Sialic acid blockade inhibits the metastatic spread of prostate cancer to bone.

IF 9.7 1区医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL

EBioMedicine Pub Date : 2024-06-01 Epub Date: 2024-05-20 DOI:10.1016/j.ebiom.2024.105163

Kirsty Hodgson, Margarita Orozco-Moreno, Emily Archer Goode, Matthew Fisher, Rebecca Garnham, Richard Beatson, Helen Turner, Karen Livermore, Yuhan Zhou, Laura Wilson, Eline A Visser, Johan Fa Pijnenborg, Nienke Eerden, Sam J Moons, Emiel Rossing, Gerald Hysenaj, Rashi Krishna, Ziqian Peng, Kyla Putri Nangkana, Edward N Schmidt, Adam Duxfield, Ella P Dennis, Rakesh Heer, Michelle A Lawson, Matthew Macauley, David J Elliott, Christian Büll, Emma Scott, Thomas J Boltje, Richard R Drake, Ning Wang, Jennifer Munkley

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引用次数: 0

Abstract

Background: Bone metastasis is a common consequence of advanced prostate cancer. Bisphosphonates can be used to manage symptoms, but there are currently no curative treatments available. Altered tumour cell glycosylation is a hallmark of cancer and is an important driver of a malignant phenotype. In prostate cancer, the sialyltransferase ST6GAL1 is upregulated, and studies show ST6GAL1-mediated aberrant sialylation of N-glycans promotes prostate tumour growth and disease progression.

Methods: Here, we monitor ST6GAL1 in tumour and serum samples from men with aggressive prostate cancer and using in vitro and in vivo models we investigate the role of ST6GAL1 in prostate cancer bone metastasis.

Findings: ST6GAL1 is upregulated in patients with prostate cancer with tumours that have spread to the bone and can promote prostate cancer bone metastasis in vivo. The mechanisms involved are multi-faceted and involve modification of the pre-metastatic niche towards bone resorption to promote the vicious cycle, promoting the development of M2 like macrophages, and the regulation of immunosuppressive sialoglycans. Furthermore, using syngeneic mouse models, we show that inhibiting sialylation can block the spread of prostate tumours to bone.

Interpretation: Our study identifies an important role for ST6GAL1 and α2-6 sialylated N-glycans in prostate cancer bone metastasis, provides proof-of-concept data to show that inhibiting sialylation can suppress the spread of prostate tumours to bone, and highlights sialic acid blockade as an exciting new strategy to develop new therapies for patients with advanced prostate cancer.

Funding: Prostate Cancer Research and the Mark Foundation For Cancer Research, the Medical Research Council and Prostate Cancer UK.

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Sialic acid 阻断剂可抑制前列腺癌向骨骼的转移扩散。

背景：骨转移是晚期前列腺癌的常见后果：骨转移是晚期前列腺癌的常见后果。双膦酸盐可用于控制症状，但目前尚无根治性治疗方法。肿瘤细胞糖基化改变是癌症的标志，也是恶性表型的重要驱动因素。方法：在此，我们监测了侵袭性前列腺癌男性患者肿瘤和血清样本中的ST6GAL1，并使用体外和体内模型研究了ST6GAL1在前列腺癌骨转移中的作用：研究结果：ST6GAL1在肿瘤已扩散至骨骼的前列腺癌患者体内上调，并能促进前列腺癌的体内骨转移。其中涉及的机制是多方面的，包括改变骨转移前的骨吸收龛位以促进恶性循环，促进类似 M2 的巨噬细胞的发展，以及调节免疫抑制性硅藻糖。此外，我们利用合成小鼠模型表明，抑制硅氨酰化可阻止前列腺肿瘤向骨扩散：我们的研究确定了ST6GAL1和α2-6糖基化N-聚糖在前列腺癌骨转移中的重要作用，提供了概念验证数据，表明抑制糖基化可抑制前列腺肿瘤向骨骼扩散，并强调了糖基化阻断是为晚期前列腺癌患者开发新疗法的一种令人兴奋的新策略：资助机构：前列腺癌研究中心、马克癌症研究基金会、医学研究委员会和英国前列腺癌协会。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

EBioMedicine Biochemistry, Genetics and Molecular Biology-General Biochemistry,Genetics and Molecular Biology

CiteScore

17.70

自引率

0.90%

发文量

579

审稿时长

5 weeks

期刊介绍： eBioMedicine is a comprehensive biomedical research journal that covers a wide range of studies that are relevant to human health. Our focus is on original research that explores the fundamental factors influencing human health and disease, including the discovery of new therapeutic targets and treatments, the identification of biomarkers and diagnostic tools, and the investigation and modification of disease pathways and mechanisms. We welcome studies from any biomedical discipline that contribute to our understanding of disease and aim to improve human health.