title: Systematic analysis of proteins from different signaling pathways in the tumor center and the invasive front of colorectal cancer.
abstract: In colorectal cancer, the functional impact of proteins from different signaling pathways varies between tumor center and tumor front. Our objective was to identify differential protein expression profiles between the tumor center and the tumor front of colorectal cancer. Twenty proteins from different signaling pathways (epidermal growth factor receptor [EGFR], phosphorylated extracellular signal regulated kinase [pERK], receptor for hyalouronic acid mediated motility [RHAMM], Raf-1 kinase inhibitor protein [RKIP], β-catenin, E-cadherin, phosphorylated AK transforming [pAKT], p16, p21, Ki-67, B-cell Lymphoma-2 [BCL2], vascular endothelial growth factor, apoptosis protease activating factor 1 [APAF-1], mucin1 [MUC1], ephrin B2 receptor [EphB2], matrix metalloproteinase 7 [MMP7], phosphorylated mothers against decapentaplegic 2 [pSMAD2], caudal type homeobox transcription factor 2 [CDX2], Laminin5γ2, and mammalian sterile 20-like kinase 1 [MST1]) involved in colorectal cancer progression were studied immunohistochemically on 220 well-characterized patients using a multiple-punch tissue microarray including 437 and 430 samples from the tumor center and the invasive front, respectively. Mean expression between the tumor center and the tumor front varied statistically significantly for pSMAD2, pERK, Raf-1 kinase inhibitor protein, E-cadherin, pAKT, BCL2, vascular endothelial growth factor, EphB2, matrix metalloproteinase 7, CDX2, Laminin5γ2, MST1, and APAF-1. Overexpression of pAKT, BCL2, vascular endothelial growth factor, APAF-1, pERK, EphB2, Raf-1 kinase inhibitor protein, CDX2, E-cadherin, MST1 (P < .001 each), and pSMAD2 (P = .002) was more frequently observed in the tumor center, whereas matrix metalloproteinase 7 and Laminin5γ2 (P < .001 each) overexpression was associated with the invasive front. In multivariate analysis, vascular endothelial growth factor (P < .001), Raf-1 kinase inhibitor protein (P = .009), and Laminin5γ2 (P < .001) were the most relevant proteins with the multimarker phenotypes positive/positive/negative and negative/negative/positive being most discriminating between the tumor center and the tumor front. Moreover, the combination negative/negative/positive vascular endothelial growth factor/Raf-1 kinase inhibitor protein/Laminin5γ2 at the tumor front was associated with vascular/lymphatic invasion (P = .014), distant metastasis (P = .019), higher tumor grade (P < .001), and poorer survival (P = .05). Our findings show that, in colorectal cancer progression, vascular endothelial growth factor overexpression seems to play a role in the tumor center, whereas Laminin5γ2-positivity combined with Raf-1 kinase inhibitor protein loss is associated with tumor invasion at the front.
authors.affiliation: Second Department of Pathology, University of Athens, 12464 Athens, Greece. ekaramit@med.uoa.gr
authors.forename: Eva
authors.initials: E
authors.lastname: Karamitopoulou
authors.forename: Inti
authors.initials: I
authors.lastname: Zlobec
authors.forename: Ioannis
authors.initials: I
authors.lastname: Panayiotides
authors.forename: Efstratios S
authors.initials: ES
authors.lastname: Patsouris
authors.forename: George
authors.initials: G
authors.lastname: Peros
authors.forename: George
authors.initials: G
authors.lastname: Rallis
authors.forename: Christos
authors.initials: C
authors.lastname: Lapas
authors.forename: Petros
authors.initials: P
authors.lastname: Karakitsos
authors.forename: Luigi M
authors.initials: LM
authors.lastname: Terracciano
authors.forename: Alessandro
authors.initials: A
authors.lastname: Lugli
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000032:analysis / Q000378:metabolism*; D015179:Colorectal Neoplasms / Q000378:metabolism* / Q000401:mortality / Q000473:pathology* / Q000628:therapy; D018450:Disease Progression; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D053208:Kaplan-Meier Estimate; D007797:Laminin / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D060787:Neoplasm Grading; D009361:Neoplasm Invasiveness; D009367:Neoplasm Staging; D049488:Phosphatidylethanolamine Binding Protein / Q000378:metabolism; D011379:Prognosis; D015398:Signal Transduction; D016019:Survival Analysis; D046888:Tissue Array Analysis; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
chemical_list: D014408:Biomarkers, Tumor; C400567:LAMC2 protein, human; D007797:Laminin; C511482:PEBP1 protein, human; D049488:Phosphatidylethanolamine Binding Protein; D042461:Vascular Endothelial Growth Factor A