Glycosylation Characteristics of Colorectal Cancer

Holst, Stephanie; Wuhrer, Manfred; Rombouts, Yoann

doi:10.1016/bs.acr.2014.11.004

Cited by 124 publications

(140 citation statements)

References 247 publications

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“…Downregulation of both these genes has been previously shown to lead to enhanced cell migration and invasion, resulting in aggressive cancers, consistent with our results showing FUT9 knockdown leads to increased colony formation and cell migration (Fig 3D and F) (Huang et al , 2006; Chiu et al , 2011). Previous studies in colorectal cancer have shown that higher levels of core 1 glycans, T antigen, and Tn antigen are the most predominantly observed O‐glycosylation changes (Holst et al , 2015). Consistent with this, loss of FUT9 showed an upregulation of the N‐acetylgalactosaminyl transferases, GALNT8 (fold change = 11.80), GALNT13 (fold change = 4.21), and GALNT12 (fold change = 1.94) (Appendix Fig S3B).…”

Section: Resultsmentioning

confidence: 98%

An integrated computational and experimental study uncovers FUT 9 as a metabolic driver of colorectal cancer

Auslander

Cunningham

Toosi

et al. 2017

Molecular Systems Biology

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Metabolic alterations play an important role in cancer and yet, few metabolic cancer driver genes are known. Here we perform a combined genomic and metabolic modeling analysis searching for metabolic drivers of colorectal cancer. Our analysis predicts FUT9, which catalyzes the biosynthesis of Ley glycolipids, as a driver of advanced‐stage colon cancer. Experimental testing reveals FUT9's complex dual role; while its knockdown enhances proliferation and migration in monolayers, it suppresses colon cancer cells expansion in tumorspheres and inhibits tumor development in a mouse xenograft models. These results suggest that FUT9's inhibition may attenuate tumor‐initiating cells (TICs) that are known to dominate tumorspheres and early tumor growth, but promote bulk tumor cells. In agreement, we find that FUT9 silencing decreases the expression of the colorectal cancer TIC marker CD44 and the level of the OCT4 transcription factor, which is known to support cancer stemness. Beyond its current application, this work presents a novel genomic and metabolic modeling computational approach that can facilitate the systematic discovery of metabolic driver genes in other types of cancer.

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Section: Resultsmentioning

confidence: 98%

An integrated computational and experimental study uncovers FUT 9 as a metabolic driver of colorectal cancer

Auslander

Cunningham

Toosi

et al. 2017

Molecular Systems Biology

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“…The Tn and sialyl-Tn epitopes appear to be colon cancer-associated antigens that act as markers of poorly differentiated adeno- and mucinous carcinomas [49]. Of colon carcinoma tissues, 82% express Tn antigens, and 73% express STn antigens on mucins in the cytoplasm or in luminal cell membranes [50].…”

Section: Discussionmentioning

confidence: 99%

Mucins and associated glycan signatures in colon adenoma–carcinoma sequence: Prospective pathological implication(s) for early diagnosis of colon cancer

et al. 2016

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Development of biomarkers that detect early stage resectable premalignant lesions of colon can provide critical aid in prevention of colorectal cancer. Recent evidences advocate the utility of mucin expression to predict malignant transformation of colon pre-neoplastic lesions. In this study, we investigated the combined expression of multiple mucins and mucin-associated glycans during the adenoma-carcinoma sequence of colon cancer progression. Further, we evaluated their applicability as markers for differentiating adenomas/adenocarcinomas from hyperplastic polyps. Immunohistochemical analyses performed on colon disease tissue microarrays revealed that MUC2, MUC4 expression were downregulated (p<0.0001) and MUC1, MUC5AC expression were upregulated (p=0.01) during adenoma-adenocarcinoma progression. Expression of MUC17 was downregulated in inflamed tissues compared to normal tissues, but its increased expression differentiated adenomas (p=0.0028) and adenocarcinomas (p=0.025) from inflammation. MUC1 specific glycan-Tn/STn-MUC1 showed higher expression in hyperplastic polyps (p=0.023), adenomas (p=0.042) and adenocarcinomas (p=0.0096) compared to normal. Multivariate regression analyses indicated that a combination of MUC2, MUC5AC, and MUC17 could effectively discriminate adenoma-adenocarcinoma from hyperplastic polyps. Altogether, a combined analysis of altered mucins and mucin-associated glycans is a useful approach to distinguish premalignant/malignant lesions of colon from benign polyps.

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“…High mannose N-glycans could be an indicator of an embryonic, undifferentiated phenotype 45 . Increased expression of high mannose type N-glycans also have been observed in colorectal cancer cell lines of varying malignancy 46-48 and in breast cancer cell lines and tissue 49-51 . The biological significance of this glycomic alteration in cancer is not clear, yet the presence of high (truncated) mannose indicates some level of incomplete N-linked glycosylation prossessing 52 .…”

Section: Discussionmentioning

confidence: 89%

Integrated Transcriptomic and Glycomic Profiling of Glioma Stem Cell Xenografts

Wildburger¹,

Zhou

Zacharias

et al. 2015

J. Proteome Res.

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Bone marrow-derived human mesenchymal stem cells (BM-hMSCs) have the innate ability to migrate or home towards, and engraft in tumors such as glioblastoma (GBM). Due to this unique property of BM-hMSCs we have explored their use for cell-mediated therapeutic delivery for the advancement of GBM treatment. Extravasation, the process by which blood-borne cells – such as BM-hMSCs – enter the tissue is a highly complex process but is heavily dependent upon glycosylation for glycan-glycan and glycan-protein adhesion between the cell and endothelium. However, in a translationally significant pre-clinical glioma stem cell xenograft (GSCX) model of GBM, BM-hMSCs demonstrate unequal tropism towards these tumors. We hypothesized that there may be differences in the glycan compositions between the GSCXs that elicit homing (“attractors”) and those that do not (“non-attractors”) that facilitate or impede the engraftment of BM-hMSCs to the tumor. In this study, glycotranscriptomic analysis revealed significant heterogeneity within the attractor phenotype and the enrichment of high mannose type N-glycan biosynthesis in the non-attractor phenotype. Orthogonal validation with topical PNGase F deglycosylation on the tumor regions of xenograft tissue, followed by nLC-ESI-MS, confirmed the presence of increased high mannose type N-glycans in the non-attractors. Additional evidence provided by our glycomic study revealed the prevalence of terminal sialic acid-containing N-glycans in non-attractors and terminal galactose and N-acetyl-glucosamine N-glycans in attractors. Our results provide the first evidence for differential glycomic profiles in attractor and non-attractor GSCXs and extend the scope of molecular determinates in BM-hMSC homing to glioma.

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Glycosylation Characteristics of Colorectal Cancer

Cited by 124 publications

References 247 publications

An integrated computational and experimental study uncovers FUT 9 as a metabolic driver of colorectal cancer

An integrated computational and experimental study uncovers FUT 9 as a metabolic driver of colorectal cancer

Mucins and associated glycan signatures in colon adenoma–carcinoma sequence: Prospective pathological implication(s) for early diagnosis of colon cancer

Integrated Transcriptomic and Glycomic Profiling of Glioma Stem Cell Xenografts

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