Elevated levels of circulating microbial-associated uremic toxins are associated with metastatic duodenopancreatic neuroendocrine tumors in patients with Multiple Endocrine Neoplasia Type 1

被引：0

作者：

Ballaro, Riccardo ^{[1
,8
]}

Wasylishen, Amanda R. ^{[2
]}

Pieterman, Carolina R. C. ^{[3
,8
]}

Olsen, Courtney ^{[4
,8
]}

Irajizad, Ehsan ^{[1
,5
,8
]}

Wu, Ranran ^{[1
,8
]}

Katayama, Hiroyuki ^{[1
,8
]}

Liu, Huiling ^{[1
,8
]}

Cai, Yining ^{[1
,8
]}

Leon-Letelier, Ricardo A. ^{[1
,8
]}

Dennison, Jennifer B. ^{[1
,8
]}

Waguespack, Steven ^{[6
,8
]}

Doe, Kim-Anh ^{[7
,8
]}

Agarwal, Sunita K.

Walter, Mary ^{[7
,8
]}

Welch, James ^{[7
,8
]}

Weinstein, Lee ^{[7
,8
]}

Blau, Jenny E. ^{[7
,8
]}

Jha, Smita ^{[7
,8
]}

Nilubol, Naris ^{[8
]}

Vriens, Menno R. ^{[8
,9
,10
]}

van Leeuwaardej, Rachel S. ^{[3
,8
,10
]}

van Treijenj, Mark J. C. ^{[3
]}

Valk, Gerlof D. ^{[3
]}

Perrierd, Nancy D. ^{[8
]}

Hanasha, Samir M. ^{[1
]}

Fahrmann, Johannes F. ^{[1
]}

机构：

[1] Univ Texas MD Anderson Canc Ctr, Dept Clin Canc Prevent, Houston, TX USA

[2] Univ Cincinnati, Coll Med, Dept Canc Biol, Cincinnati, OH 45267 USA

[3] Univ Med Ctr Utrecht, Dept Endocrine Oncol, Utrecht, Netherlands

[4] Univ Texas MD Anderson Canc Ctr, Dept Surg Oncol, Sect Surg Endocrinol, Houston, TX USA

[5] Univ Texas MD Anderson Canc Ctr, Dept Biostat, Houston, TX USA

[6] Univ Texas MD Anderson Canc Ctr, Dept Endocrine Neoplasia & Hormonal Disorders, Houston, TX USA

[7] NIDDKD, Metab Dis Branch, NIH, Bethesda, MD 20892 USA

[8] NCI, Surg Oncol Program, NIH, Bethesda, MD USA

[9] Univ Med Ctr Utrecht, Dept Surg Oncol & Endocrine Surg, Utrecht, Netherlands

[10] Netherlands Canc Inst Amsterdam, Univ Med Ctr, ENETs Ctr Excellence, Amsterdam, Netherlands

来源：

CANCER LETTERS | 2025年 / 614卷

关键词：

Multiple Endocrine Neoplasia Type 1; Pancreatic neuroendocrine cancer; Microbiome; Metabolites; PANCREATIC-CANCER; DISEASE; CHOLINE; INDOLE; RISK; GENE;

D O I：

10.1016/j.canlet.2025.217537

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

Metastatic duodenopancreatic neuroendocrine tumors (dpNETs) are the primary cause of mortality among patients with Multiple Endocrine Neoplasia Type 1 (MEN1). Emerging evidence implicates the microbiome and microbial-derived secreted factors in promoting cancer development and progression. In the current study, we report that the circulating microbial-associated uremic toxins trimethylamine N-oxide (TMAO), indoxyl sulfate (IS), cresol sulfate (CS), cresol glucuronide (CG), and phenol sulfate (PS) are elevated in MEN1 patients with metastatic dpNETs. Proteomic- and metabolomic-based analysis of resected dpNET tissues from MEN1 patients also revealed detectable levels of uremic toxins that positively correlated with peptide-based signatures corresponding to Fusobacterium nucleatum, Faecalibacterium prausnitzii, and Klebsiella pneumoniae and negatively correlated with Streptococcus pneumoniae and Streptococcus thermophilus. A microbial-associated uremic toxin panel (MUTP) was developed and, in an independent case-control validation cohort, the panel yielded an area under the receiver operating characteristic curve (AUC) of 0.94 (95 % CI: 0.85-1.00) with 67 % sensitivity at 95 % specificity for identifying MEN1 patients with metastatic dpNETS. Increases in circulating microbial-associated uremic toxins during early stages of neoplasia were also found to be associated with poor overall survival in an Men1fl/flPdx1-CreTg mouse model of MEN1 pancreatic NETs. Our findings suggest that microbial dysbiosis is associated with disease aggressiveness and that increases in circulating microbial-associated uremic toxins may be a prognostic indication for MEN1 individuals who are at risk of having metastatic dpNETs.

引用

页数：12