Abstract
Simple SummaryThe traditional approach in identifying cancer related protein biomarkers has focused on evaluation of a single peptide/protein in tissue or circulation. At best, this approach has had limited success for clinical applications, since multiple pathological tumor pathways may be involved during initiation or progression of cancer which diminishes the significance of a single candidate protein/peptide. Emerging sensitive proteomic based technologies like liquid chromatography mass spectrometry (LC-MS)-based quantitative proteomics can provide a platform for evaluating serial serum or plasma samples to interrogate secreted products of tumor–host interactions, thereby revealing a more “complete” repertoire of biological variables encompassing heterogeneous tumor biology. However, several challenges need to be met for successful application of serum/plasma based proteomics. These include uniform pre-analyte processing of specimens, sensitive and specific proteomic analytical platforms and adequate attention to study design during discovery phase followed by validation of discovery-level signatures for prognostic, predictive, and diagnostic cancer biomarker applications.Blood is a readily accessible biofluid containing a plethora of important proteins, nucleic acids, and metabolites that can be used as clinical diagnostic tools in diseases, including cancer. Like the on-going efforts for cancer biomarker discovery using the liquid biopsy detection of circulating cell-free and cell-based tumor nucleic acids, the circulatory proteome has been underexplored for clinical cancer biomarker applications. A comprehensive proteome analysis of human serum/plasma with high-quality data and compelling interpretation can potentially provide opportunities for understanding disease mechanisms, although several challenges will have to be met. Serum/plasma proteome biomarkers are present in very low abundance, and there is high complexity involved due to the heterogeneity of cancers, for which there is a compelling need to develop sensitive and specific proteomic technologies and analytical platforms. To date, liquid chromatography mass spectrometry (LC-MS)-based quantitative proteomics has been a dominant analytical workflow to discover new potential cancer biomarkers in serum/plasma. This review will summarize the opportunities of serum proteomics for clinical applications; the challenges in the discovery of novel biomarkers in serum/plasma; and current proteomic strategies in cancer research for the application of serum/plasma proteomics for clinical prognostic, predictive, and diagnostic applications, as well as for monitoring minimal residual disease after treatments. We will highlight some of the recent advances in MS-based proteomics technologies with appropriate sample collection, processing uniformity, study design, and data analysis, focusing on how these integrated workflows can identify novel potential cancer biomarkers for clinical applications.
Highlights
An accumulation of genetic and epigenetic alterations that change protein expression can lead to tumorigenesis and the aggressiveness of cancer post diagnosis
Some of the serum/plasma tumor markers recently developed for the detection, diagnosis, prognosis, or management of lung cancers include cytokeratin 19 fragments (CYFRA 21-1), carcinoembryonic antigen (CEA), epidermal growth factor receptor (EGFR), soluble mesothelin-related proteins (SMRP), and Osteopontin [123,124,166,167]
The majority of the markers reported by single breast cancer studies are based on a limited number of samples, the validation of biomarker candidates by the targeted profiling analysis of large cohorts of samples and populations is crucial for implementing those in clinical application
Summary
An accumulation of genetic and epigenetic alterations that change protein expression can lead to tumorigenesis and the aggressiveness of cancer post diagnosis. The patterns of protein expression are quantitatively measured and compared between cancer and non-cancer samples This enables the researcher to identify potential candidate biomarkers for clinical applications [10,11,12]. A big analytical challenge in proteomic research for the characterization and validation of the proteome biomarker candidates is to deal with the dynamic nature and complexity of the cellular proteomes from different biological specimen types, such as blood, serum, plasma, and tissue. Human serum/plasma has a vast array of proteins and complexes, which makes it an attractive diagnostic platform for disease-associated biomarkers with clinical applications It has advantages such as its minimal cost and ease of serial sample collection and processing. We discuss future perspectives for MS-based proteomics and its clinical impact on the management of disease
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