Identification of Potential Serum Protein Biomarkers and Pathways for Pancreatic Cancer Cachexia Using an Aptamer-Based Discovery Platform

被引:34
作者
Narasimhan, Ashok [1 ]
Shahda, Safi [2 ,3 ,9 ]
Kays, Joshua K. [1 ]
Perkins, Susan M. [3 ,4 ]
Cheng, Lijun [4 ,10 ]
Schloss, Katheryn N. H. [1 ]
Schloss, Daniel E., I [1 ]
Koniaris, Leonidas G. [1 ,5 ]
Zimmers, Teresa A. [1 ,3 ,5 ,6 ,7 ,8 ]
机构
[1] Indiana Univ Sch Med, Dept Surg, Indianapolis, IN 46202 USA
[2] Indiana Univ Sch Med, Dept Med, Indianapolis, IN 46202 USA
[3] Indiana Univ, Simon & Bren Comprehens Canc Ctr, Indianapolis, IN 46202 USA
[4] Indiana Univ Sch Med, Dept Biostat, Indianapolis, IN 46202 USA
[5] Indiana Ctr Musculoskeletal Hlth, Indianapolis, IN 46202 USA
[6] Indiana Univ Sch Med, Dept Otolaryngol Head & Neck Surg, Indianapolis, IN 46202 USA
[7] Indiana Univ Sch Med, Dept Biochem & Mol Biol, Indianapolis, IN 46202 USA
[8] Richard L Roudebush Vet Adm Med Ctr, Indianapolis, IN 46202 USA
[9] Eli Lilly Co, Indianapolis, IN 46225 USA
[10] Ohio State Univ, Dept Biomed Informat, Coll Med, Columbus, OH 43210 USA
基金
美国国家卫生研究院;
关键词
pancreatic adenocarcinoma; cachexia; biomarkers; humans; neoplasms; proteome; weight loss; paracrine communication; SKELETAL-MUSCLE; WEIGHT-LOSS; INTERLEUKIN-6; OBESITY; GROWTH; SURVIVAL; AXIS; IL-6; INHIBITION; EXPRESSION;
D O I
10.3390/cancers12123787
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
Simple Summary Patients with pancreatic cancer and other advanced cancers suffer from progressive weight loss that reduces treatment response and quality of life and increases treatment toxicity and mortality. Effective interventions to prevent such weight loss, known as cachexia, require molecular markers to diagnose, stage, and monitor cachexia. No such markers are currently validated or in clinical use. This study used a discovery platform to measure changes in plasma proteins in patients with pancreatic cancer compared with normal controls. We found proteins specific to pancreatic cancer and cancer stage, as well as proteins that correlate with cachexia. These include some previously known proteins along with novel ones and implicates both well-known and new molecular mechanisms. Thus, this study provides novel insights into the molecular processes underpinning cancer and cachexia and affords a basis for future validation studies in larger numbers of patients with pancreatic cancer and cachexia. Patients with pancreatic ductal adenocarcinoma (PDAC) suffer debilitating and deadly weight loss, known as cachexia. Development of therapies requires biomarkers to diagnose, and monitor cachexia; however, no such markers are in use. Via Somascan, we measured similar to 1300 plasma proteins in 30 patients with PDAC vs. 11 controls. We found 60 proteins specific to local PDAC, 46 to metastatic, and 67 to presence of >5% cancer weight loss (FC >= |1.5|, p <= 0.05). Six were common for cancer stage (Up: GDF15, TIMP1, IL1RL1; Down: CCL22, APP, CLEC1B). Four were common for local/cachexia (C1R, PRKCG, ELANE, SOST: all oppositely regulated) and four for metastatic/cachexia (SERPINA6, PDGFRA, PRSS2, PRSS1: all consistently changed), suggesting that stage and cachexia status might be molecularly separable. We found 71 proteins that correlated with cachexia severity via weight loss grade, weight loss, skeletal muscle index and radiodensity (r >= |0.50|, p <= 0.05), including some known cachexia mediators/markers (LEP, MSTN, ALB) as well as novel proteins (e.g., LYVE1, C7, F2). Pathway, correlation, and upstream regulator analyses identified known (e.g., IL6, proteosome, mitochondrial dysfunction) and novel (e.g., Wnt signaling, NK cells) mechanisms. Overall, this study affords a basis for validation and provides insights into the processes underpinning cancer cachexia.
引用
收藏
页码:1 / 23
页数:23
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