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Sclerotium rolfsii lectin induces opposite effects on normal PBMCs and leukemic Molt-4 cells by recognising TF antigen and its variants as receptors. Glycoconj J 2020; 37:251-261. [PMID: 31900725 DOI: 10.1007/s10719-019-09905-y] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2019] [Revised: 11/13/2019] [Accepted: 12/20/2019] [Indexed: 01/02/2023]
Abstract
Sclerotium rolfsii lectin (SRL) exerts apoptotic effect against various cancer cells and an antitumor activity on mice with colon and breast cancer xenografts. The current study aimed to explore its exquisite carbohydrate specificity on human peripheral blood mononuclear cells (PBMCs) and leukemic T-cells. SRL, showed strong binding (>98%) to resting/activated PBMCs, leukemic Molt-4 and Jurkat cell lines. The glycans mediated binding to these cells was effectively blocked by mucin and fetuin, exhibiting 97% and 94% inhibition respectively. SRL showed mitogenic stimulation of PBMCs at 10 μg/ml as determined by thymidine incorporation assay. In contrast, lectin induced a dose dependent growth inhibition of Molt-4 cells with 58% inhibition at 25 μg/ml. Many common membrane receptors in activated PBMCs, Molt 4 and Jurkat cells were identified by lectin blotting. However, membrane receptors that are recognized by SRL in normal resting PBMCs were totally different and are high molecular weight glycoproteins. Treatment of membrane receptors with glycosidases prior to lectin probing, revealed that fucosylated Thomsen-Friedenreich(TF) antigen glycans are increasingly expressed on transformed Molt-4 leukemic cells compared to other cells. The findings highlight the opposite effects of SRL on transformed and normal hematopoietic cells by recognizing different glycan-receptors. SRL has promising potential for diagnostics and therapeutic applications in leukaemia.
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Heublein S, Egger M, Zhu J, Berger L, Mayr D, Schindlbeck C, Kuhn C, Hofmann SS, Schuetz F, Jeschke U, Ditsch N. Evaluation of the anti-Thomsen-Friedenreich antibodies Nemod-TF1 and Nemod-TF2 as prognostic markers in breast cancer. Breast Cancer Res Treat 2019; 179:643-652. [PMID: 31828591 DOI: 10.1007/s10549-019-05503-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2019] [Accepted: 11/19/2019] [Indexed: 10/25/2022]
Abstract
PURPOSE The TF (Thomsen-Friedenreich, CD176, Galβ1-3GalNAc) carbohydrate moiety is known as a specific oncofetal carbohydrate epitope present in fetal and neoplastic tissue as well as in stem cells. TF was demonstrated to mediate tumor-promoting features and to be highly immunogenic. The current study aimed to evaluate whether presence of the TF antigen is associated with clinico-pathological parameters and prognosis of early breast cancer (BC). METHODS Primary BC tissue (n = 226) was stained for TF using two monoclonal anti-TF antibodies (Nemod-TF1, Nemod-TF2). Staining results were correlated to clinical data including survival. RESULTS Nemod-TF1 staining was positively correlated to lymph node metastasis (p = 0.03) and the presence of tumor-associated MUC1 (TA-MUC1; p = 0.003). Further, the presence of the Nemod-TF1 epitope predicted worse prognosis in TA-MUC1 positive (overall survival: p = 0.026) as well as in triple negative (overall survival: p = 0.002; distant metastasis-free survival: p = 0.012) BC. CONCLUSIONS The data presented here further support a role of TF in BC tumor biology. Whether anti-TF directed treatment approaches may gain clinical relevance in those cases determined as triple negative or TA-MUC1 positive remains to be determined.
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Affiliation(s)
- Sabine Heublein
- Department of Obstetrics and Gynecology, Heidelberg University Hospital, Heidelberg, Germany. .,Department of Obstetrics and Gynecology, Ludwig-Maximilians-University of Munich, Munich, Germany.
