␣-Dystroglycan (␣-DG) represents a highly glycosylated cell surface molecule that is expressed in the epithelial cell-basement membrane (BM) interface and plays an essential role in epithelium development and tissue organization. The ␣-DG-mediated epithelial cell-BM interaction is often impaired in invasive carcinomas, yet roles and underlying mechanisms of such an impaired interaction in tumor progression remain unclear. We report here a suppressor function of laminin-binding glycans on ␣-DG in tumor progression. In aggressive prostate and breast carcinoma cell lines, lamininbinding glycans are dramatically decreased, although the amount of ␣-DG and -dystroglycan is maintained. The decrease of lamininbinding glycans and consequent increased cell migration were associated with the decreased expression of 3-N-acetylglucosaminyltransferase-1 (3GnT1). Forced expression of 3GnT1 in aggressive cancer cells restored the laminin-binding glycans and decreased tumor formation. 3GnT1 was found to be required for laminin-binding glycan synthesis through formation of a complex with LARGE, thus regulating the function of LARGE. Interaction of the laminin-binding glycans with laminin and other adhesive molecules in BM attenuates tumor cell migratory potential by antagonizing ERK/AKT phosphorylation induced by the components in the ECM. These results identify a previously undescribed role of carbohydrate-dependent cell-BM interaction in tumor suppression and its control by 3GnT1 and LARGE.glycosylation ͉ cell adhesion ͉ basement membrane ͉ carcinoma I nteraction of epithelial cells with basement membrane (BM) is mediated by cell adhesion molecules, which operate at the interface of epithelial cell-ECM and regulate cell growth, motility, and differentiation by integrating signals from ECM or soluble factors (1-3). One of the most important epithelial cell-BM interactions is mediated by ␣-dystroglycan (␣-DG) on epithelial cells (4).␣-DG is a cell surface receptor for several major BM proteins, including laminin, perlecan, and agrin. A laminin G-like domain in all these glycoproteins binds to a unique glycan structure attached to ␣-DG, and this interaction has been shown to be critical in assembling BM (5, 6). This unique glycan structure is referred to as laminin-binding glycans hereafter. ␣-DG is not attached directly to the plasma membrane but is bound to it through attachment to the transmembrane protein -dystroglycan (-DG), which binds to the cytoplasmic protein dystrophin, which, in turn, binds to the actin cytoskeleton and many adaptor molecules involved in cellular signaling (4,5).␣-DG is highly glycosylated and contains both N-linked glycans and mucin type O-glycans. The mucin type O-glycans are clustered in a mucin-like domain at the N-terminal of mature ␣-DG, which includes unique O-mannosyl glycans and sialic acid ␣233Gal134GlcNAc132Man␣13Ser/Thr (7). Defects in glycosylation of the O-mannosyl glycans have been shown to cause muscular dystrophy (8). So far, 7 glycosyltransferases or glycosyltransferase-like ...
The O-glycan branching enzyme, core2 b-1,6-N-acetylglucosaminyltransferase (C2GnT), forms O-glycans containing an N-acetylglucosamine branch connected to N-acetylgalactosamine (core2 O-glycans) on cell-surface glycoproteins. Here, we report that upregulation of C2GnT is closely correlated with progression of bladder tumours and that C2GnT-expressing bladder tumours use a novel strategy to increase their metastatic potential. Our results showed that C2GnT-expressing bladder tumour cells are highly metastatic due to their high ability to evade NK cell immunity and revealed the molecular mechanism of the immune evasion by C2GnT expression. Engagement of an NK-activating receptor, NKG2D, by its tumour-associated ligand, Major histocompatibility complex class I-related chain A (MICA), is critical to tumour rejection by NK cells. In C2GnT-expressing bladder tumour cells, poly-N-acetyllactosamine was present on core2 O-glycans on MICA, and galectin-3 bound the NKG2D-binding site of MICA through this poly-N-acetyllactosamine. Galectin-3 reduced the affinity of MICA for NKG2D, thereby severely impairing NK cell activation and silencing the NK cells. This new mode of NK cell silencing promotes immune evasion of C2GnT-expressing bladder tumour cells, resulting in tumour metastasis.
