持 LCM。对所有感兴趣区域进行液相色谱串联质谱（LC-MS/MS）分析后，鉴定出超过 2000 种蛋白质。统计分析显示，格里森 3 级和 4 级区域（基质和上皮区室）之间的蛋白质表达存在显著差异（>100 种蛋白质）。其中一些蛋白质先前与前列腺癌有很强的关联，从而为该方法的真实性提供了证据。最后，使用独立的前列腺癌肿瘤标本队列通过免疫组织化学验证了这些蛋白质。这种无偏策略为开发具有重要诊断和预后潜力的生物标志物蛋白质组提供了坚实的基础。
