Liang Dong, Mingxiao Feng, Morgan D. Kuczler, Kengo Horie, Chi-Ju Kim, Zehua Ma, Kara Lombardo, Heather Lyons, Sarah R. Amend, Max Kates, Trinity J. Bivalacqua, David McConkey, Wei Xue, Woonyoung Choi, Kenneth J. Pienta
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引用次数: 0
摘要
基于 mRNA 的分子亚型对膀胱癌的预后和某些疗法的临床疗效有影响。细胞外小泡(sEVs)能否反映膀胱癌分子亚型尚不清楚。我们对膀胱癌患者的福尔马林固定石蜡包埋(FFPE)肿瘤组织以及从匹配的组织切片、尿液和血浆中分离出的小细胞外囊泡进行了全转录组 RNA 测序。用大约 1 克组织与培养基培养 30 分钟,即可获得高产率的 sEVs。FFPE 肿瘤组织和肿瘤组织衍生的 sEVs 在分子亚型分类方面表现出良好的一致性。所有尿液 sEV 都被归类为管腔亚型,而所有血浆 sEV 都被归类为 Ba/Sq 亚型,而与其匹配的 FFPE 肿瘤组织所显示的分子亚型无关。尿液 sEV 中的比较可能排除了样本类型的特定背景,可以发现 NMIBC 和 MIBC 之间不同的生物学特性,以及与分子亚型相关的特征基因。通过分析匹配的尿液 sEV、肿瘤组织衍生的 sEV 和邻近正常组织衍生的 sEV,确定了四个候选 sEV 相关的膀胱癌特异性 mRNA 生物标记物:FAM71E2、OR4K5、FAM138F 和 KRTAP26-1。与从生物流体中分离出的 sEVs 相比,组织衍生的 sEVs 可能更能反映组织或疾病的特异性生物学特征。尿液中的 sEVs 是很有希望用于基于液体活检的分子亚型分类的生物标记物,但目前的算法需要修改/调整。未来还需要在大型队列中验证四种新的膀胱癌特异性生物标记物。
Tumour tissue-derived small extracellular vesicles reflect molecular subtypes of bladder cancer
mRNA-based molecular subtypes have implications for bladder cancer prognosis and clinical benefit from certain therapies. Whether small extracellular vesicles (sEVs) can reflect bladder cancer molecular subtypes is unknown. We performed whole transcriptome RNA sequencing for formalin fixed paraffin embedded (FFPE) tumour tissues and sEVs separated from matched tissue explants, urine and plasma in patients with bladder cancer. sEVs were separated using size-exclusion chromatography, and characterized by transmission electron microscopy, nano flow cytometry and western blots, respectively. High yield of sEVs were obtained using approximately 1 g of tissue, incubated with media for 30 min. FFPE tumour tissue and tumour tissue-derived sEVs demonstrated good concordance in molecular subtype classification. All urinary sEVs were classified as luminal subtype, while all plasma sEVs were classified as Ba/Sq subtype, regardless of the molecular subtypes indicated by their matched FFPE tumour tissue. The comparison within urine sEVs, which may exclude the sample type specific background, could pick up the different biology between NMIBC and MIBC, as well as the signature genes related to molecular subtypes. Four candidate sEV-related bladder cancer-specific mRNA biomarkers, FAM71E2, OR4K5, FAM138F and KRTAP26-1, were identified by analysing matched urine sEVs, tumour tissue derived sEVs, and adjacent normal tissue derived sEVs. Compared to sEVs separated from biofluids, tissue-derived sEVs may reflect more tissue- or disease-specific biological features. Urine sEVs are promising biomarkers to be used for liquid biopsy-based molecular subtype classification, but the current algorithm needs to be modified/adjusted. Future work is needed to validate the four new bladder cancer-specific biomarkers in large cohorts.
期刊介绍:
The Journal of Extracellular Vesicles is an open access research publication that focuses on extracellular vesicles, including microvesicles, exosomes, ectosomes, and apoptotic bodies. It serves as the official journal of the International Society for Extracellular Vesicles and aims to facilitate the exchange of data, ideas, and information pertaining to the chemistry, biology, and applications of extracellular vesicles. The journal covers various aspects such as the cellular and molecular mechanisms of extracellular vesicles biogenesis, technological advancements in their isolation, quantification, and characterization, the role and function of extracellular vesicles in biology, stem cell-derived extracellular vesicles and their biology, as well as the application of extracellular vesicles for pharmacological, immunological, or genetic therapies.
The Journal of Extracellular Vesicles is widely recognized and indexed by numerous services, including Biological Abstracts, BIOSIS Previews, Chemical Abstracts Service (CAS), Current Contents/Life Sciences, Directory of Open Access Journals (DOAJ), Journal Citation Reports/Science Edition, Google Scholar, ProQuest Natural Science Collection, ProQuest SciTech Collection, SciTech Premium Collection, PubMed Central/PubMed, Science Citation Index Expanded, ScienceOpen, and Scopus.