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Comprehensive Proteome Analysis of an Apc Mouse Model Uncovers Proteins Associated with Intestinal Tumorigenesis

Authors' Affiliations: ¹ Department of Medicine, Tufts Medical Center, Boston, Massachusetts; ² Harvard-Partners Center for Genetics and Genomics and Harvard Medical School, Boston, Massachusetts; ³ Molecular Diagnostics, Fred Hutchinson Cancer Research Center, Seattle, Washington; ⁴ Cancer Immunodiagnostics, Van Andel Research Institute, Grand Rapids, Michigan; and ⁵ Center for Molecular Imaging Research, Massachusetts General Hospital, Boston, Massachusetts

Requests for reprints: Kenneth E. Hung, 750 Washington Street, Box 233, Boston, MA 02111. Phone: 617-636-8337; Fax: 617-636-4505; E-mail: khung{at}tuftsmedicalcenter.org.

Tumor-derived proteins may occur in the circulation as a result of secretion, shedding from the cell surface, or cell turnover. We have applied an in-depth comprehensive proteomic strategy to plasma from intestinal tumor–bearing Apc mutant mice to identify proteins associated with tumor development. We used quantitative tandem mass spectrometry of fractionated mouse plasma to identify differentially expressed proteins in plasma from intestinal tumor–bearing Apc mutant mice relative to matched controls. Up-regulated proteins were assessed for the expression of corresponding genes in tumor tissue. A subset of proteins implicated in colorectal cancer were selected for further analysis at the tissue level using antibody microarrays, Western blotting, tumor immunohistochemistry, and novel fluorescent imaging. We identified 51 proteins that were elevated in plasma with concordant up-regulation at the RNA level in tumor tissue. The list included multiple proteins involved in colon cancer pathogenesis: cathepsin B and cathepsin D, cullin 1, Parkinson disease 7, muscle pyruvate kinase, and Ran. Of these, Parkinson disease 7, muscle pyruvate kinase, and Ran were also found to be up-regulated in human colon adenoma samples. We have identified proteins with direct relevance to colorectal carcinogenesis that are present both in plasma and in tumor tissue in intestinal tumor–bearing mice. Our results show that integrated analysis of the plasma proteome and tumor transcriptome of genetically engineered mouse models is a powerful approach for the identification of tumor-related plasma proteins.

Key Words: Proteomics • mass spectrometry • plasma proteome • colorectal cancer • mouse model

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