A mouse to human search for plasma proteome changes associated with pancreatic tumor development.
BACKGROUND
The 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.


RESULTS
Plasma 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.


CONCLUSIONS
Our 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.
Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America.
Vitor M
VM
Faca
Kenneth S
KS
Song
Hong
H
Wang
Qing
Q
Zhang
Alexei L
AL
Krasnoselsky
Lisa F
LF
Newcomb
Ruben R
RR
Plentz
Sushma
S
Gurumurthy
Mark S
MS
Redston
Sharon J
SJ
Pitteri
Sandra R
SR
Pereira-Faca
Renee C
RC
Ireton
Hiroyuki
H
Katayama
Veronika
V
Glukhova
Douglas
D
Phanstiel
Dean E
DE
Brenner
Michelle A
MA
Anderson
David
D
Misek
Nathalie
N
Scholler
Nicole D
ND
Urban
Matt J
MJ
Barnett
Cim
C
Edelstein
Gary E
GE
Goodman
Mark D
MD
Thornquist
Martin W
MW
McIntosh
Ronald A
RA
DePinho
Nabeel
N
Bardeesy
Samir M
SM
Hanash
D000818:Animals; D014408:Biomarkers, Tumor / Q000097:blood*; D006801:Humans; D013058:Mass Spectrometry; D051379:Mice; D010190:Pancreatic Neoplasms / Q000097:blood / Q000175:diagnosis*; D020543:Proteome / Q000378:metabolism*; D040901:Proteomics / Q000379:methods; D012333:RNA, Messenger / Q000378:metabolism
D014408:Biomarkers, Tumor; D020543:Proteome; D012333:RNA, Messenger