MUC4 mucin expression in human pancreatic tumours is affected by organ environment: the possible role of TGFβ2

Choudhury, Amit; Moniaux, Nicolas; Ulrich, Alexis; Schmied, Bruno M.; Standop, Jens; Pour, Parviz M.; Gendler, Sandra J.; Hollingsworth, Michael A.; Jp, Aubert; Batra, Surinder K.

doi:10.1038/sj.bjc.6601604

Cited by 26 publications

(19 citation statements)

References 49 publications

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“…This result does not agree with a previous similar study [23] in pancreatic cancer cell lines, implying that not only methylation but also other mechanisms, including histone modification [22], various transcription factors, growth factors, cytokines and other components [36][37][38][39][40] may regulate the expression of MUC4 in vivo.…”

Section: Discussioncontrasting

confidence: 74%

The increase in the expression and hypomethylation of MUC4 gene with the progression of pancreatic ductal adenocarcinoma

et al. 2010

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The MUC4 gene could have a key role in the progression of pancreatic cancer, but the quantitative measurement of its expression in clinical tissue samples remains a challenge. The correlations between MUC4 promoter methylation status in vivo and either pancreatic cancer progression or MUC4 mRNA expression need to be demonstrated. We used the techniques of quantitative real-time PCR and DNA methylation-specific PCR combined microdissection to precisely detect MUC4 expression and promoter methylation status in 116 microdissected foci from 57 patients with pancreatic ductal adenocarcinoma. Both mRNA expression and hypomethylation frequency increased from normal to precancerous lesions to pancreatic cancer. Multivariate Cox regression analysis showed that high-level MUC4 expression (P = 0.008) and tumor-node-metastasis staging (P = 0.038) were significant independent risk factors for predicting the prognosis of 57 patients. The MUC4 mRNA expression was not significantly correlated with promoter methylation status in 30 foci of pancreatic ductal adenocarcinoma. These results suggest that high mRNA expression and hypomethylation of the MUC4 gene could be involved in carcinogenesis and in the malignant development of pancreatic ductal adenocarcinoma. The MUC4 mRNA expression may become a new prognostic marker for pancreatic cancer. Microdissection-based quantitative real-time PCR and methylation-specific PCR contribute to the quantitative detection of MUC4 expression in clinical samples and reflect the epigenetic regulatory mechanisms of MUC4 in vivo.

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Section: Discussioncontrasting

confidence: 74%

The increase in the expression and hypomethylation of MUC4 gene with the progression of pancreatic ductal adenocarcinoma

et al. 2010

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“…Alterations in glycosylation influence growth, differentiation, transformation, adhesion, metastasis, and immune surveillance of the tumor (4). In breast cancer, the presence of increasing concentrations of highly glycosylated proteins (mucins) and other changes in glycosylation correlate with increasing tumor burden and poor prognosis (3).…”

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confidence: 99%

A Serum Glycomics Approach to Breast Cancer Biomarkers

Kirmiz

et al. 2007

Molecular & Cellular Proteomics

215

207

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Because the glycosylation of proteins is known to change in tumor cells during the development of breast cancer, a glycomics approach is used here to find relevant biomarkers of breast cancer. These glycosylation changes are known to correlate with increasing tumor burden and poor prognosis. Current antibody-based immunochemical tests for cancer biomarkers of ovarian (CA125), breast (CA27.29 or CA15-3), pancreatic, gastric, colonic, and carcinoma (CA19-9) target highly glycosylated mucin proteins. However, these tests lack the specificity and sensitivity for use in early detection. This glycomics approach to find glycan biomarkers of breast cancer involves chemically cleaving oligosaccharides (glycans) from glycosylated proteins that are shed or secreted by breast cancer tumor cell lines. The resulting free glycan species are analyzed by MALDI-FT-ICR MS. Further structural analysis of the glycans can be performed in FTMS through the use of tandem mass spectrometry with infrared multiphoton dissociation. Glycan profiles were generated for each cell line and compared. These methods were then used to analyze sera obtained from a mouse model of breast cancer and a small number of serum samples obtained from human patients diagnosed with breast cancer or patients with no known history of breast cancer. In addition to the glycosylation changes detected in mice as mouse mammary tumors developed, glycosylation profiles were found to be sufficiently different to distinguish patients with cancer from those without. Although the small number of patient samples analyzed so far is inadequate to make any legitimate claims at this time, these promising but very preliminary results suggest that glycan profiles may contain distinct glycan biomarkers that may correspond to glycan "signatures of cancer." Molecular & Cellular Proteomics 6:43-55, 2007.

