Hunt Allison L, Barakat Waleed, Makohon-Moore Sasha C, Hood Brian L, Conrads Kelly A, Wilson Katlin N, Abulez Tamara, Ogata Jonathan, Pienta Kenneth J, Lotan Tamara L, Mani Haresh, Trump Donald L, Bateman Nicholas W, Conrads Thomas P
Women's Health Integrated Research Center, Inova Women's Service Line, Inova Health System, 3289 Woodburn Rd, Annandale, VA, 22003, USA.
Gynecologic Cancer Center of Excellence and the Women's Health Integrated Research Center, Department of Gynecologic Surgery and Obstetrics, Uniformed Services University and Walter Reed National Military Medical Center, 8901 Wisconsin Avenue, Bethesda, MD, 20889, USA.
Clin Proteomics. 2025 Apr 20;22(1):14. doi: 10.1186/s12014-025-09534-8.
Prostate cancer is one of the most frequently diagnosed cancers in men. Prostate tumor staging and disease aggressiveness are evaluated based on the Gleason scoring system, which is further used to direct clinical intervention. The Gleason scoring system provides an estimate of tumor aggressiveness through quantitation of the serum level of prostate specific antigen (PSA) and histologic assessment of Grade Group, determined by the Gleason Grade of the tumor specimen.
To improve our understanding of the proteomic characteristics differentiating low- versus high-grade prostate cancer tumors, we performed a deep proteomic characterization of laser microdissected epithelial and stromal subpopulations from surgically resected tissue specimens from patients with Gleason 6 (n = 23 specimens from n = 15 patients) and Gleason 9 (n = 15 specimens from n = 15 patients) prostate cancer via quantitative high-resolution liquid chromatography-tandem mass spectrometry analysis.
In total, 789 and 295 grade-specific significantly altered proteins were quantified in the tumor epithelium and tumor-involved stroma, respectively. Benign epithelial and stromal populations were not inherently different between Gleason 6 versus Gleason 9 specimens. Notably, 598 proteins were exclusively significantly altered between Gleason 9 (but not Gleason 6) tumor-involved stroma and benign stroma, including several proteins involved in cholesterol biosynthesis and nucleotide metabolism.
Proteomic alterations between Gleason 6 versus Gleason 9 were exclusive to the disease microenvironment, observed in both the tumor epithelium and tumor-involved stroma. Further, the molecular alterations measured in the tumor-involved stroma from Gleason 9 cases relative to the benign stroma have unique significance in disease aggressiveness, development, and/or progression. Our data provide supportive evidence of a need for further investigations into targeting stromal reservoirs of cholesterol and/or deoxynucleoside triphosphates in PCa tumors and further highlight the necessity for independent examination of the TME epithelial and stromal compartments.
前列腺癌是男性中最常被诊断出的癌症之一。前列腺肿瘤分期和疾病侵袭性是基于 Gleason 评分系统进行评估的，该系统进一步用于指导临床干预。Gleason 评分系统通过定量前列腺特异性抗原（PSA）的血清水平以及对肿瘤标本的 Gleason 分级所确定的分级组进行组织学评估，来估计肿瘤的侵袭性。
为了更好地理解区分低级别与高级别前列腺癌肿瘤的蛋白质组学特征，我们通过定量高分辨率液相色谱 - 串联质谱分析，对来自 Gleason 6（n = 15 例患者的 23 个标本）和 Gleason 9（n = 15 例患者的 15 个标本）前列腺癌患者手术切除组织标本中的激光显微切割上皮和基质亚群进行了深度蛋白质组学表征。
总共在肿瘤上皮和肿瘤相关基质中分别定量了 789 种和 295 种分级特异性显著改变的蛋白质。Gleason 6 与 Gleason 9 标本之间的良性上皮和基质群体本质上没有差异。值得注意的是，在 Gleason 9（而非 Gleason 6）肿瘤相关基质和良性基质之间，有 598 种蛋白质仅发生了显著改变，包括几种参与胆固醇生物合成和核苷酸代谢的蛋白质。
Gleason 6 与 Gleason 9 之间的蛋白质组学改变仅限于疾病微环境，在肿瘤上皮和肿瘤相关基质中均有观察到。此外，相对于良性基质，在 Gleason 9 病例的肿瘤相关基质中测得的分子改变在疾病侵袭性、发展和/或进展方面具有独特意义。我们的数据为进一步研究靶向前列腺癌肿瘤中胆固醇和/或脱氧核苷三磷酸的基质储存库提供了支持性证据，并进一步强调了独立检查肿瘤微环境上皮和基质区室的必要性。
