Department of Surgery, University of Miami, Miller School of Medicine, Miami, USA.
Sylvester Comprehensive Cancer Center, University of Miami, Miller School of Medicine, Miami, USA.
J Exp Clin Cancer Res. 2022 Aug 24;41(1):258. doi: 10.1186/s13046-022-02425-y.
Pancreatic cancer is one of the most difficult cancers to detect early and most patients die from complications arising due to distant organ metastases. The lack of bona fide early biomarkers is one of the primary reasons for late diagnosis of pancreatic cancer. It is a multifactorial disease and warrants a novel approach to identify early biomarkers.
In order to characterize the proteome, Extracellular vesicles (EVs) isolated from different in vitro conditions mimicking tumor-microenvironment interactions between pancreatic cancer epithelial and stromal cells were analyzed using high throughput mass spectrometry. The biological activity of the secreted EVome was analyzed by investigating changes in distant organ metastases and associated early changes in the microbiome. Candidate biomarkers (KIF5B, SFRP2, LOXL2, and MMP3) were selected and validated on a mouse-human hybrid Tissue Microarray (TMA) that was specifically generated for this study. Additionally, a human TMA was used to analyze the expression of KIF5B and SFRP2 in progressive stages of pancreatic cancer.
The EVome of co-cultured epithelial and stromal cells is different from individual cells with distinct protein compositions. EVs secreted from stromal and cancer cells cultures could not induce significant changes in Pre-Metastatic Niche (PMN) modulation, which was assessed by changes in the distant organ metastases. However, they did induce significant changes in the early microbiome, as indicated by differences in α and β-diversities. KIF5B and SFRP2 show promise for early detection and investigation in progressive pancreatic cancer. These markers are expressed in all stages of pancreatic cancer such as low grade PanINs, advanced cancer, and in liver and soft tissue metastases.
Proteomic characterization of EVs derived from mimicking conditions of epithelial and stromal cells in the tumor-microenvironment resulted in the identification of several proteins, some for the first time in EVs. These secreted EVs cannot induce changes in distant organ metastases in in vivo models of EV education, but modulate changes in the early murine microbiome. Among all the proteins that were analyzed (MMP3, KIF5B, SFRP2, and LOXL2), KIF5B and SFRP2 show promise as bona fide early pancreatic cancer biomarkers expressed in progressive stages of pancreatic cancer.
胰腺癌是最难早期发现的癌症之一，大多数患者死于远处器官转移引起的并发症。缺乏真正的早期生物标志物是导致胰腺癌晚期诊断的主要原因之一。它是一种多因素疾病，需要一种新的方法来识别早期生物标志物。
为了描述蛋白质组，我们使用高通量质谱分析了不同体外条件下分离的胰腺癌细胞上皮细胞和基质细胞之间肿瘤微环境相互作用的细胞外囊泡（EVs）。通过研究远处器官转移的变化和相关早期微生物组的变化，分析分泌的 EVome 的生物学活性。选择候选生物标志物（KIF5B、SFRP2、LOXL2 和 MMP3）并在专门为此研究生成的小鼠-人杂交组织微阵列（TMA）上进行验证。此外，还使用人类 TMA 分析了 KIF5B 和 SFRP2 在胰腺癌进展阶段的表达。
共培养的上皮细胞和基质细胞的 EVome 与单个细胞不同，具有不同的蛋白质组成。来自基质和癌细胞培养物的 EVs 不能诱导前转移龛（PMN）调节的显著变化，PMN 调节通过远处器官转移的变化来评估。然而，它们确实诱导了早期微生物组的显著变化，这表明 α 和 β 多样性存在差异。KIF5B 和 SFRP2 有望用于早期检测和研究进展性胰腺癌。这些标志物在胰腺癌的所有阶段（包括低级别 PanINs、晚期癌症以及肝和软组织转移）均有表达。
对肿瘤微环境中上皮细胞和基质细胞模拟条件下衍生的 EV 的蛋白质组学特征进行分析，确定了几种蛋白质，其中一些是首次在 EV 中发现。这些分泌的 EVs 不能在 EV 教育的体内模型中诱导远处器官转移的变化，但可调节早期小鼠微生物组的变化。在分析的所有蛋白质（MMP3、KIF5B、SFRP2 和 LOXL2）中，KIF5B 和 SFRP2 有望成为在胰腺癌进展阶段表达的真正早期胰腺癌生物标志物。
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