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“…17 The microenvironment has also been shown to modify the phenotype of pancreatic cancer cells in xenografts. 18 For CDX2 in the context of CRCs, histopathological analyses have reported that gene expression is low in invasive cells but restored in metastases at the level corresponding to the primary tumors. 3 However, there was still no experimental evidence for the dynamic nature and reversibility of these CDX2 changes.…”

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confidence: 99%

The Microenvironment Controls CDX2 Homeobox Gene Expression in Colorectal Cancer Cells

Benahmed¹,

Groß²,

Guenot³

et al. 2007

The American Journal of Pathology

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The homeobox gene CDX2 plays a major role in development, especially in the gut, and it also acts as a tumor suppressor in the adult colon. Using orthotopic and heterotopic xenografts of human primary colorectal tumor cells and cell lines in nude mice, we addressed the effect of the microenvironment on CDX2 expression. In cells expressing CDX2 at a high level in culture, this level was maintained in subcutaneous grafts but was reduced when implanted into the cecum wall. Reciprocally, in cells with low CDX2 expression in culture, the level remained low in grafts into the cecum wall but was stimulated subcutaneously. In vitro co-cultures showed that CDX2 expression was activated in cells grown on layers of skin fibroblasts but not on intestinal fibroblasts. The stimulation was transcriptional, as assessed by transfection experiments with reporter plasmids containing the murine Cdx2 promoter. Together, these data demonstrate experimentally that CDX2 expression is adaptable and strongly dependent on the microenvironment surrounding the tumor cells. We exclude a role of the Notch pathway in this regulation. The regulation of CDX2 by the microenvironment might be relevant during the process of metastatic dissemination when the gene is transiently turned down in invasive cells. Colorectal cancer (CRC) is a major problem of public health because of its severity and high incidence. The severity is mainly attributable to the propensity of tumor cells to invade the stroma and eventually to disseminate into metastases. It is generally thought that the progression along the adenoma, carcinoma, metastasis sequence is accompanied by the accumulation of an increasing number of irreversible genomic alterations.1 In addition, reversible changes induced by the microenvironment facing malignant cells are also considered to be of prime importance for tumor cell invasion and metastatic dissemination.2 For instance, the epithelial-mesenchymal transition is a hallmark of invasive cells that escape the primary tumor, whereas the circulating tumor cells can undergo mesenchymal-epithelial transition at the homing site to form metastases.The major reversible changes reported in invasive cells spreading out from primary tumors include the decrease of membranous E-cadherin, the massive nuclear translocation of ␤-catenin, the activation of the cell cycle inhibitor p16, and the intracellular accumulation of the basement membrane molecule laminin-␥2. 2 Recently, a careful analysis of primary CRCs and liver metastases led us to show that invasive CRC cells are also characterized by a reversible decline of the intestine-specific homeoprotein CDX2.3 CDX2 is a transcription factor that plays a central role in embryos to define the organ-specific identity of the presumptive gut endoderm. 4 -7 At the adult stage, it belongs to the network that controls proliferation and differentiation of the continuously renewing gut epithelium.8,9 CDX2 also has a tumor suppressor function in the colon, because Cdx2 ϩ/Ϫ mice are hypersensitive to CRC progression in...

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MUC4 mucin expression in human pancreatic tumours is affected by organ environment: the possible role of TGFβ2

Cited by 26 publications

References 49 publications

The increase in the expression and hypomethylation of MUC4 gene with the progression of pancreatic ductal adenocarcinoma

The increase in the expression and hypomethylation of MUC4 gene with the progression of pancreatic ductal adenocarcinoma

A Serum Glycomics Approach to Breast Cancer Biomarkers

The Microenvironment Controls CDX2 Homeobox Gene Expression in Colorectal Cancer Cells

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