| | - Markus Egger
- Department of Obstetrics and Gynecology, Ludwig-Maximilians-University of Munich, Munich, Germany.,St. Anna Kinderspital, Vienna, Austria
| | - Junyan Zhu
- Department of Obstetrics and Gynecology, Ludwig-Maximilians-University of Munich, Munich, Germany
| | - Luisa Berger
- Department of Obstetrics and Gynecology, Ludwig-Maximilians-University of Munich, Munich, Germany
| | - Doris Mayr
- Department of Pathology, Ludwig-Maximilians-University of Munich, Munich, Germany
| | | | - Christina Kuhn
- Department of Obstetrics and Gynecology, Ludwig-Maximilians-University of Munich, Munich, Germany
| | - Simone S Hofmann
- Department of Obstetrics and Gynecology, Ludwig-Maximilians-University of Munich, Munich, Germany
| | - Florian Schuetz
- Department of Obstetrics and Gynecology, Heidelberg University Hospital, Heidelberg, Germany
| | - Udo Jeschke
- Department of Obstetrics and Gynecology, Ludwig-Maximilians-University of Munich, Munich, Germany.,Department of Obstetrics and Gynecology, University Hospital Augsburg, Augsburg, Germany
| | - Nina Ditsch
- Department of Obstetrics and Gynecology, Ludwig-Maximilians-University of Munich, Munich, Germany.,Department of Obstetrics and Gynecology, University Hospital Augsburg, Augsburg, Germany
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Barton S, Li B, Siuta M, Vaibhav J, Song J, Holt CM, Tomono T, Ukawa M, Kumagai H, Tobita E, Wilson K, Sakuma S, Pham W. SPECIFIC MOLECULAR RECOGNITION AS A STRATEGY TO DELINEATE TUMOR MARGIN USING TOPICALLY APPLIED FLUORESCENCE EMBEDDED NANOPARTICLES. PRECISION NANOMEDICINE 2018; 1:194-207. [PMID: 31773101 DOI: 10.33218/prnano1(3).181009.1] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/15/2023] Open
Abstract
The Thomsen-Friedenreich (TF) antigen is a tumor-associated antigen consistently expressed on the apical surface of epithelial-based cancer cells, including pancreatic cancer. In this work, we report the development of multimodal imaging probe, the tripolymer fluorescent nanospheres, whose surface was fabricated with peanut agglutinin (PNA) moieties as TF molecular recognition molecules. Here, we demonstrate that the probe is able to detect TF antigen in human pancreatic cancer tissues and differentiate from normal tissue. What is most noteworthy regarding the probe is its ability to visualize tumor margins defined by epithelial TF antigen expression. Further, in vivo preclinical studies using an orthotopic mouse model of pancreatic cancer suggest the potential use of the nanospheres for laparoscopic imaging of pancreatic cancer tumor margins to enhance surgical resection and improve clinical outcomes.
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Affiliation(s)
- Shawn Barton
- Vanderbilt University Institute of Imaging Science, Nashville, TN
| | - Bo Li
- Vanderbilt University Institute of Imaging Science, Nashville, TN
| | - Michael Siuta
- Vanderbilt University Institute of Imaging Science, Nashville, TN
| | - Janve Vaibhav
- Vanderbilt University Institute of Imaging Science, Nashville, TN
| | - Jessica Song
- Vanderbilt University Institute of Imaging Science, Nashville, TN
| | - Clinton M Holt
- Vanderbilt University Institute of Imaging Science, Nashville, TN
| | - Takumi Tomono
- Faculty of Pharmaceutical Sciences, Setsunan University, Hirakata, Osaka, Japan
| | - Masami Ukawa
- Faculty of Pharmaceutical Sciences, Setsunan University, Hirakata, Osaka, Japan
| | | | - Etsuo Tobita
- Advanced Materials R&D Laboratory, ADEKA Corp., Tokyo, Japan
| | - Kevin Wilson
- Vanderbilt University Institute of Imaging Science, Nashville, TN
| | - Shinji Sakuma
- Faculty of Pharmaceutical Sciences, Setsunan University, Hirakata, Osaka, Japan
| | - Wellington Pham
- Vanderbilt University Institute of Imaging Science, Nashville, TN.,Department of Radiology and Radiological Sciences, Vanderbilt University, Nashville, TN.,Department of Biomedical Engineering, Vanderbilt University, Nashville, TN.,Vanderbilt Ingram Cancer Center, Vanderbilt School of Medicine Nashville, TN.,Vanderbilt Brain Institute, Nashville, Vanderbilt University, TN.,Vanderbilt Institute of Chemical Biology, Nashville, TN
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Heublein S, Page SK, Mayr D, Ditsch N, Jeschke U. p53 determines prognostic significance of the carbohydrate stem cell marker TF1 (CD176) in ovarian cancer. J Cancer Res Clin Oncol 2016; 142:1163-70. [PMID: 26935926 DOI: 10.1007/s00432-016-2126-3] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2015] [Accepted: 01/28/2016] [Indexed: 01/01/2023]
Abstract
