title: Reverse phase protein microarrays which capture disease progression show activation of pro-survival pathways at the cancer invasion front.
abstract: Protein arrays are described for screening of molecular markers and pathway targets in patient matched human tissue during disease progression. In contrast to previous protein arrays that immobilize the probe, our reverse phase protein array immobilizes the whole repertoire of patient proteins that represent the state of individual tissue cell populations undergoing disease transitions. A high degree of sensitivity, precision and linearity was achieved, making it possible to quantify the phosphorylated status of signal proteins in human tissue cell subpopulations. Using this novel protein microarray we have longitudinally analysed the state of pro-survival checkpoint proteins at the microscopic transition stage from patient matched histologically normal prostate epithelium to prostate intraepithelial neoplasia (PIN) and then to invasive prostate cancer. Cancer progression was associated with increased phosphorylation of Akt (P<0.04), suppression of apoptosis pathways (P<0.03), as well as decreased phosphorylation of ERK (P<0.01). At the transition from histologically normal epithelium to PIN we observed a statistically significant surge in phosphorylated Akt (P<0.03) and a concomitant suppression of downstream apoptosis pathways which proceeds the transition into invasive carcinoma.
authors.affiliation: Tissue Proteomics Unit, Division of Therapeutic Proteins, CBER, Food and Drug Administration, Bethesda, Maryland, MD 20892, USA.
authors.forename: C P
authors.initials: CP
authors.lastname: Paweletz
authors.forename: L
authors.initials: L
authors.lastname: Charboneau
authors.forename: V E
authors.initials: VE
authors.lastname: Bichsel
authors.forename: N L
authors.initials: NL
authors.lastname: Simone
authors.forename: T
authors.initials: T
authors.lastname: Chen
authors.forename: J W
authors.initials: JW
authors.lastname: Gillespie
authors.forename: M R
authors.initials: MR
authors.lastname: Emmert-Buck
authors.forename: M J
authors.initials: MJ
authors.lastname: Roth
authors.forename: E F
authors.initials: EF
authors.lastname: Petricoin III
authors.forename: L A
authors.initials: LA
authors.lastname: Liotta
mesh_terms: D014408:Biomarkers, Tumor / Q000378:metabolism*; D002455:Cell Division / Q000502:physiology; D002470:Cell Survival / Q000502:physiology; D002471:Cell Transformation, Neoplastic / Q000378:metabolism / Q000473:pathology*; D018450:Disease Progression; D004210:Dissection; D004847:Epithelial Cells / Q000166:cytology / Q000378:metabolism; D006801:Humans; D007834:Lasers; D008297:Male; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009363:Neoplasm Proteins / Q000378:metabolism*; D010766:Phosphorylation; D011467:Prostate / Q000166:cytology* / Q000378:metabolism; D019048:Prostatic Intraepithelial Neoplasia / Q000378:metabolism / Q000473:pathology*; D011471:Prostatic Neoplasms / Q000378:metabolism / Q000473:pathology*; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D015203:Reproducibility of Results; D012680:Sensitivity and Specificity; D015398:Signal Transduction / Q000502:physiology
chemical_list: D014408:Biomarkers, Tumor; D009363:Neoplasm Proteins; D011518:Proto-Oncogene Proteins; C494918:AKT1 protein, human; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D020928:Mitogen-Activated Protein Kinases