Elevated level of anterior gradient-2 in pancreatic juice from patients with pre-malignant pancreatic neoplasia

Chen, Ru; Pan, Sheng; Duan, Xinrui; Nelson, Brad H.; Sahota, Rob A.; Rham, Sarah de; Kozarek, Richard A.; McIntosh, Martin W.; Brentnall, Teresa A.

doi:10.1186/1476-4598-9-149

Cited by 58 publications

(45 citation statements)

References 30 publications

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“…Although Chen et al, found diagnostic relevance for AGR2 in pancreatic juice, their analysis in six paired serum and pancreatic juice samples from PanIN patients found no correlation between serum and pancreatic juice AGR2 levels. Further analysis by this group in serum of nine pancreatic cancer and nine cancer-free controls showed no significant difference in AGR2 levels as well (62). Despite this, given that AGR2 was highly elevated in the majority of cancer cell line CM (based on spectral counting in this study) as well as its identification in pancreatic juice, we tested its levels in our screening set of plasma samples by ELISA and found a significant elevation in AGR2 levels in pancreatic cancer plasma versus controls ( Fig 5A).…”

Section: Discussionmentioning

confidence: 99%

“…AGR2 is an ortholog of the Xenopus laevis protein XAG-2, which is a protein shown to play a role in ectodermal patterning (102). The function of AGR2 in normal human states is largely unknown; however in human cancers, AGR2 has been associated with several cancer types (103)(104)(105) and recently, increased AGR2 levels were reported in pancreatic juice (62). In this latter study, Chen et al, used quantitative proteomics to profile pancreatic juice samples from pancreatic intraepithelial neoplasia (PanIN) patients in comparison to controls, and AGR2 was one of the proteins with an over twofold increase in PanIN-stage III.…”

Section: Discussionmentioning

confidence: 99%

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Integrated Proteomic Profiling of Cell Line Conditioned Media and Pancreatic Juice for the Identification of Pancreatic Cancer Biomarkers

Makawita

Smith

Batruch

et al. 2011

Molecular & Cellular Proteomics

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Pancreatic cancer is one of the leading causes of cancerrelated deaths, for which serological biomarkers are urgently needed. Most discovery-phase studies focus on the use of one biological source for analysis. The present study details the combined mining of pancreatic cancerrelated cell line conditioned media and pancreatic juice for identification of putative diagnostic leads. Using strong cation exchange chromatography, followed by LC-MS/MS on an LTQ-Orbitrap mass spectrometer, we extensively characterized the proteomes of conditioned media from six pancreatic cancer cell lines (BxPc3, MIAPaCa2, PANC1, CAPAN1, CFPAC1, and SU.86.86), the normal human pancreatic ductal epithelial cell line HPDE, and two pools of six pancreatic juice samples from ductal adenocarcinoma patients. All samples were analyzed in triplicate. Between 1261 and 2171 proteins were identified with two or more peptides in each of the cell lines, and an average of 521 proteins were identified in the pancreatic juice pools. In total, 3479 nonredundant proteins were identified with high confidence, of which ϳ40% were extracellular or cell membrane-bound based on Genome Ontology classifications. Three strategies were employed for identification of candidate biomarkers: (1) examination of differential protein expression between the cancer and normal cell lines using label-free protein quantification, (2) integrative analysis, focusing on the overlap of proteins among the multiple biological fluids, and (3) tissue specificity analysis through mining of publically available databases. Preliminary verification of anterior gradient homolog 2, syncollin, olfactomedin-4, polymeric immunoglobulin receptor, and collagen alpha-1(VI) chain in plasma samples from pancreatic cancer patients and healthy controls using ELISA, showed a significant increase (p < 0.01) of these proteins in plasma from pancreatic cancer patients. The combination of these five proteins showed an improved area under the receiver operating characteristic curve to CA19.9 alone.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Integrated Proteomic Profiling of Cell Line Conditioned Media and Pancreatic Juice for the Identification of Pancreatic Cancer Biomarkers

Makawita

Smith

Batruch

et al. 2011

Molecular & Cellular Proteomics

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“…Indeed, exclusion of E-cadherin expression from the multivariate analysis revealed that AGR2 downregulation was an independent prognostic marker (data not shown), suggesting the strong correlation between AGR2 downregulation and decreased membranous E-cadherin expression. In the view of a prognostic marker, as AGR2 is secreted into the pancreatic fluid, unlike E-cadherin or vimentin, 38 it may represent a useful and convenient pre-operative prognostic marker. To the best of our knowledge, our study is the first report demonstrating the prognostic significance of decreased AGR2 expression in PDAC patients.…”

Section: Discussionmentioning

confidence: 99%

Anterior gradient 2 downregulation in a subset of pancreatic ductal adenocarcinoma is a prognostic factor indicative of epithelial–mesenchymal transition