INTRODUCTION The oncofoetal Thomsen-Friedenreich (TF1, CD176) epitope is a carbohydrate cancer stem cell (CSC) antigen, and TF1-mediated cancer progression can be widely reversed by anti-TF1 antibodies. Particularly, CSC-like cells are regarded to be tumorigenic and chemoresistant. Aberrant p53 is probably the factor most closely associated with chemoresistance and tumour aggressiveness in ovarian tumours. We thus questioned whether TF1 in combination with p53 or as a single marker may be related to clinico-pathological features and survival of ovarian cancer patients. PATIENTS AND METHODS Both markers were quantified in ovarian cancer tissue (n = 151) by immunohistochemistry. p53 staining was subdivided into three subgroups [n (completely negative) = 57, n (moderately stained) = 28, n (overexpressing) = 66]. TF1 was scored as positive (n = 30) versus negative (n = 121). RESULTS Only in those cancers classified with moderate p53 staining-and thus most likely displaying with wild-type TP53-TF1 positivity turned out to be a predictor for shortened overall survival (univariate: p < 0.001, multivariate: p = 0.001). By screening 17 different protein markers for correlation with TF1, only mucin-1 emerged as a potential TF1 carrier protein. CONCLUSION It is hypothesized that TF1 may confer tumour-promoting features, especially in a TP53 wild-type genetic background. In addition, TF1 is an attractive immunotherapeutic target. Whether those cases classified as TF1 positive and at the same time as moderately stained for p53 might particularly benefit from a future anti-TF1 antibody treatment or from TF1 vaccination therapy remains to be determined.
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Affiliation(s)
- Sabine Heublein
- Department of Obstetrics and Gynaecology - National Center for Tumor Diseases (NCT), Heidelberg University Hospital, Heidelberg, Germany.
- Department of Obstetrics and Gynaecology, Ludwig Maximilians University of Munich, Munich, Germany.
| | - Sabina K Page
- Department of Obstetrics and Gynaecology, Ludwig Maximilians University of Munich, Munich, Germany
| | - Doris Mayr
- Department of Pathology, Ludwig Maximilians University of Munich, Munich, Germany
| | - Nina Ditsch
- Department of Obstetrics and Gynaecology, Ludwig Maximilians University of Munich, Munich, Germany
| | - Udo Jeschke
- Department of Obstetrics and Gynaecology, Ludwig Maximilians University of Munich, Munich, Germany
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Corfield AP. Mucins: A biologically relevant glycan barrier in mucosal protection. Biochim Biophys Acta Gen Subj 2015; 1850:236-52. [PMID: 24821013 DOI: 10.1016/j.bbagen.2014.05.003] [Citation(s) in RCA: 368] [Impact Index Per Article: 36.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2013] [Revised: 04/05/2014] [Accepted: 05/02/2014] [Indexed: 02/08/2023]
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Heimburg-Molinaro J, Lum M, Vijay G, Jain M, Almogren A, Rittenhouse-Olson K. Cancer vaccines and carbohydrate epitopes. Vaccine 2011; 29:8802-26. [PMID: 21964054 PMCID: PMC3208265 DOI: 10.1016/j.vaccine.2011.09.009] [Citation(s) in RCA: 175] [Impact Index Per Article: 12.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2011] [Revised: 08/18/2011] [Accepted: 09/06/2011] [Indexed: 12/17/2022]
Abstract
Tumor-associated carbohydrate antigens (TACA) result from the aberrant glycosylation that is seen with transformation to a tumor cell. The carbohydrate antigens that have been found to be tumor-associated include the mucin related Tn, Sialyl Tn, and Thomsen-Friedenreich antigens, the blood group Lewis related Lewis(Y), Sialyl Lewis(X) and Sialyl Lewis(A), and Lewis(X) (also known as stage-specific embryonic antigen-1, SSEA-1), the glycosphingolipids Globo H and stage-specific embryonic antigen-3 (SSEA-3), the sialic acid containing glycosphingolipids, the gangliosides GD2, GD3, GM2, fucosyl GM1, and Neu5GcGM3, and polysialic acid. Recent developments have furthered our understanding of the T-independent type II response that is seen in response to carbohydrate antigens. The selection of a vaccine target antigen is based on not only the presence of the antigen in a variety of tumor tissues but also on the role this antigen plays in tumor growth and metastasis. These roles for TACAs are being elucidated. Newly acquired knowledge in understanding the T-independent immune response and in understanding the key roles that carbohydrates play in metastasis are being applied in attempts to develop an effective vaccine response to TACAs. The role of each of the above mentioned carbohydrate antigens in cancer growth and metastasis and vaccine attempts using these antigens will be described.
