The Proteome of Prostate Cancer Bone Metastasis Reveals Heterogeneity with Prognostic Implications
The Proteome of Prostate Cancer Bone Metastasis Reveals Heterogeneity with Prognostic Implications
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DOI：
10.1158/1078-0432.ccr-18-1229
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发表时间：
2018-11-01
影响因子：
11.5
通讯作者：
Wikstrom, Pernilla
中科院分区：
文献类型：
--
作者：
Iglesias-Gato, Diego;Thysell, Elin;Wikstrom, Pernilla
目的：骨是前列腺癌远处转移最主要的部位，现阶段患者的治疗选择有限。实验设计：我们对 22 名接受手术以缓解脊髓压迫的患者的骨转移性前列腺肿瘤进行了系统范围的定量蛋白质组学分析。手术时，大多数患者在雄激素剥夺治疗后复发，而 5 名患者之前未接受治疗。使用前列腺癌骨转移的扩展队列 (n = 65) 进行免疫组织化学验证。结果：平均每个肿瘤有 5,067 个蛋白质被鉴定和定量。与原发性肿瘤 (n = 26) 相比，骨转移瘤的异质性更强，并且参与细胞周期进展、DNA 损伤反应、RNA 加工和脂肪酸 b-氧化的蛋白质水平增加；蛋白质水平的降低与细胞粘附和碳水化合物代谢有关。在骨转移中，我们确定了两个表型亚组：BM1，表达较高水平的 AR 典型靶标，以及线粒体和高尔基体驻留蛋白；和 BM2，增殖和 DNA 修复相关蛋白的表达增加。通过 MCM3 和前列腺特异性抗原免疫反应性之间的负相关性验证的两个亚组与疾病预后相关，表明在开发个性化治疗时应考虑这种分子异质性。结论：这项工作是前列腺癌骨转移蛋白质组的第一个全系统定量表征，也是了解前列腺癌进展病因的宝贵资源。 (C) 2018 年 AACR。
Purpose: Bone is the most predominant site of distant metastasis in prostate cancer, and patients have limited therapeutic options at this stage.Experimental Design: We performed a system-wide quantitative proteomic analysis of bone metastatic prostate tumors from 22 patients operated to relieve spinal cord compression. At the time of surgery, most patients had relapsed after androgen-deprivation therapy, while 5 were previously untreated. An extended cohort of prostate cancer bone metastases (n = 65) was used for immunohistochemical validation.Results: On average, 5,067 proteins were identified and quantified per tumor. Compared with primary tumors (n = 26), bone metastases were more heterogeneous and showed increased levels of proteins involved in cell-cycle progression, DNA damage response, RNA processing, and fatty acid b-oxidation; and reduced levels of proteins were related to cell adhesion and carbohydrate metabolism. Within bone metastases, we identified two phenotypic subgroups: BM1, expressing higher levels of AR canonical targets, and mitochondrial and Golgi apparatus resident proteins; and BM2, with increased expression of proliferation and DNA repair-related proteins. The two subgroups, validated by the inverse correlation between MCM3 and prostate specific antigen immunoreactivity, were related to disease prognosis, suggesting that this molecular heterogeneity should be considered when developing personalized therapies.Conclusions: This work is the first system-wide quantitative characterization of the proteome of prostate cancer bone metastases and a valuable resource for understanding the etiology of prostate cancer progression. (C) 2018 AACR.