Mizuuchi

Aishima

Ohuchida

et al. 2015

Laboratory Investigation

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Anterior gradient 2 (AGR2), a member of the protein disulfide isomerase family, has been implicated in various cancers including pancreatic ductal adenocarcinoma (PDAC) and is known to promote cancer progression. However, the prognostic value of AGR2 expression and the interaction with epithelial-mesenchymal transition (EMT) remain unclear. We investigated the clinical significance of AGR2 and EMT markers in PDAC patients by immunohistochemical analyses. Although AGR2 expression was not observed in normal pancreas, all pancreatic precursor neoplastic lesions were positive for AGR2, even at the earliest stages, including pancreatic intraepithelial neoplasia-1A, AGR2 expression was reduced in 27.7% (54/195 cases) of PDAC patients. AGR2 downregulation correlated with EMT markers (vimentin overexpression and reduced membranous E-cadherin expression), high Union for International Cancer Control stage (Po0.0001), high histological cellular grade (Po0.0001), and adverse outcome (Po0.0001). In vitro, targeted silencing of AGR2 in cancer cells using siRNA reduced cell proliferation, colony formation, cell invasiveness, and migration, but did not alter EMT markers. To confer a more aggressive phenotype and induce EMT in PDAC cells, we co-cultured PDAC cell lines with primary-cultured pancreatic stellate cells (PSCs) and found that AGR2 was downregulated in co-cultured PDAC cells compared with PDAC monocultures. Treatment with transforming growth factor beta-1 (TGF-b), secreted from PSCs, decreased AGR2 expression, whereas inhibition of TGF-b signaling using recombinant soluble human TGF-b receptor type II and TGF-b-neutralizing antibodies restored AGR2 expression. We conclude that AGR2 downregulation is a useful prognostic marker, induced by EMT, and that secreted TGF-b from PSCs may partially contribute to AGR2 downregulation in PDAC patients. AGR2 downregulation does not induce EMT or a more aggressive phenotype, but is a secondary effect of these processes in advanced PDAC.

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“…While the stage 1 patient had high levels of HIP/PAP-1 in the pancreatic juice, both stage 2 patients had HIP/PAP-2 levels that overlapped with that of IPMN cases. Another recent study identified 20 proteins that were significantly elevated (p<0.05) at least 2-fold or greater in pancreatic juice collected from three patients with PanIN-3 lesions compared to a control sample comprising pooled pancreatic juice from five patients with benign pancreatic diseases (sphincter of Oddi dysfunction and CP) [140]. Some of these have also been previously shown to be elevated in PanIN tissues including anterior gradient-2, MUC5AC, cytoplasmic actin and Annexin A4 (Figure 1).…”

Section: Biomarkers In Body Fluidsmentioning

confidence: 99%

Current status of molecular markers for early detection of sporadic pancreatic cancer

Chakraborty

Baine

Sasson

et al. 2011

Biochimica et Biophysica Acta (BBA) - Reviews on Cancer

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Pancreatic cancer (PC) is a highly lethal malignancy with near 100% mortality. This is in part due to the fact that most patients present with metastatic or locally advanced disease at the time of diagnosis. Significantly, in nearly 95% of PC patients there is neither an associated family history of PC nor of diseases known to be associated with an increased risk of PC. These groups of patients who comprise the bulk of PC cases are termed as "sporadic PC" in contrast to the familial PC cases that comprise only about 5% of all PCs. Given the insidious onset of the malignancy and its extreme resistance to chemo and radiotherapy, an abundance of research in recent years has focused on identifying biomarkers for the early detection of PC, specifically aiming at the sporadic PC cohort. However, while several studies have established that asymptomatic individuals with a positive family history of PC and those with certain heritable syndromes are candidates for PC screening, the role of screening in identifying sporadic PC is still an unsettled question. The present review attempts to assess this critical question by investigating the recent advances made in molecular markers with potential use in the early diagnosis of sporadic PC-the largest cohort of PC cases worldwide. It also outlines a novel yet simple risk-factor based stratification system that could be potentially employed by clinicians to identify those individuals who at an elevated-risk for the development of sporadic PC and therefore candidates for screening. Keywords diagnosis; PanIN; biomarkers PrologueIt seems that pancreatic cancer (PC) has recently crept further and further into the consciousness of the general public. The news that Luciano Pavarotti, the renowned opera Address for Correspondence: Surinder K. Batra, Ph.D., Department of Biochemistry and Molecular Biology, Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, 985870 Nebraska Medical Center, Omaha, NE 68198-5870, U.S.A., Phone: 402-559-5455; Fax: 402-559-6650. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. NIH Public Access Author ManuscriptBiochim Biophys Acta. Author manuscript; available in PMC 2012 January 1. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript singer and one of the legendary "three tenors" had been diagnosed with PC came as a shock to millions of his followers the world over. A year-and-a-half later, the famous actor and heartthrob, Patrick Swayze, also received the diagnosis of PC and succumbed to his disease in just 19 months. Former United States...

show abstract

Elevated level of anterior gradient-2 in pancreatic juice from patients with pre-malignant pancreatic neoplasia

Cited by 58 publications

References 30 publications

Integrated Proteomic Profiling of Cell Line Conditioned Media and Pancreatic Juice for the Identification of Pancreatic Cancer Biomarkers

Integrated Proteomic Profiling of Cell Line Conditioned Media and Pancreatic Juice for the Identification of Pancreatic Cancer Biomarkers

Anterior gradient 2 downregulation in a subset of pancreatic ductal adenocarcinoma is a prognostic factor indicative of epithelial–mesenchymal transition

Current status of molecular markers for early detection of sporadic pancreatic cancer

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