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1.
Genes Dev ; 2024 Oct 25.
Artigo em Inglês | MEDLINE | ID: mdl-39455281

RESUMO

Squamous cell carcinomas (SCCs), arising from the skin, head and neck, lungs, esophagus, and cervix, are collectively among the most common cancers and a frequent cause of cancer morbidity and mortality. Despite distinct stratified epithelial tissues of origin, converging evidence points toward shared biologic pathways across SCCs. With recent breakthroughs in molecular technologies have come novel SCC treatment paradigms, including immunotherapies and targeted therapy. This review compares commonalities and differences across SCCs from different anatomical sites, including risk factors and genetics, as well as cellular and molecular programs driving tumorigenesis. We review landmark discoveries of the "cancer stem cells" (CSCs) that initiate and propagate SCCs and their gene and translational regulation programs. This has led to an appreciation that interactions between CSCs and the immune system play key roles in invasion and therapeutic resistance. Here, we review the unifying principles of SCCs that have emerged from these exciting advances in our understanding of these epithelial cancers.

2.
Glycobiology ; 33(7): 567-578, 2023 08 14.
Artigo em Inglês | MEDLINE | ID: mdl-37216646

RESUMO

There is an urgent need to develop new tumor biomarkers for early cancer detection, but the variability of tumor-derived antigens has been a limitation. Here we demonstrate a novel anti-Tn antibody microarray platform to detect Tn+ glycoproteins, a near universal antigen in carcinoma-derived glycoproteins, for broad detection of cancer. The platform uses a specific recombinant IgG1 to the Tn antigen (CD175) as a capture reagent and a recombinant IgM to the Tn antigen as a detecting reagent. These reagents were validated by immunohistochemistry in recognizing the Tn antigen using hundreds of human tumor specimens. Using this approach, we could detect Tn+ glycoproteins at subnanogram levels using cell lines and culture media, serum, and stool samples from mice engineered to express the Tn antigen in intestinal epithelial cells. The development of a general cancer detection platform using recombinant antibodies for detection of altered tumor glycoproteins expressing a unique antigen could have a significant impact on cancer detection and monitoring.


Assuntos
Antígenos Glicosídicos Associados a Tumores , Carcinoma , Humanos , Animais , Camundongos , Glicosilação , Glicoproteínas , Biomarcadores Tumorais , Linhagem Celular
3.
Glycobiology ; 30(5): 282-300, 2020 04 20.
Artigo em Inglês | MEDLINE | ID: mdl-31742337

RESUMO

The Tn antigen is a neoantigen abnormally expressed in many human carcinomas and expression correlates with metastasis and poor survival. To explore its biomarker potential, new antibodies are needed that specifically recognize this antigen in tumors. Here we generated two recombinant antibodies to the Tn antigen, Remab6 as a chimeric human IgG1 antibody and ReBaGs6 as a murine IgM antibody and characterized their specificities using multiple biochemical and biological approaches. Both Remab6 and ReBaGs6 recognize clustered Tn structures, but most importantly do not recognize glycoforms of human IgA1 that contain potential cross-reactive Tn antigen structures. In flow cytometry and immunofluorescence analyses, Remab6 recognizes human cancer cell lines expressing the Tn antigen, but not their Tn-negative counterparts. In immunohistochemistry (IHC), Remab6 stains many human cancers in tissue array format but rarely stains normal tissues and then mostly intracellularly. We used these antibodies to identify several unique Tn-containing glycoproteins in Tn-positive Colo205 cells, indicating their utility for glycoproteomics in future biomarker studies. Thus, recombinant Remab6 and ReBaGs6 are useful for biochemical characterization of cancer cells and IHC of tumors and represent promising tools for Tn biomarker discovery independently of recognition of IgA1.


Assuntos
Antígenos Glicosídicos Associados a Tumores/análise , Biomarcadores Tumorais/análise , Carcinoma/diagnóstico , Glicoproteínas/análise , Imunoglobulina G/imunologia , Imunoglobulina M/imunologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Animais , Antígenos Glicosídicos Associados a Tumores/genética , Antígenos Glicosídicos Associados a Tumores/imunologia , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/imunologia , Carcinoma/genética , Carcinoma/imunologia , Feminino , Glicoproteínas/genética , Glicoproteínas/imunologia , Humanos , Lactente , Masculino , Camundongos , Pessoa de Meia-Idade , Proteínas Recombinantes/imunologia , Células Tumorais Cultivadas , Adulto Jovem
4.
Nat Methods ; 13(6): 528-34, 2016 06.
Artigo em Inglês | MEDLINE | ID: mdl-27135973

RESUMO

Glycans have essential roles in biology and the etiology of many diseases. A major hurdle in studying glycans through functional glycomics is the lack of methods to release glycans from diverse types of biological samples. Here we describe an oxidative strategy using household bleach to release all types of free reducing N-glycans and O-glycan-acids from glycoproteins, and glycan nitriles from glycosphingolipids. Released glycans are directly useful in glycomic analyses and can be derivatized fluorescently for functional glycomics. This chemical method overcomes the limitations in glycan generation and promotes archiving and characterization of human and animal glycomes and their functions.


