Shenzhen Key Laboratory of Viral Oncology, The Clinical Innovation & Research Center (CIRC), Shenzhen Hospital, Southern Medical University, Shenzhen, Guangdong Province, China.
Department of Medical Genetics and Developmental Biology, School of Medicine, Southeast University, Nanjing, China.
J Transl Med. 2023 Jan 21;21(1):40. doi: 10.1186/s12967-022-03860-3.
Current diagnosis tools for prostate cancer (PCa) such as serum PSA detection and prostate biopsy cannot distinguish dormant tumors from invasive malignancies, either be used as prognosis marker for castration resistant prostate cancer (CRPC), the lethal stage of PCa patients. Exosomes have been widely investigated as promising biomarkers for various diseases. We aim to characterize the proteomic and metabolomic profile of exosomes and to evaluate their potential value for the diagnosis of PCa, especially CRPC. We also investigate the functions of some specific exosome biomarkers in the progression of CRPC.
Integrated proteomics and metabolomics analysis were performed for plasma-derived exosomes collected from tumor-free controls (TFC), PCa and CRPC patients. Expression of specific exosomal proteins were further validated by targeted 4D-parallel reaction monitoring (PRM) mass spectrometry among the three cohorts. Tissue distribution and functional role of exosomal protein LRG1 was studied in clinical PCa tissue samples and cell line models.
Three potential exosomal protein markers were identified. The apolipoprotein E level in PCa samples was 1.7-fold higher than that in TFC (receiver operating characteristic value, 0.74). Similarly, the levels of exosome-derived leucine-rich alpha2-glycoprotein 1 (LRG1) and inter-alpha-trypsin inhibitor heavy chain H3 (ITIH3) in the CRPC group were 1.7 and 2.04 times, respectively, higher than those in the PCa group (ROC values, 0.84 and 0.85, respectively), indicating that LRG1 and ITIH3 could serve as predictive markers for CRPC. For metabolomic evaluation of exosomes, a series of differentially expressed metabolites were identified, and a combined metabolite panel showed ROC value of 0.94 for distinguishing PCa from TFC and 0.97 for distinguishing CRPC from PCa. Immunohistochemistry of tissue microarray showed that LRG1 protein was significantly upregulated in advanced prostate cancer and functional assay revealed that ectopic expression of LRG1 can significantly enhance the malignant phenotype of prostate cancer cells. More importantly, PCa cell derived LRG1-overexpressed exosomes remarkably promoted angiogenesis.
Integration of proteomics and metabolomics data generated proteomic and metabolic signatures of plasma exosomes that may facilitate discrimination of CRPC from PCa and TFC patients, suggesting the potential of exosomal proteins and metabolites as CRPC markers. The study also confirmed the important role of exosomal protein LRG1 in PCa malignant progression.
目前用于前列腺癌（PCa）的诊断工具，如血清 PSA 检测和前列腺活检，无法区分休眠肿瘤与侵袭性恶性肿瘤，也无法作为去势抵抗性前列腺癌（CRPC）的预后标志物，后者是 PCa 患者的致命阶段。外泌体作为各种疾病有前途的生物标志物已经得到广泛研究。我们旨在描述外泌体的蛋白质组学和代谢组学特征，并评估其在 PCa 诊断中的潜在价值，特别是在 CRPC 中的诊断价值。我们还研究了一些特定外泌体生物标志物在 CRPC 进展中的功能。
对来自无肿瘤对照（TFC）、PCa 和 CRPC 患者的血浆衍生外泌体进行了综合蛋白质组学和代谢组学分析。在这三个队列中，通过靶向 4D-平行反应监测（PRM）质谱进一步验证了特定外泌体蛋白的表达。在临床 PCa 组织样本和细胞系模型中研究了外泌体蛋白 LRG1 的组织分布和功能作用。
鉴定出三个潜在的外泌体蛋白标志物。PCa 样本中的载脂蛋白 E 水平比 TFC 高 1.7 倍（ROC 值为 0.74）。同样，CRPC 组中外泌体衍生的亮氨酸丰富α2-糖蛋白 1（LRG1）和α-胰蛋白酶抑制剂重链 H3（ITIH3）的水平分别比 PCa 组高 1.7 和 2.04 倍（ROC 值分别为 0.84 和 0.85），表明 LRG1 和 ITIH3 可以作为 CRPC 的预测标志物。对外泌体的代谢组学评估显示，鉴定出一系列差异表达的代谢物，联合代谢物谱对区分 PCa 与 TFC 和区分 CRPC 与 PCa 的 ROC 值分别为 0.94 和 0.97。组织微阵列的免疫组织化学显示，LRG1 蛋白在晚期前列腺癌中显著上调，功能测定显示，LRG1 的异位表达可显著增强前列腺癌细胞的恶性表型。更重要的是，PCa 细胞衍生的 LRG1 过表达外泌体可显著促进血管生成。
蛋白质组学和代谢组学数据的整合生成了血浆外泌体的蛋白质组学和代谢组学特征，这可能有助于区分 CRPC 与 PCa 和 TFC 患者，提示外泌体蛋白和代谢物作为 CRPC 标志物的潜力。该研究还证实了外泌体蛋白 LRG1 在 PCa 恶性进展中的重要作用。
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