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Affiliation(s)
| | - Michelle Lum
- Department of Cellular and Molecular Biology, Roswell Park Cancer Institute, Buffalo, NY 14263
| | - Geraldine Vijay
- University of Texas, MD Anderson Cancer Center, Houston, Texas 77030
| | - Miten Jain
- Department of Biomolecular Engineering, University of California Santa Cruz, CA 95064
| | - Adel Almogren
- Department Of Pathology, College of Medicine, King Saud University, Riyadh, 11461 Saudi Arabia
| | - Kate Rittenhouse-Olson
- Department Of Pathology, College of Medicine, King Saud University, Riyadh, 11461 Saudi Arabia
- Department of Biotechnical and Clinical Laboratory Sciences, University at Buffalo, Buffalo, NY 14214
- Department of Microbiology and Immunology, University at Buffalo, Buffalo, NY 14214
- Department of Immunology, Roswell Park Cancer Institute, Buffalo, NY 14263
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Zhao Q, Guo X, Nash GB, Stone PC, Hilkens J, Rhodes JM, Yu LG. Circulating galectin-3 promotes metastasis by modifying MUC1 localization on cancer cell surface. Cancer Res 2009; 69:6799-806. [PMID: 19690136 DOI: 10.1158/0008-5472.can-09-1096] [Citation(s) in RCA: 124] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Adhesion of circulating tumor cells to the blood vessel endothelium is a critical step in cancer metastasis. We show in this study that galectin-3, the concentration of which is greatly increased in the circulation of cancer patients, increases cancer cell adhesion to macrovascular and microvascular endothelial cells under static and flow conditions, increases transendothelial invasion, and decreases the latency of experimental metastasis in athymic mice. These effects of galectin-3 are shown to be a consequence of its interaction with cancer-associated MUC1, which breaks the "protective shield" of the cell-surface MUC1 by causing MUC1 polarization, leading to exposure of smaller cell-surface adhesion molecules/ligands including CD44 and ligand(s) for E-selectin. Thus, the interaction in the bloodstream of cancer patients between circulating galectin-3 and cancer cells expressing MUC1 bearing the galectin-3 ligand TF (Galbeta1,3GalNAc-) promotes metastasis. This provides insight into the molecular regulation of metastasis and has important implications for the development of novel therapeutic strategies for prevention of metastasis.
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Affiliation(s)
- Qicheng Zhao
- Gastroenterology Research Unit, School of Clinical Sciences, University of Liverpool, Liverpool, United Kingdom
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Baldus SE, Engelmann K, Hanisch FG. MUC1 and the MUCs: A Family of Human Mucins with Impact in Cancer Biology. Crit Rev Clin Lab Sci 2008; 41:189-231. [PMID: 15270554 DOI: 10.1080/10408360490452040] [Citation(s) in RCA: 137] [Impact Index Per Article: 8.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/21/2023]
Abstract
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.
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Affiliation(s)
- Stephan E Baldus
- Institute of Pathology and Center of Biochemistry, University of Cologne, Cologne, Germany.
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9
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Abstract
Mucins are high molecular weight glycoproteins with complex oligosaccharide side chains attached to the apomucin protein backbone byO-glycosidic linkage; they are found in crude mucus gels that protect epithelial surfaces in the major tracts of the body and as transmembrane proteins expressed on the apical cell surface of glandular and ductal epithelia of various organs. Changes in the sequence of glycosylation of mucins in different settings generate a variety of epitopes in the oligosaccharide side chains of mucins, including newly expressed blood-group antigens, distinguishing between normal and diseased states. Tumour-associated epitopes on mucins and their antigenicity make them suitable as immunotargets on malignant epithelial cells and their secretions, creating a surge of interest in mucins as diagnostic and prognostic markers for various diseases, and even influencing the design of mucin-based vaccines. This review discusses the emerging roles of mucins such as MUC1 and MUC4 in cancer and some other diseases, and stresses how underglycosylated and truncated mucins are exploited as markers of disease and to monitor widespread metastasis, making them useful in patient management. Furthermore the type, pattern and amount of mucin secreted in some tissues have been considered in the classification and terminology of neoplasia and in specific organs such as the pancreas. These factors have been instrumental in pathological classification, diagnosis and prognostication of neoplasia.
