背景: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,但目前尚无治疗方法。改变的肿瘤细胞糖基化是癌症的标志,并且是恶性表型的重要驱动因素。在前列腺癌中,唾液酸转移酶ST6GAL1上调,研究表明ST6GAL1介导的N-聚糖的异常唾液酸化促进前列腺肿瘤生长和疾病进展。
方法:这里,我们监测男性侵袭性前列腺癌患者的肿瘤和血清样本中的ST6GAL1,并使用体外和体内模型研究ST6GAL1在前列腺癌骨转移中的作用.
结果:ST6GAL1在肿瘤已扩散至骨的前列腺癌患者中上调,可促进体内前列腺癌骨转移。所涉及的机制是多方面的,涉及改变转移前的生态位朝向骨吸收以促进恶性循环,促进M2样巨噬细胞的发育,和免疫抑制唾液酸的调节。此外,使用同基因小鼠模型,我们表明,抑制唾液酸化可以阻止前列腺肿瘤向骨骼的扩散。
结论:我们的研究确定了ST6GAL1和α2-6唾液酸化N-聚糖在前列腺癌骨转移中的重要作用,提供概念验证数据表明,抑制唾液酸化可以抑制前列腺肿瘤向骨骼的扩散,并强调唾液酸阻断是开发晚期前列腺癌患者新疗法的令人兴奋的新策略。
背景:前列腺癌研究和马克癌症研究基金会,医学研究委员会和英国前列腺癌。
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.
RESULTS: 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.
CONCLUSIONS: 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.
BACKGROUND: Prostate Cancer Research and the Mark Foundation For Cancer Research, the Medical Research Council and Prostate Cancer UK.