Comprehensive proteome analysis of an Apc mouse model uncovers proteins associated with intestinal tumorigenesis.
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.
Hung
Kenneth E
KE
Department of Medicine, Tufts Medical Center, Boston, Massachusetts, USA. khung@tuftsmedicalcenter.org
Faca
Vitor
V
Song
Kenneth
K
Sarracino
David A
DA
Richard
Larissa Georgeon
LG
Krastins
Bryan
B
Forrester
Sara
S
Porter
Andrew
A
Kunin
Alexandra
A
Mahmood
Umar
U
Haab
Brian B
BB
Hanash
Samir M
SM
Kucherlapati
Raju
R
D025601:Adenomatous Polyposis Coli Protein / Q000378:metabolism* / Q000502:physiology; D000818:Animals; D001798:Blood Proteins / Q000737:chemistry; D002462:Cell Membrane / Q000378:metabolism; D019295:Computational Biology / Q000379:methods; D004195:Disease Models, Animal; D015972:Gene Expression Regulation, Neoplastic; D017491:Genes, APC; D007150:Immunohistochemistry / Q000379:methods; D007414:Intestinal Neoplasms / Q000097:blood* / Q000235:genetics* / Q000378:metabolism*; D013058:Mass Spectrometry / Q000379:methods; D051379:Mice; D008810:Mice, Inbred C57BL; D040901:Proteomics / Q000379:methods*; D020931:ran GTP-Binding Protein / Q000378:metabolism
D025601:Adenomatous Polyposis Coli Protein; D001798:Blood Proteins; D020931:ran GTP-Binding Protein