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10
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Yu LG. The oncofetal Thomsen-Friedenreich carbohydrate antigen in cancer progression. Glycoconj J 2007; 24:411-20. [PMID: 17457671 DOI: 10.1007/s10719-007-9034-3] [Citation(s) in RCA: 140] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2006] [Revised: 03/22/2007] [Accepted: 03/23/2007] [Indexed: 12/11/2022]
Abstract
The oncofetal Thomsen-Friedenreich carbohydrate antigen (Galbeta1-3GalNAcalpha1-Ser/Thr TF or T antigen) is a pan-carcinoma antigen highly expressed by about 90% of all human carcinomas. Its broad expression and high specificity in cancer have attracted many investigations into its potential use in cancer diagnosis and immunotherapy. Over the past few years increasing evidence suggests that the increased TF occurrence in cancer cells may be functionally important in cancer progression by allowing increased interaction/communication of the cells with endogenous carbohydrate-binding proteins (lectins), particularly the members of the galactoside-binding galectin family. This review focuses on the recent progress in understanding of the regulation and functional significance of increased TF occurrence in cancer progression and metastasis.
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Affiliation(s)
- Lu-Gang Yu
- The Henry Wellcome Laboratory of Molecular and Cellular Gastroenterology, School of Clinical Science, University of Liverpool, Liverpool, L69 3BX, UK.
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11
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Schindlbeck C, Jeschke U, Schulze S, Karsten U, Janni W, Rack B, Krajewski S, Sommer H, Friese K. Prognostic impact of Thomsen-Friedenreich tumor antigen and disseminated tumor cells in the bone marrow of breast cancer patients. Breast Cancer Res Treat 2006; 101:17-25. [PMID: 16807671 DOI: 10.1007/s10549-006-9271-3] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2006] [Accepted: 05/05/2006] [Indexed: 12/11/2022]
Abstract
PURPOSE The Thomsen-Friedenreich antigen (TF, CD176) is a specific oncofetal carbohydrate epitope (Gal beta1-3GalNAc alpha-O-Ser/Thr) expressed on the surface of various carcinomas. It mediates endothelium adhesion and formation of metastases. As it also causes immune response, its prognostic impact is indeterminate. The presence of disseminated tumor cells in the bone marrow of breast cancer patients (DTC-BM) indicates worse prognosis. We examined the expression of TF in primary breast cancer tissue of 265 patients with known BM status at the time of first diagnosis. METHODS BM aspiration, cytospin preparation and immunocytochemical staining with the anti-Cytokeratin antibody A45 B/B3 was done following a standardised protocol. TF expression was examined immunohistochemically on Tissue Micro Arrays (TMA) with the anti-TF antibody A78-G/A7. Evaluation was done using the immunoreactive score (IRS). RESULTS Median IRS for TF expression was 2 (0-12). 68 of 265 patients (25.7%) showed DTC-BM with a median of 2/2 x 10(6) cells (1-1500). There was no correlation between TF expression and DTC-BM. After a median follow up of 60.1 months (7-119), the detection of DTC-BM showed prognostic significance for overall survival (OS, p = 0.034), whereas TF positivity (IRS > 2) indicated prolonged disease-free (p = 0.01), distant disease-free (p = 0.005), and overall survival (p = 0.005). DISCUSSION Patients with TF-positive tumors had a significantly better prognosis. Dissemination routes, TF-mediated metastasis formation, and the immunogeneity of TF might determine the prognostic impact of TF expression in different tumor entities. Further characterisation of primary tumors and DTC-BM could help to improve the biological understanding of metastases and develop targeted therapies.
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Affiliation(s)
- Christian Schindlbeck
- First Department of Obstetrics & Gynecology, Ludwig Maximilians University of Munich, Maistrasse 11, D-80337, Munich, Germany.
