The O‐ glycan branching enzyme, core2 β ‐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.

α-Dystroglycan (α-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 α-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 α-DG in tumor progression. In aggressive prostate and breast carcinoma cell lines, laminin-binding glycans are dramatically decreased, although the amount of α-DG and β-dystroglycan is maintained. The decrease of laminin-binding glycans and consequent increased cell migration were associated with the decreased expression of β3- N -acetylglucosaminyltransferase-1 (β3GnT1). Forced expression of β3GnT1 in aggressive cancer cells restored the laminin-binding glycans and decreased tumor formation. β3GnT1 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 β3GnT1 and LARGE.

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.

Neoadjuvant chemotherapy (NAC) use for patients with locally advanced upper tract urothelial carcinoma (UTUC) is debatable. To investigate the efficacy and safety of platinum-based NAC for locally advanced UTUC. Of 233 consecutive patients who underwent radical nephroureterectomy, 55 patients received NAC (NAC group) and 138 patients did not (Ctrl group). The two arms (Ctrl vs NAC) were matched using propensity scores to minimize selection bias. We retrospectively evaluated tumor response, post-therapy pathological downstaging, lymphovascular invasion, Ki67 status, and prognosis between pair-matched patients. Multivariate Cox regression analysis was performed for independent factors for prognosis. We selected 51 pair-matched patients in each group. The regimens in the NAC group included gemcitabine and carboplatin, and gemcitabine and cisplatin. The median response rate in the NAC group was 28%. NAC-related adverse events were tolerable. Pathological downstaging of the primary tumor was significantly higher in the NAC group than in the Ctrl group. The MIB1 index (immunostaining for Ki67) was significantly higher in the NAC group. NAC for locally advanced UTUC significantly prolonged progression-free, cancer-specific, and overall survival. Multivariate Cox regression analysis using an inverse probability of treatment weighting method showed that NAC was selected as an independent predictor for prolonged cancer-specific survival. Limitations are the retrospective design and the small sample size. Platinum-based NAC for advanced UTUC potentially improves oncological outcomes. Further prospective studies are needed. 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.

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.