title: Role of the mitogen-activated protein kinase and phosphoinositide 3-kinase/AKT pathways downstream molecules, phosphorylated extracellular signal-regulated kinase, and phosphorylated AKT in colorectal cancer-a tissue microarray-based approach.
abstract: Tumor budding is defined as dedifferentiated cancer cells at the invasive margin of colorectal cancer (CRC) and correlates with a worse prognosis. The invasive margin and tumor budding are normally not present in a superficial diagnostic biopsy specimen. The aim of this study was to investigate the expression/overexpression of 2 downstream molecules of the mitogen-activated protein kinase and phosphoinositide 3-kinase/AKT pathways, phosphorylated AKT (pAKT) and phosphorylated extracellular signal-regulated kinase (pERK), in areas of CRC away from the invasive margin and determining if these variables were predictive of tumor budding or prognosis. A series of 1420 unselected, nonconsecutive CRC resections were subdivided into 3 groups: (1) DNA mismatch repair (MMR) proficient, (2) MLH1-negative, and (3) presumed HNPCC. Immunohistochemical analysis of pAKT and pERK expression (0% versus > 0%) and overexpression (increasing percentage of positivity) was performed using the tissue microarray technique. The results were correlated with clinicopathologic parameters. Fifty-seven samples of normal colon mucosa were included as a control group. Nuclear pERK expression (P = .008) was associated with presence of tumor budding in the MMR-proficient, but not in the MLH1-negative and presumed-HNPCC groups. In contrast, cytoplasmic pAKT overexpression was associated with early T stage (P = .04), early N stage (P = .02), and absence of tumor budding (P = .03) only in the MLH1-negative group. There was no association between pERK or pAKT and clinicopathologic parameters in the HNPCC group. Dysregulation of the mitogen-activated protein kinase pathway is likely to be implicated in the mechanism of tumor budding only in MMR-proficient CRC, whereas the phosphoinositide 3-kinase/AKT pathway is associated with early stage in MLH1-negative CRC.
authors.affiliation: Department of Pathology, McGill University, Montreal, Canada H3A-2B4. alugli@po-box.mcgill.ca
authors.forename: Alessandro
authors.initials: A
authors.lastname: Lugli
authors.forename: Inti
authors.initials: I
authors.lastname: Zlobec
authors.forename: Parham
authors.initials: P
authors.lastname: Minoo
authors.forename: Kristi
authors.initials: K
authors.lastname: Baker
authors.forename: Luigi
authors.initials: L
authors.lastname: Tornillo
authors.forename: Luigi
authors.initials: L
authors.lastname: Terracciano
authors.forename: Jeremy R
authors.initials: JR
authors.lastname: Jass
mesh_terms: D000230:Adenocarcinoma / Q000201:enzymology* / Q000556:secondary; D000368:Aged; D014408:Biomarkers, Tumor / Q000378:metabolism; D002467:Cell Nucleus / Q000378:metabolism / Q000473:pathology; D003106:Colon / Q000378:metabolism; D015179:Colorectal Neoplasms / Q000201:enzymology* / Q000473:pathology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D005260:Female; D019084:Fluorescent Antibody Technique, Indirect; D006801:Humans; D007124:Immunoenzyme Techniques; D008297:Male; D008875:Middle Aged; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D046888:Tissue Array Analysis / Q000379:methods
chemical_list: D014408:Biomarkers, Tumor; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D048049:Extracellular Signal-Regulated MAP Kinases; D020928:Mitogen-Activated Protein Kinases