Abstract
BackgroundThe complexity and heterogeneity of the human plasma proteome have presented significant challenges in the identification of protein changes associated with tumor development. Refined genetically engineered mouse (GEM) models of human cancer have been shown to faithfully recapitulate the molecular, biological, and clinical features of human disease. Here, we sought to exploit the merits of a well-characterized GEM model of pancreatic cancer to determine whether proteomics technologies allow identification of protein changes associated with tumor development and whether such changes are relevant to human pancreatic cancer.Methods and FindingsPlasma was sampled from mice at early and advanced stages of tumor development and from matched controls. Using a proteomic approach based on extensive protein fractionation, we confidently identified 1,442 proteins that were distributed across seven orders of magnitude of abundance in plasma. Analysis of proteins chosen on the basis of increased levels in plasma from tumor-bearing mice and corroborating protein or RNA expression in tissue documented concordance in the blood from 30 newly diagnosed patients with pancreatic cancer relative to 30 control specimens. A panel of five proteins selected on the basis of their increased level at an early stage of tumor development in the mouse was tested in a blinded study in 26 humans from the CARET (Carotene and Retinol Efficacy Trial) cohort. The panel discriminated pancreatic cancer cases from matched controls in blood specimens obtained between 7 and 13 mo prior to the development of symptoms and clinical diagnosis of pancreatic cancer.ConclusionsOur findings indicate that GEM models of cancer, in combination with in-depth proteomic analysis, provide a useful strategy to identify candidate markers applicable to human cancer with potential utility for early detection.
Highlights
A major goal of the cancer biomarker field is the development of noninvasive tests that allow early cancer detection
The complexity and heterogeneity of the human plasma proteome have presented significant challenges in the identification of protein changes associated with tumor development
We sought to exploit the merits of a well-characterized genetically engineered mouse (GEM) model of pancreatic cancer to determine whether proteomics technologies allow identification of protein changes associated with tumor development and whether such changes are relevant to human pancreatic cancer
Summary
A major goal of the cancer biomarker field is the development of noninvasive tests that allow early cancer detection. The complexity and heterogeneity of the human plasma proteome have presented significant challenges in the identification of protein changes associated with tumor development. We sought to exploit the merits of a well-characterized GEM model of pancreatic cancer to determine whether proteomics technologies allow identification of protein changes associated with tumor development and whether such changes are relevant to human pancreatic cancer. Many cancers are detected only when they are large enough to press against surrounding tissues and cause pain or other symptoms By this time, surgical removal of the original (primary) tumor may be impossible and there may be secondary cancers scattered around the body. One cancer type for which late detection is a particular problem is pancreatic adenocarcinoma This cancer rarely causes any symptoms in its early stages. Pancreatic cancer has usually spread before it is diagnosed, and most patients die within a year of their diagnosis
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