Department of Clinical Science, Intervention and Technology, Karolinska Institutet, Stockholm 17177, Sweden.
Department of Biochemistry and Molecular Genetics, University of Colorado Denver - Anschutz Medical Campus, Aurora 80045, Colorado, United States.
J Proteome Res. 2021 May 7;20(5):2725-2738. doi: 10.1021/acs.jproteome.1c00018. Epub 2021 Mar 15.
Pancreatic cancer is the seventh leading cause of cancer-related death worldwide, with a 5 year survival rate as low as 9%. One factor complicating the management of pancreatic cancer is the lack of reliable tools for early diagnosis. While up to 50% of the adult population has been shown to develop precancerous pancreatic cysts, limited and insufficient approaches are currently available to determine whether a cyst is going to progress into pancreatic cancer. Recently, we used metabolomics approaches to identify candidate markers of disease progression in patients diagnosed with intraductal papillary mucinous neoplasms (IPMNs) undergoing pancreatic resection. Here, we enrolled an independent cohort to verify the candidate markers from our previous study with orthogonal quantitative methods in plasma and cyst fluid from serous cystic neoplasm and IPMN (either low- or high-grade dysplasia or pancreatic ductal adenocarcinoma). We thus validated these markers with absolute quantitative methods through the auxilium of stable isotope-labeled internal standards in a new independent cohort. Finally, we identified novel markers of IPMN status and disease progression-including amino acids, carboxylic acids, conjugated bile acids, free and carnitine-conjugated fatty acids, purine oxidation products, and trimethylamine-oxide. We show that the levels of these metabolites of potential bacterial origin correlated with the degree of bacterial enrichment in the cyst, as determined by 16S RNA. Overall, our findings are interesting per se, owing to the validation of previous markers and identification of novel small molecule signatures of IPMN and disease progression. In addition, our findings further fuel the provoking debate as to whether bacterial infections may represent an etiological contributor to the development and severity of the disease in pancreatic cancer, in like fashion to other cancers (e.g., and gastric cancer).
胰腺癌是全球第七大癌症相关死亡原因，5 年生存率仅为 9%。影响胰腺癌管理的一个因素是缺乏可靠的早期诊断工具。尽管多达 50%的成年人已经显示出患有癌前胰腺囊肿，但目前可用的方法有限且不足，无法确定囊肿是否会发展为胰腺癌。最近，我们使用代谢组学方法来鉴定在接受胰腺切除术的导管内乳头状黏液性肿瘤（IPMN）患者中疾病进展的候选标志物。在这里，我们招募了一个独立的队列，通过正交定量方法验证我们之前研究中来自浆液性囊腺瘤和 IPMN（低级别或高级别异型增生或胰腺导管腺癌）的候选标志物的血浆和囊液。因此，我们通过稳定同位素标记内部标准的辅助作用，在一个新的独立队列中使用绝对定量方法验证了这些标志物。最后，我们确定了 IPMN 状态和疾病进展的新标志物，包括氨基酸、羧酸、结合胆汁酸、游离和肉碱结合脂肪酸、嘌呤氧化产物和三甲胺氧化物。我们表明，这些具有潜在细菌来源的代谢物的水平与通过 16S RNA 确定的囊内细菌富集程度相关。总的来说，我们的发现本身就很有趣，因为验证了以前的标志物，并确定了 IPMN 和疾病进展的新小分子特征。此外，我们的发现进一步引发了关于细菌感染是否可能代表胰腺癌发展和严重程度的病因学因素的争议，就像其他癌症（例如胃癌）一样。
