Chemotherapy, radiation, and growth inhibitory drugs preferentially eliminate actively growing cancer cells. Cancer recurrence is currently thought to be due to nondividing cancer stem/progenitor cells that are resistant to these therapies. Different therapeutic approaches need to be considered for the elimination of the cancer stem cell population. Immunotherapy is one such approach. In addition to specificity and lack of toxicity, immunotherapy targets cancer cells irrespective of their state of proliferation, as long as they express particular tumor antigens. For that reason, it is important to examine if the tumor antigens that are currently being tested as immunotherapeutic agents are also present on cancer stem cells. This study aimed to determine if one well-known tumor antigen, MUC1, which is being tested as an immunotherapy target on tumor cells, is also expressed on the quiescent cancer stem/progenitor cells. We used the so-called side population (SP) cells found in the MCF7 breast cancer cell line, which we first confirmed by cell surface markers and gene profiling to be highly enriched in cells that fulfill specific functional, phenotypic, and molecular criteria for being tumor stem/progenitor cells. We show that these cells express MUC1 and give rise to MUC1 + tumors in vivo, which maintain the MUC1 + SP population. MUC1 on SP cells is hypoglycosylated and heavily sialylated; the characteristics of the tumorspecific form were expressed on mature cancer cells and recognized by tumor-specific T cells and antibodies. This suggests that stem/progenitor cells, like mature tumor cells, would be targets of MUC1-directed immunotherapy. [Cancer Res 2008;68(7):2419-26]
Purpose: Overexpression of MUC1 and cytosolic interaction of the mucin with -catenin are claimed to be involved in colorectal carcinogenesis. In vitro data published recently suggest that MUC1 overexpression results in an increase of steady state levels of nuclear -catenin. We tried to elucidate the coexpression of both molecules in colorectal cancer to demonstrate possible correlations with clinical, pathological, and prognostic data.Experimental Design: An immunohistochemical double staining study was performed to characterize the expression and subcellular distribution of MUC1 and -catenin in a series of 205 patients with colorectal carcinoma. The results were correlated with clinicopathological variables as well as overall survival.Results: MUC1 was strongly expressed in the tumor center and at the invasion front in ϳ50% of the cases. Similar results were obtained with regard to nuclear accumulation of -catenin at the invasive tumor parts. MUC1 protein expression in the tumor center correlated significantly with a low grade of differentiation, and nuclear -catenin in the tumor periphery was more frequent in carcinomas of the left colon and rectum. Overexpression of MUC1 and -catenin, as well as their nuclear coexpression at the invasion front correlated with a worse overall survival in an univariate analysis. However, only pathological tumornode-metastasis staging and MUC1 at the invasion front revealed as independent prognostic factors. Conclusions:These results suggest that MUC1 and -catenin are coexpressed at the invasion front of colorectal carcinomas and that this feature is associated with an accelerated course of disease and worse prognosis.
Mucins represent a family of glycoproteins characterized by repeat domains and a dense O-glycosylation. During the last two decades, the gene and peptide structures of various mucins as well as their glycosylation states were partly elucidated. Characteristic tumor-associated alterations of the expression patterns and glycosylation profiles were observed in biochemical, immunochemical, and histological studies and are discussed in the light of efforts to use the most prominent member in this family, MUC1, as a tumor target in anti-tumor strategies. Within this context the present review, focusing on MUC1, describes recent work on the regulation of mucin biosynthesis by cytokines and hormones, the role of mucins in cell adhesion, and their interaction with the immune system. Important aspects of clinical diagnostics based on mucin antigens are discussed, including the application of tumor serum assays and the significance of numerous studies revealing correlations between the expression of peptide cores or mucin-associated carbohydrates and clinicopathological parameters like tumor progression and prognosis.
The human mucin MUC1 is expressed both as a transmembrane heterodimeric protein complex that recycles via the trans-Golgi network (TGN) and as a secreted isoform. To determine whether differences in cellular trafficking might influence the O-glycosylation profiles on these isoforms, we developed a model system consisting of membrane-bound and secretory-recombinant glycosylation probes. Secretory MUC1-S contains only a truncated repeat domain, whereas in MUC1-M constructs this domain is attached to the native transmembrane and cytoplasmic domains of MUC1 either directly (M0) or via an intermitting nonfunctional (M1) or functional sperm protein-enterokinase-agrin (SEA) module (M2); the SEA module contains a putative proteolytic cleavage site and is associated with proteins receiving extensive O-glycosylation. We showed that MUC1-M2 simulates endogenous MUC1 by recycling from the cell surface of Chinese hamster ovary (CHO) mutant ldlD14 cells through intracellular compartments where its glycosylation continues. The profiles of O-linked glycans on MUC1-S secreted by epithelial EBNA-293 and MCF-7 breast cancer cells revealed patterns dominated by core 2-based oligosaccharides. In contrast, the respective membrane-shed probes expressed in the same cells showed a complete shift to patterns dominated by sialyl core 1. In conclusion, glycan core profiles reflected the subcellular trafficking pathways of the secretory or membranous probes and the modifying activities of the resident glycosyltransferases.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.