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van Leeuwen EBM, Cloosen S, Senden-Gijsbers BLMG, Agervig Tarp M, Mandel U, Clausen H, Havenga MJE, Duffour MT, García-Vallejo JJ, Germeraad WTV, Bos GMJ. Expression of aberrantly glycosylated tumor mucin-1 on human DC after transduction with a fiber-modified adenoviral vector. Cytotherapy 2006; 8:24-35. [PMID: 16627342 DOI: 10.1080/14653240500513018] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
BACKGROUND DC-presenting tumor Ag are currently being developed to be used as a vaccine in human cancer immunotherapy. To increase chances for successful therapy it is important to deliver full-length tumor Ag instead of loading single peptides. METHODS In this study we used a fiber-modified adenoviral vector (rAd5F35) containing full-length tumor Ag cDNA to transduce human monocyte (Mo)-derived DC in vitro. Cells were efficiently transduced and survived for at least 3 days after adenoviral transduction. Phenotype and function after maturation of Mo-DC were not impaired by infection with adenovirus particles. Expression of the tumor-associated Ag mucin-1 (MUC1) was detected using MAb defining different MUC1 glycoforms. RESULTS Non-transduced mature Mo-DC express endogenous MUC1 with normal glycosylation. After transduction with the rAd5F35-MUC1 adenoviral vector, Mo-DC also expressed MUC1 with tumor-associated glycosylation (Tn and T glycoforms), although no changes in mRNA levels of relevant glycosyltransferases could be demonstrated. DISCUSSION The presence of aberrantly glycosylated MUC1 may influence Ag presentation of the tumor glycoforms of MUC1 to immune cells, affecting tumor cell killing. These findings could be highly relevant to developing strategies for cancer immunotherapy based on DC vaccines using MUC1 as tumor Ag.
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Affiliation(s)
- E B M van Leeuwen
- Department of Internal Medicine, Division of Hemato-Oncology, University Hospital Maastricht, Maastricht, The Netherlands
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Irazoqui FJ, Sendra VG, Lardone RD, Nores GA. Immune response to Thomsen-Friedenreich disaccharide and glycan engineering. Immunol Cell Biol 2005; 83:405-12. [PMID: 16033536 DOI: 10.1111/j.1440-1711.2005.01348.x] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/20/2023]
Abstract
Cancer-associated mucins show frequent alterations of their oligosaccharide chain profile, with a switch to unmask normally cryptic O-glycan backbone and core regions. Epithelial tumour cells typically show overexpression of the uncovered Gal(beta)1-3GalNAc(alpha)-O-Ser/Thr (Core 1) structure, known as the T antigen or the Thomsen-Friedenreich antigen, the oligosaccharide chain of which is called the Thomsen-Friedenreich disaccharide (TFD). T antigen expression has been associated with immunosuppression, metastasis dissemination, and the proliferation of cancer cells. Several different strategies have been used to trigger a specific immune response to TFD. Natural T antigen and synthetic TFD residues have low immunodominance. In the T antigen, flexibility of the glycosidic bond reduces the immunogenicity of the sugar residue. Enhanced rigidity should favour certain glycan conformations and thereby improve TFD immunotargeting. We propose the term 'glycan engineering' for this approach. Such engineering of TFD should reduce the flexibility of its glycan moiety and thereby enhance its stability, rigidity and immunogenicity.
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Affiliation(s)
- Fernando J Irazoqui
- CIQUIBIC-CONICET/Department of Biological Chemistry, Faculty of Chemical Sciences, National University of Cordoba, Ciudad Universitaria, Cordoba, Argentina.
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Santos-Silva F, Fonseca A, Caffrey T, Carvalho F, Mesquita P, Reis C, Almeida R, David L, Hollingsworth MA. Thomsen-Friedenreich antigen expression in gastric carcinomas is associated with MUC1 mucin VNTR polymorphism. Glycobiology 2004; 15:511-7. [PMID: 15604091 DOI: 10.1093/glycob/cwi027] [Citation(s) in RCA: 30] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023] Open
Abstract
Aberrant glycosylation of mucins is a common phenomenon associated with oncogenic transformation. We investigated the association between expression of the tumor-associated antigens T, Tn, and sialyl-Tn and polymorphism in the length of the MUC1 mucin tandem repeat in a series of gastric carcinomas. We further evaluated the relevance of MUC1 tandem repeat length on the expression of these tumor-associated carbohydrate antigens (TACAs) using a gastric carcinoma cell line model expressing recombinant MUC1 constructs carrying 0, 3, 9, and 42 repeats. Gastric carcinomas showed a high prevalence of Tn and sialyl-Tn antigens, whereas T antigen was less frequently expressed. The expression of T antigen was significantly higher in gastric carcinomas from patients homozygous for MUC1 large tandem repeat alleles. No significant associations were found for Tn and sialyl-Tn antigens. This novel association was reinforced by the gastric carcinoma cell line model experiments, where de novo expression of T antigen was detected in clones transfected with larger VNTR regions. Our results indicate that polymorphism in the MUC1 tandem repeat influences the expression of TACAs in gastric cancer cells and may therefore allow the identification of subgroups of patients that develop more aggressive tumors expressing T antigen.
