生长分化因子15前体肽通过增强骨微环境促进去势抵抗性前列腺癌的骨转移。

GDF15 propeptide promotes bone metastasis of castration-resistant prostate cancer by augmenting the bone microenvironment.

作者信息

Yamamichi Gaku, Kato Taigo, Arakawa Noriaki, Ino Yoko, Ujike Takeshi, Nakano Kosuke, Koh Yoko, Motoyama Yuichi, Outani Hidetatsu, Myoba Shohei, Ishizuya Yu, Yamamoto Yoshiyuki, Hatano Koji, Kawashima Atsunari, Fukuhara Shinichiro, Uemura Hiroji, Okada Seiji, Morii Eiichi, Nonomura Norio, Uemura Motohide

机构信息

Department of Urology, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka, 565-0871, Japan.

Division of Medicinal Safety Science, National Institute of Health Sciences, 3-25-26, Tonomachi, Kawasaki, Kanagawa, 210-9501, Japan.

出版信息

Biomark Res. 2024 Nov 25;12(1):147. doi: 10.1186/s40364-024-00695-6.

DOI:10.1186/s40364-024-00695-6

PMID:39587633

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11590406/

Abstract

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.

摘要

背景

骨转移（BM）是去势抵抗性前列腺癌（CRPC）患者常见的致命病症。然而，对于伴有BM的CRPC患者，尚无有效的血液生物标志物，且BM的潜在机制尚不清楚。在本研究中，我们探究了用于评估BM的精确血液生物标志物，其可改善CRPC患者的预后。

方法

我们使用轨道阱质谱全面检测了四种前列腺癌细胞系的培养上清液，以鉴定前列腺癌细胞大量分泌的特定蛋白质。研究了该蛋白对前列腺癌细胞、成骨细胞、破骨细胞的影响，并建立了BM小鼠模型。此外，我们测量了接受骨闪烁显像测定骨扫描指数（BSI）的CRPC患者血浆中该蛋白的浓度。

结果

通过分泌蛋白质组分析共鉴定出2787种蛋白质。我们聚焦于由成骨细胞、破骨细胞和前列腺癌细胞分泌的生长分化因子15前体肽（GDPP）。GDPP促进了PC3和DU145 CRPC细胞的增殖、侵袭和迁移，并且GDPP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等单个转录因子来增强成骨细胞和破骨细胞的增殖，从而加速骨微环境中的骨形成和吸收。在包括416例患者的临床研究中，与前列腺特异性抗原（PSA）（AUC分别为0.92和0.78）以及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、抗酒石酸酸性磷酸酶5b、骨钙素、I型前胶原N端前肽和成熟GDF15）相比，GDPP对CRPC患者BM的诊断价值更高。全身治疗期间BSI随时间的变化与GDPP相关（r = 0.63），但与PSA无关（r = -0.16）。