GDF15 propeptide通过增强骨微环境促进阉割耐药前列腺癌的骨转移。

IF 9.5 2区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Biomarker Research Pub Date : 2024-11-25 DOI:10.1186/s40364-024-00695-6
Gaku Yamamichi, Taigo Kato, Noriaki Arakawa, Yoko Ino, Takeshi Ujike, Kosuke Nakano, Yoko Koh, Yuichi Motoyama, Hidetatsu Outani, Shohei Myoba, Yu Ishizuya, Yoshiyuki Yamamoto, Koji Hatano, Atsunari Kawashima, Shinichiro Fukuhara, Hiroji Uemura, Seiji Okada, Eiichi Morii, Norio Nonomura, Motohide Uemura
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引用次数: 0

摘要

背景:骨转移(BM)是耐阉割前列腺癌(CRPC)患者常见的致命疾病。然而,对于伴有骨转移的 CRPC,目前还没有有用的血液生物标志物,而且骨转移的机制也不清楚。在这项研究中,我们调查了用于评估BM的精确血液生物标志物,这些标志物可改善CRPC患者的预后:方法:我们使用 Orbitrap 质谱仪全面检测了四种前列腺癌(PCa)细胞系的培养上清,以确定 PCa 细胞大量分泌的特定蛋白质。我们还研究了这种蛋白质对 PCa 细胞、成骨细胞、破骨细胞以及 BM 小鼠模型的影响。此外,我们还测量了通过骨闪烁成像检测骨扫描指数(BSI)的CRPC患者血浆中这种蛋白质的浓度:结果:分泌组分析共鉴定出2787种蛋白质。我们重点研究了由成骨细胞、破骨细胞和 PCa 细胞分泌的 GDF15 丙肽(GDPP)。GDPP 促进了 PC3 和 DU145 CRPC 细胞的增殖、侵袭和迁移,并在小鼠模型中加重了 BM。重要的是,GDPP 通过上调 RUNX2、OSX、ATF4、NFATc1 和 DC-STAMP 等转录因子,增强成骨细胞和破骨细胞的增殖,从而加速骨微环境中骨的形成和吸收。在包括总共416名患者在内的临床环境中,在CRPC患者中,GDPP比前列腺特异性抗原(PSA)(AUC = 0.92和0.78)和其他七种血液生物标志物(碱性磷酸酶、乳酸脱氢酶、骨碱性磷酸酶、抗酒石酸磷酸酶5b、骨钙素、原胶原蛋白I N端前肽、成熟GDF15)更能诊断BM。随着系统治疗的进行,BSI的变化与GDPP的变化相关(r = 0.63),但与PSA的变化无关(r = -0.16):结论:GDPP能增强BM的肿瘤微环境,是CRPC中BM的一种新型血液生物标志物,可对CRPC患者进行早期治疗干预。
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GDF15 propeptide promotes bone metastasis of castration-resistant prostate cancer by augmenting the bone microenvironment.

Background: Bone metastasis (BM) is a common and fatal condition in patients with castration-resistant prostate cancer (CRPC). However, there are no useful blood biomarkers for CRPC with BM, and the mechanism underlying BM is unclear. In this study, we investigated precise blood biomarkers for evaluating BM that can improve the prognosis of patients with CRPC.

Methods: We comprehensively examined culture supernatants from four prostate cancer (PCa) cell lines using Orbitrap mass spectrometry to identify specific proteins secreted abundantly by PCa cells. The effects of this protein to PCa cells, osteoblasts, osteoclasts were examined, and BM mouse model. In addition, we measured the plasma concentration of this protein in CRPC patients for whom bone scan index (BSI) by bone scintigraphy was performed.

Results: A total of 2,787 proteins were identified by secretome analysis. We focused on GDF15 propeptide (GDPP), which is secreted by osteoblasts, osteoclasts, and PCa cells. GDPP promoted the proliferation, invasion, and migration of PC3 and DU145 CRPC cells, and GDPP aggravated BM in a mouse model. Importantly, GDPP accelerated bone formation and absorption in the bone microenvironment by enhancing the proliferation of osteoblasts and osteoclasts by upregulating individual transcription factors such as RUNX2, OSX, ATF4, NFATc1, and DC-STAMP. In clinical settings, including a total of 416 patients, GDPP was more diagnostic of BM than prostate-specific antigen (PSA) (AUC = 0.92 and 0.78) and the seven other blood biomarkers (alkaline phosphatase, lactate dehydrogenase, bone alkaline phosphatase, tartrate-resistant acid phosphatase 5b, osteocalcin, procollagen I N-terminal propeptide and mature GDF15) in patients with CRPC. The changes in BSI over time with systemic treatment were correlated with that of GDPP (r = 0.63) but not with that of PSA (r = -0.16).

Conclusions: GDPP augments the tumor microenvironment of BM and is a novel blood biomarker of BM in CRPC, which could lead to early treatment interventions in patients with CRPC.

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来源期刊
Biomarker Research
Biomarker Research Biochemistry, Genetics and Molecular Biology-Molecular Medicine
CiteScore
15.80
自引率
1.80%
发文量
80
审稿时长
10 weeks
期刊介绍: Biomarker Research, an open-access, peer-reviewed journal, covers all aspects of biomarker investigation. It seeks to publish original discoveries, novel concepts, commentaries, and reviews across various biomedical disciplines. The field of biomarker research has progressed significantly with the rise of personalized medicine and individual health. Biomarkers play a crucial role in drug discovery and development, as well as in disease diagnosis, treatment, prognosis, and prevention, particularly in the genome era.
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