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Affiliation(s)
- F Santos-Silva
- Institute of Molecular Pathology and Immunology of the University of Porto, IPATIMUP, 4200-465 Porto, Portugal.
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Wang JY, Chang CT, Hsieh JS, Lee LW, Huang TJ, Chai CY, Lin SR. Role of MUC1 and MUC5AC expressions as prognostic indicators in gastric carcinomas. J Surg Oncol 2003; 83:253-60. [PMID: 12884239 DOI: 10.1002/jso.10222] [Citation(s) in RCA: 32] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
BACKGROUND AND OBJECTIVES The aim of this study is to clarify the relationship between the expression of MUC1 and MUC5AC mucins and the clinicopathological features in human gastric carcinomas using the mouse monoclonal antibodies VU-4H5 and Clone 45M1, respectively. Furthermore, the possibility of using phenotypes (MUC1+/MUC5AC+, MUC1+/MUC5AC-, MUC1-/MUC5AC-, MUC1-/MUC5AC+) to predict prognosis of the patients is evaluated. METHODS Formalin-fixed, paraffin wax-embedded tissues from 76 cases of gastric cancer were examined for the expression of MUC1 and MUC5AC mucin antigens immunohistochemically using the avidin-biotin-peroxidase method. RESULTS Of the 76 cases, MUC1 and MUC5AC immunoreactivities were observed in 49 (64.5%) and in 32 (42.1%) of gastric carcinoma tissues, respectively. MUC1 expression was significantly correlated to the depth of invasion, lymph node metastasis, peritoneal dissemination, and tumor stage. On the other hand, MUC5AC was inversely associated with depth of invasion, lymph node metastasis, liver metastasis, and tumor stage. Multivariate analyses indicated that tumor stage and MUC1 mucin expression were independently correlated with overall survival. The patients with MUC1+/MUC5AC- antigen staining in carcinoma tissues showed the lowest survival rate among four phenotypes. In contrast, the patients with MUC1-/MUC5AC+ antigen staining in carcinoma tissues showed the highest survival rate. CONCLUSIONS Altogether these data suggest that combined evaluation of MUC1 and MUC5AC mucin staining may be clinically helpful to predict outcome in patients with gastric cancer.
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Affiliation(s)
- Jaw-Yuan Wang
- Department of Surgery, Kaohsiung Medical University, Kaohsiung, Taiwan.
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Wang RQ, Fang DC. Alterations of MUC1 and MUC3 expression in gastric carcinoma: relevance to patient clinicopathological features. J Clin Pathol 2003; 56:378-84. [PMID: 12719460 PMCID: PMC1769961 DOI: 10.1136/jcp.56.5.378] [Citation(s) in RCA: 59] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
AIMS Several studies have reported conflicting and inconclusive results concerning the clinical relevance of mucin expression in gastric carcinoma. This study investigated the correlations between aberrant expression of mucins in gastric carcinoma and patient clinicopathological features. METHODS The expression of MUC1, MUC2, MUC3, MUC5AC, and MUC6 was investigated immunohistochemically in gastric carcinoma (n = 46) in relation to patient clinicopathological features. RESULTS All normal gastric mucosa samples expressed MUC1, MUC5AC, and MUC6. MUC1, MUC2, MUC3, MUC5AC, and MUC6 were expressed in 29, 31, 30, 18, and 21 of the 46 cases of gastric carcinoma, respectively. The number of cases expressing MUC1 was significantly higher (p < 0.01) in patients with a small tumour size (>/= 5 cm) and in patients in clinical stages I-II, compared with clinical stages III-IV (p < 0.05). Expression was significantly lower (p < 0.05) in patients exhibiting metastasis. The number of cases expressing MUC3 was significantly higher in patients in clinical stages III-IV (p < 0.05), and in those with serosal invasion (p < 0.05) or metastasis (p<0.01). No significant relations were found between MUC2, MUC5AC, MUC6, and clinical stage, metastasis, or tumour size. CONCLUSIONS Membrane bound mucins MUC1 and MUC3 appear to be associated with the development of gastric carcinoma. Patients who maintained high immunoreactivity for anti-MUC1 antibody had a better prognosis, whereas those with an increase in anti-MUC3 immunoreactivity had a poorer prognosis, as judged by tumour size, serosal invasion, and metastasis. However, no correlation was found between MUC2, MUC5AC, or MUC6 and clinical prognosis.
