Immunohistochemistry for cell polarity protein lethal giant larvae 2 differentiates pancreatic intraepithelial neoplasia-3 and ductal adenocarcinoma of the pancreas from lower-grade pancreatic intraepithelial neoplasias
ABSTRACT Pancreatic intraepithelial neoplasia is a precursor to ductal adenocarcinoma of the pancreas that shows gastric differentiation. Pancreatic intraepithelial neoplasia-3 has the highest potential to progress to adenocarcinoma, and its distinction from lower-grade pancreatic intraepithelial neoplasias is important for clinical management. However, morphologic grading of pancreatic intraepithelial neoplasia suffers from significant interobserver variability. A product of cell polarity gene lethal giant larvae 2 is a marker of gastric foveolar epithelium expressed in a basolateral fashion, which is lost or mislocalized in gastric epithelial dysplasia and adenocarcinoma. In this study, we investigated a role of lethal giant larvae 2 expression in differentiating low-grade pancreatic intraepithelial neoplasias, that is, pancreatic intraepithelial neoplasia-1 and pancreatic intraepithelial neoplasia-2, from pancreatic intraepithelial neoplasia-3 and pancreatic ductal adenocarcinoma. The immunohistochemical patterns of lethal giant larvae 2 expression were examined in normal pancreatic ducts, 48 pancreatic intraepithelial neoplasia lesions of all histologic grades, and 91 adenocarcinomas on a tissue microarray or conventional sections. The expression pattern was recorded as basolateral, cytoplasmic, negative, or combinations of any of them. Whereas normal duct epithelia did not exhibit lethal giant larvae immunoreactivity, all but one lesion of low-grade pancreatic intraepithelial neoplasia showed basolateral lethal giant larvae staining. Conversely, all lesions of pancreatic intraepithelial neoplasia-3 and adenocarcinoma showed loss of lethal giant larvae 2 staining and/or its cytoplasmic localization. Interestingly, a basolateral expression was focally seen in 4 adenocarcinomas with a foamy gland pattern and was always admixed with negatively stained areas. In conclusion, our results show that low-grade pancreatic intraepithelial neoplasias express lethal giant larvae 2 in a basolateral fashion recapitulating expression in normal gastric epithelium. Loss or abnormal lethal giant larvae 2 expression is seen in pancreatic intraepithelial neoplasia-3 and adenocarcinoma and might be useful in separating them from lower-grade pancreatic intraepithelial neoplasias.
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ABSTRACT: Loss of cell-cell adhesion and cell polarity is commonly observed in tumors of epithelial origin and correlates with their invasion into adjacent tissues and formation of metastases. Growing evidence indicates that loss of cell polarity and cell-cell adhesion may also be important in early stage of cancer. In first part of this review, we delineate the current understanding of the mechanisms that establish and maintain the polarity of epithelial tissues and discuss the involvement of cell polarity and apical junctional complex components in tumor pathogenesis. In the second part we address the clinical significance of cell polarity and junctional complex components in cancer diagnosis and prognosis. Finally, we explore their potential use as therapeutic targets in the treatment of cancer.Acta Pharmacologica Sinica 05/2011; 32(5):552-64. DOI:10.1038/aps.2011.20 · 2.50 Impact Factor
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ABSTRACT: Atypical protein kinase Cι (PKCι) has roles in cell growth, cellular polarity, and migration, and its abundance is frequently increased in cancer. We identified a protein interaction surface containing a dibasic motif (RIPR) that bound a distinct subset of PKCι substrates including lethal giant larvae 2 (LLGL2) and myosin X, but not other substrates such as Par3. Further characterization demonstrated that Arg(471) in this motif was important for binding to LLGL2, whereas Arg(474) was critical for interaction with myosin X, indicating that multiple complexes could be formed through this motif. A somatic mutation of the dibasic motif (R471C) was the most frequent mutation of PKCι in human cancer, and the intact dibasic motif was required for normal polarized epithelial morphogenesis in three-dimensional cysts. Thus, the R471C substitution is a change-of-function mutation acting at this substrate-specific recruitment site to selectively disrupt the polarizing activity of PKCι.Science Signaling 09/2013; 6(293):ra82. DOI:10.1126/scisignal.2004068 · 7.65 Impact Factor
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ABSTRACT: One-fifth of patients with seemingly 'curable' pancreatic ductal adenocarcinoma (PDA) experience an early recurrence and death, receiving no definable benefit from a major operation. Some patients with advanced stage tumors are deemed 'unresectable' by conventional staging criteria (e.g. liver metastasis), yet progress slowly. Effective biomarkers that stratify PDA based on biologic behavior are needed. To help researchers sort through the maze of biomarker data, a compendium of ∼2500 published candidate biomarkers in PDA was compiled (PLoS Med, 2009. 6(4) p. e1000046). Building on this compendium, we constructed a survival tissue microarray (termed s-TMA) comprised of short-term (cancer-specific death <12 months, n = 58) and long-term survivors (>30 months, n = 79) who underwent resection for PDA (total, n = 137). The s-TMA functions as a biological filter to identify bona fide prognostic markers associated with survival group extremes (at least 18 months separate survival groups). Based on a stringent selection process, 13 putative PDA biomarkers were identified from the public biomarker repository. Candidates were tested against the s-TMA by immunohistochemistry to identify the best markers of tumor biology. In a multivariate model, MUC1 (odds ratio, OR = 28.95, 3+ vs. negative expression, p = 0.004) and MSLN (OR = 12.47, 3+ vs. negative expression, p = 0.01) were highly predictive of early cancer-specific death. By comparison, pathologic factors (size, lymph node metastases, resection margin status, and grade) had ORs below three, and none reached statistical significance. ROC curves were used to compare the four pathologic prognostic features (ROC area = 0.70) to three univariate molecular predictors (MUC1, MSLN, MUC2) of survival group (ROC area = 0.80, p = 0.07). MUC1 and MSLN were superior to pathologic features and other putative biomarkers as predicting survival group. Molecular assays comparing cancers from short and long survivors are an effective strategy to screen biomarkers and prioritize candidate cancer genes for diagnostic and therapeutic studies.PLoS ONE 07/2012; 7(7):e40157. DOI:10.1371/journal.pone.0040157 · 3.53 Impact Factor