AGR2 Is a Novel Surface Antigen That Promotes the Dissemination of Pancreatic Cancer Cells through Regulation of Cathepsins B and D

Dumartin, Laurent; Whiteman, Hannah J.; Weeks, Mark E.; Hariharan, Deepak; Dmitrović, Branko; Iacobuzio‐Donahue, Christine A.; Brentnall, Teresa A.; Bronner, Mary P.; Feakins, Roger; Timms, John F.; Brennan, Caroline H.; Lemoine, Nick R.; Crnogorac‐Jurčević, Tatjana

doi:10.1158/0008-5472.can-11-1367

Cited by 127 publications

(138 citation statements)

References 47 publications

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“…It should be noted that AGR2 expression can also be upregulated in PDAC, as other publications have suggested. 14,16 Previous reports have documented conflicting results regarding the prognostic value of AGR2 expression. In prostate cancer tissue, AGR2 downregulation correlated with increased Gleason grade, a histological grading system of prostate cancer, and increased cancer recurrence in Gleason grades 4 or 5.…”

Section: Discussionmentioning

confidence: 99%

“…AGR2 immunoreactivity was determined using an intensity score, graded on a scale from 0 to 3, and a proportional score, corresponding to the percentage of stained cells (0: no staining, 1:o20%; 2: 20-50%, and 3:450%), as previously described. 16 The total score was the product of intensity and the proportional score. AGR2 high-expressing patients scored between 4 and 6 (n ¼ 139) and low-expressing patients between 0 and 3 (n ¼ 54).…”

Section: Evaluation Of Immunohistochemical Stainingmentioning

confidence: 99%

“…15 Previous reports have also shown that AGR2 promotes dissemination of pancreatic cancer via regulation of lysosomal proteases (cathepsin B and D); however, conversely, AGR2 expression is decreased in PDAC compared with PanIN. 16 Epithelial-mesenchymal transition (EMT), a well-known hallmark of highly invasive cancer cells, is a critical phenotypic alteration involved in the morphological change from epithelial to mesenchymal phenotype. Emerging evidence suggests that the acquisition of a mesenchymal phenotype has a key role in migration, invasion, resistance to chemoradiotherapy, and extravasation of cancer cells from the primary tumor microenvironment.…”

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confidence: 99%

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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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Section: Discussionmentioning

confidence: 99%

Section: Evaluation Of Immunohistochemical Stainingmentioning

confidence: 99%

mentioning

confidence: 99%

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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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“…Agr2 is overexpressed in various cancer cells, and aberrant Agr2 expression in several tumor types predicts worse clinical outcomes (32)(33)(34)(35)(36)(37). Previously, however, the functions of secreted Agr2 and its significance in the progression of gastric SRCC had not been extensively examined.…”

Section: Discussionmentioning

confidence: 99%

Agr2 Mediates Paracrine Effects on Stromal Fibroblasts That Promote Invasion by Gastric Signet-Ring Carcinoma Cells

et al. 2015

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Agr2 is a disulfide isomerase residing in the endoplasmic reticulum (ER), which physiologically regulates protein folding and mediates resistance to ER stress. Agr2 is overexpressed in adenocarcinomas of various organs, where it participates in neoplastic transformation and metastasis, therefore acts as a pro-oncogenic protein. Besides its normal localization in the ER, Agr2 is also found in the serum and urine of cancer patients, although the physiological significance of extracellular Agr2 is poorly understood. In this study, we demonstrated that extracellular Agr2 can activate stromal fibroblasts and promote fibroblastassociated cancer invasion in gastric signet-ring cell carcinoma (SRCC), where Agr2 is highly expressed. Agr2 secreted from SRCC cells was incorporated by the surrounding gastric fibroblasts and promoted invasion by these cells. In turn, activated fibroblasts coordinated the invasive behavior of fibroblasts and cancer cells. Our findings suggested that Agr2 drives progression of gastric SRCC by exerting paracrine effects on fibroblasts in the tumor microenvironment, acting also to increase the growth and resistance of SRCC cells to oxidative and hypoxic stress as cell autonomous effects. Cancer Res; 75(2); 356-66. Ó2014 AACR.

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“…AGR2 expression was shown to be significantly increased in HER2 positive breast tumors [147]. High levels of AGR2 were also associated with cell dissemination of pancreatic carcinoma [148] and with poor prognosis of lung cancer [149]. Worth of note, this protein appears highly represented in the tumor tissues (when present) and almost absent in the normal ones.…”

Section: Anterior Gradient Protein 2 Homolog Agr2 (Agr2)mentioning

confidence: 98%

Retrospective Proteomic Screening of 100 Breast Cancer Tissues

Pucci‐Minafra¹,

Cara²,

Musso³

et al. 2017

Preprint

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Abstract:The present investigation has been conducted on one hundred tissue fragments of breast cancer, collected and immediately cryopreserved following the surgical resection. The fragments were selected from patients with invasive ductal carcinoma of the breast, the most common and potentially aggressive type of mammary cancer, with the objective to increase the knowledge of breast cancer molecular markers, useful for diagnostic and prognostic categorization of patients, in assessing postsurgical therapeutic regimes. The proteomic screening, by 2D-IPG and mass spectrometry, allowed us to identify two main classes of protein clusters: proteins expressed ubiquitously at high levels in all patients, and proteins expressed sporadically among the same patients. Within the group of ubiquitous proteins, glycolytic enzymes and proteins with anti-apoptotic activity were predominant. Among the sporadic ones, proteins involved in cell motility, molecular chaperones and proteins involved in the detoxification appeared prevalent. The data of the present study indicates that the primary tumor growth is generally supported by two concurrent pathways: the inhibition of apoptosis and the stimulation of cellular proliferation. The second phase of the evolution of the tumor can be prematurely scheduled by the occasional presence of proteins involved in cell motility and in the defenses of the oxidative stress. To our knowledge this report on large-scales proteomics of breast cancer is currently a unique approach in the literature that offers the opportunity to evaluate the presence and recurrence of proteins to be used as prognostic indicators and susceptibility to metastasis in patients operated on for invasive ductal carcinoma of the breast.

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AGR2 Is a Novel Surface Antigen That Promotes the Dissemination of Pancreatic Cancer Cells through Regulation of Cathepsins B and D

Cited by 127 publications

References 47 publications

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

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

Agr2 Mediates Paracrine Effects on Stromal Fibroblasts That Promote Invasion by Gastric Signet-Ring Carcinoma Cells

Retrospective Proteomic Screening of 100 Breast Cancer Tissues

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