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Affiliation(s)
- R-Q Wang
- Department of Gastroenterology, Southwestern Hospital, Third Military Medical University, Chongqing 400038, PR China.
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Song ZB, Gao SS, Yi XN, Li YJ, Wang QM, Zhuang ZH, Wang LD. Expression of MUC1 in esophageal squamous-cell carcinoma and its relationship with prognosis of patients from Linzhou city, a high incidence area of northern China. World J Gastroenterol 2003; 9:404-7. [PMID: 12632485 PMCID: PMC4621549 DOI: 10.3748/wjg.v9.i3.404] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To further characterize the possible relationship between the molecular changes and prognosis of ESC and to elucidate the possible mechanisms involved.
METHODS: 114 specimens of ESC were collected from Linzhou city, and all patients were followed up for more than 5 years after resection. Histopathological analysis and immunohistochemical staining (ABC) were employed to detect the alteration of MUC1.
RESULTS: The positive immunostaining rate for MUC1 was 79% (90/114), and the high-expression rate was 63% (72/114). The mean survival periods (months) of those with high- and low-expression rates of MUC1 were 41 (95%CI: 35, 47) and 52 (95%CI: 45, 59), respectively. Patients in the low-expression group obviously survived longer than those in high-expression group, and the difference was significant (P < 0.05). The expression of MUC1 protein in the esophageal carcinoma specimens with metastasis was stronger than those without metastasis, the difference was also significant (P < 0.05). The stepwise multivariate analysis showed that “differentiation”, “expression of MUC1” and “TNM staging” were the most important factors affecting the prognosis of esophageal carcinoma patients (P < 0.05).
CONCLUSION: A good correlation between the alteration of MUC1 and the regional lymph node metastasis was observed. Furthermore, high-expression of MUC1 was associated with poor prognosis for esophageal cancer patients. These results indicated that MUC1 is a promising biomarker for predicting lymph node metastasis and prognosis in esophageal cancer.
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Affiliation(s)
- Zi-Bo Song
- Institute of Medical Genetics, People's Hospital of Henan Province, 450003, Henan Province, China.
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Goletz S, Cao Y, Danielczyk A, Ravn P, Schoeber U, Karsten U. Thomsen-Friedenreich Antigen: The “Hidden” Tumor Antigen. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2003; 535:147-62. [PMID: 14714894 DOI: 10.1007/978-1-4615-0065-0_10] [Citation(s) in RCA: 29] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/23/2023]
Affiliation(s)
- S Goletz
- NEMOD Immuntherapie AG and Max Delbrück Centre for Molecular Medicine, Berlin-Buch, Germany
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Baldus SE, Mönig SP, Arkenau V, Hanisch FG, Schneider PM, Thiele J, Hölscher AH, Dienes HP. Correlation of MUC5AC immunoreactivity with histopathological subtypes and prognosis of gastric carcinoma. Ann Surg Oncol 2002; 9:887-93. [PMID: 12417511 DOI: 10.1007/bf02557526] [Citation(s) in RCA: 29] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
BACKGROUND MUC5AC represents a mucin peptide core expressed in normal gastric epithelia. Its presence in gastric carcinomas was previously described as a characteristic of gastric differentiation. METHODS MUC5AC reactivity was investigated by immunohistochemistry and correlated with clinicopathological variables in a large series (n = 200) of gastric carcinomas. RESULTS A statistically significant association between MUC5AC positivity and parameters of cancer progression (pTNM staging and grading) could not be observed. However, MUC5AC exhibited correlations with certain subtypes of histopathological differentiation. A significant reduction of MUC5AC expression was evident in mucinous and undifferentiated carcinomas according to the World Health Organization classification, as well as in type III cancers according to the Goseki classification system. Furthermore, reduced MUC5AC reactivity (confined to up to 35% of the tumor area) was significantly correlated with an unfavorable prognosis of all patients in univariate and multivariate analysis. The same association could be observed in the subgroup of pTNM stage I patients (n = 60). CONCLUSIONS A significant reduction of gastric differentiation as reflected by MUC5AC immunoreactivity represents a marker of worse survival probability in gastric cancer. Finally, reduced MUC5AC positivity defines a high-risk subgroup of pTNM stage I patients.
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Affiliation(s)
- Stephan E Baldus
- Institute of Pathology and Center of Biochemistry, Medical Faculty, University of Cologne, Cologne, Germany.
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