Predictive proteomic biomarkers for inflammatory bowel disease-associated cancer: where are we now in the era of the next generation proteomics?

Abstract

Recent advances in genomic medicine have opened up the possibility of tailored medicine that may eventually replace traditional "one-size-fits all" approaches to the treatment of inflammatory bowel disease (IBD). In addition to exploring the interactions between hosts and microbes, referred to as the microbiome, a variety of strategies that can be tailored to an individual in the coming era of personalized medicine in the treatment of IBD are being investigated. These include prompt genomic screening of patients at risk of developing IBD, the utility of molecular discrimination of IBD subtypes among patients diagnosed with IBD, and the discovery of proteome biomarkers to diagnose or predict cancer risks. Host genetic factors influence the etiology of IBD, as do microbial ecosystems in the human bowel, which are not uniform, but instead represent many different microhabitats that can be influenced by diet and might affect processes essential to bowel metabolism. Further advances in basic research regarding intestinal inflammation may reveal new insights into the role of inflammatory mediators, referred to as the inflammasome, and the macromolecular complex of metabolites formed by intestinal bacteria. Collectively, knowledge of the inflammasome and metagenomics will lead to the development of biomarkers for IBD that target specific pathogenic mechanisms involved in the spontaneous progress of IBD. In this review article, our recent results regarding the discovery of potential proteomic biomarkers using a label-free quantification technique are introduced and on-going projects contributing to either the discrimination of IBD subtypes or to the prediction of cancer risks are accompanied by updated information from IBD biomarker research.

Keywords: Biomarker; Colitic cancer; Inflammatory bowel disease; Proteomics; Tailored medicine.

Figure 1

Schematic presentation showing proteome analysis to discover potential biomarkers and label-free quantification analysis in inflammatory bowel disease. A: Applying the label-free quantification method to discover proteomic biomarkers in patients with different types and different stage of inflammatory bowel disease (IBD). Comparative analysis was done in eight patients with ulcerative colitis (UC), eight patients with Crohn’s disease (CD) and eight patients with irritable bowel syndrome (IBS). Biopsied colon tissues were obtained during colonoscopy after written consent, and stored in a deep freeze until assayed. Using Agilent HPLC-Chip 6520 Q-time-of-flight mass spectrometry (TOF-MS) and label-free quantitative proteome analysis (IDEAL-Q v1.0.6.3), significant signal pathway analysis was done. In the current review, the analysis done according to the degree of intestinal inflammation, type of IBD, and extent of inflammation from 24 patients, eight from non-IBD normal patients; i.e., IBS patients, eight from patients with UC, and from patients with CD; B: Label-free protein quantification scheme for potential biomarker for colitis-associated cancer (CAC) risk in 16 patients with IBD.

Figure 2

Potential proteomic markers signifying colitis-associated cancer risks in inflammatory bowel disease. A: Proteomic markers for colitis-associated cancer (CAC) risk in patients with ulcerative colitis (UC). The analysis was performed according to the degree of intestinal inflammation, type of inflammatory bowel disease and extent of inflammation. Compared with the analysis of CAC, 22 significant potential biomarkers of CAC risk were obtained from patients as p with UC, six biomarkers existing in the extracellular space, two biomarkers at the plasma membrane, seven are from the cytoplasm, and seven are nuclear proteins; B: Proteomic markers for CAC risk in patients with Crohn’s disease (CD). Eighteen potential biomarkers for the risk of CAC were identified in patients with CD. Four were from the plasma membrane, 11 from the cytoplasm, and three from the nucleus.

Figure 3

Proteomic markers for colitis-associated cancer risk in patients with both ulcerative colitis and Crohn’s disease. After analyzing signaling pathways from label-free quantitative analysis, four important proteome biomarkers were identified: proteoglycan 2 (PRG2), S100 calcium binding protein A8 (S100A8), ribosomal protein L18 (RPL18), and UDP-glucose dehydrogenase (UGDH), all of which showed fold changes. Validation is ongoing to investigate these biomarkers for predicting colitis-associated cancer risk in patients with inflammatory bowel disease. UC: Ulcerative colitis; CD: Crohn’s disease.