Although numerous carbohydrates play significant roles in mammalian cells, carbohydrate-based drug discovery has not been explored due to the technical difficulty of chemically synthesizing complex carbohydrate structures. Previously, we identified a series of carbohydrate mimetic peptides and found that a 7-mer peptide, designated I-peptide, inhibits hematogenous carbohydrate-dependent cancer cell colonization. During analysis of the endothelial surface receptor for I-peptide, we found that I-peptide bound to annexin 1 (Anxa1). Because Anxa1 is a highly specific tumor vasculature surface marker, we hypothesized that an I-peptide-like peptide could target anticancer drugs to the tumor vasculature. This study identifies IFLLWQR peptide, designated IF7, as homing to tumors. When synthetic IF7 peptide was conjugated to fluorescent Alexa 488 (A488) and injected intravenously into tumor-bearing mice, IF7-A488 targeted tumors within minutes. IF7 conjugated to the potent anticancer drug SN-38 and injected intravenously into nude mice carrying human colon HCT116 tumors efficiently suppressed tumor growth at low dosages with no apparent side effects. These results suggest that IF7 serves as an efficient drug delivery vehicle by targeting Anxa1 expressed on the surface of tumor vasculature. Given its extremely specific tumor-targeting activity, IF7 may represent a clinically relevant vehicle for anticancer drugs.angiogenesis | carbohydrate binding protein | geldanamycin | phage display | chemiluminescence
SUMMARY Heparan sulfate can bind several adhesion molecules involved in lymphocyte trafficking. However, the in vivo function of endothelial heparan sulfate in lymphocyte homing and stimulation of the immune response has not been elucidated. Here, we generated mutant mice deficient in the enzyme Ext1, which is required for heparan sulfate synthesis, in a Tek-dependent and inducible manner. Chemokine presentation was diminished in the mutant mice, causing the lack of appropriate integrin-mediated adhesion, and resulted in a marked decrease in lymphocyte sticking to high endothelial venules and in recruitment of resident dendritic cells through lymphatic vessels to the lymph nodes. As a consequence, mutant mice displayed a severe impairment in lymphocyte homing and a compromised contact hypersensitivity response. By contrast, lymphocyte rolling was increased due to loss of electrostatic repulsion by heparan sulfate. These results demonstrate critical roles of endothelial heparan sulfate in immune surveillance and immune response generation.
Cancer cells often express surface carbohydrates different from normal cells (1). One such change is expression of sialyl Lewis X and Lewis B blood group antigens in cancer cells (2, 3). These structural elements are seen as capping oligosaccharides attached to the underlying glycan backbone where they likely function as ligands for cell adhesion molecules.The structure of underlying glycans also changes during malignant transformation and differentiation. In particular, there are several reports that an increase in the 1,6-N-acetylglucosaminyl branch in N-glycans synthesized by 1,6-Nacetylglucosaminyltransferase-V is associated with oncogenic transformation (4 -7). Similar structural changes are seen in mucin-type O-glycans, which have N-acetylgalactosamine at the reducing end linked to polypeptide threonine or serine residues. Addition of different carbohydrate residues to N-acetylgalactosamine confers a variety of backbone structures on mucin-type O-glycans; the most abundant of those are classified as core1, core2, core3, and core4 O-glycans (8) (Fig.
The application of prostate-specific antigen (PSA) in prostate cancer (PC) screening, diagnosis, and prognosis has improved the clinical management of PC patients. However, the PSA assay has been faced with criticism due to its potential association with over-diagnosis and subsequent overtreatment of patients with indolent disease. The United States Preventive Services Task Force incited much debate over PSA-based screening in 2012 by recommending against this approach. However, the PSA assay remains the first-line tool for the early detection of PC. This debate highlights the unmet need for non-invasive PC biomarkers with greater sensitivity and specificity that are capable of distinguishing aggressive disease from indolent disease, predicting treatment response, and guiding treatment decisions. Recent investigations into putative PC biomarkers have focused on PSA isoform assays (prostate health index, 4-kallikurein panel), PC-associated genes in the urine (PCA3 and TMPRSS2-ERG), glycan-associated biomarkers (S2, 3PSA, GCNT1, and tri- and tetra-antennary serum N-glycans), and circulating tumor cells. Although substantial efforts to identify novel PC biomarkers that might replace PSA have been put forth, the majority of the putative PC biomarkers reported in the last few years are still under investigation or validation. This review provides an overview of the current state of PC biomarker research and focuses on a few promising PC biomarkers in development.
Platinum-based neoadjuvant chemotherapy for locally advanced upper tract urothelial carcinoma was safe and potentially improves oncological outcomes. A carboplatin-based regimen may be used as an alternative in patients with impaired renal function.
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