Assuntos
Glicômica/métodos , Oxidantes/química , Polissacarídeos/química , Hipoclorito de Sódio/química , Animais , Galinhas , Cromatografia Líquida de Alta Pressão , Cromatografia em Camada Fina , Ovos/análise , Feminino , Trato Gastrointestinal/química , Glicoproteínas/química , Glicoesfingolipídeos/química , Camundongos Endogâmicos C57BL , Oxirredução , Lectinas de Plantas/química , Polissacarídeos/análise , Espectrometria de Massas por Ionização e Dessorção a Laser Assistida por Matriz
5.
Nat Methods ; 13(1): 81-6, 2016 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-26619014

RESUMO

Protein O-glycosylation has key roles in many biological processes, but the repertoire of O-glycans synthesized by cells is difficult to determine. Here we describe an approach termed Cellular O-Glycome Reporter/Amplification (CORA), a sensitive method used to amplify and profile mucin-type O-glycans synthesized by living cells. Cells convert added peracetylated benzyl-α-N-acetylgalactosamine to a large variety of modified O-glycan derivatives that are secreted from cells, allowing for easy purification for analysis by HPLC and mass spectrometry (MS). Relative to conventional O-glycan analyses, CORA resulted in an ∼100-1,000-fold increase in sensitivity and identified a more complex repertoire of O-glycans in more than a dozen cell types from Homo sapiens and Mus musculus. Furthermore, when coupled with computational modeling, CORA can be used for predictions about the diversity of the human O-glycome and offers new opportunities to identify novel glycan biomarkers for human diseases.


Assuntos
Polissacarídeos/metabolismo , Animais , Cromatografia Líquida de Alta Pressão , Espectrometria de Massas , Camundongos
6.
Proc Natl Acad Sci U S A ; 113(51): 14787-14792, 2016 12 20.
Artigo em Inglês | MEDLINE | ID: mdl-27930307

RESUMO

Inflammatory bowel disease (IBD) results from aberrant immune stimulation against a dysbiotic mucosal but relatively preserved luminal microbiota and preferentially affects males in early onset disease. However, factors contributing to sex-specific risk and the pattern of dysbiosis are largely unexplored. Core 1 ß3GalT-specific molecular chaperone (Cosmc), which encodes an X-linked chaperone important for glycocalyx formation, was recently identified as an IBD risk factor by genome-wide association study. We deleted Cosmc in mouse intestinal epithelial cells (IECs) and found marked reduction of microbiota diversity in progression from the proximal to the distal gut mucosa, but not in the overlying lumen, as seen in IBD. This loss of diversity coincided with local emergence of a proinflammatory pathobiont and distal gut restricted pathology. Mechanistically, we found that Cosmc regulates host genes, bacterial ligands, and nutrient availability to control microbiota biogeography. Loss of one Cosmc allele in males (IEC-Cosmc-/y) resulted in a compromised mucus layer, spontaneous microbe-dependent inflammation, and enhanced experimental colitis; however, females with loss of one allele and mosaic deletion of Cosmc in 50% of crypts (IEC-Cosmc+/-) were protected from spontaneous inflammation and partially protected from experimental colitis, likely due to lateral migration of normal mucin glycocalyx from WT cells over KO crypts. These studies functionally validate Cosmc as an IBD risk factor and implicate it in regulating the spatial pattern of dysbiosis and sex bias in IBD.


Assuntos
Microbioma Gastrointestinal , Genes Ligados ao Cromossomo X , Doenças Inflamatórias Intestinais/genética , Chaperonas Moleculares/genética , Fatores Sexuais , Alelos , Animais , Colite/microbiologia , Feminino , Deleção de Genes , Ligação Genética , Estudo de Associação Genômica Ampla , Glicocálix , Inflamação , Doenças Inflamatórias Intestinais/microbiologia , Mucosa Intestinal/microbiologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Mosaicismo , Fatores de Risco , Cromossomo X
7.
Glycobiology ; 28(4): 214-222, 2018 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-29390058

RESUMO

Mucin-type O-glycans decorate >80% of secretory and cell surface proteins and contribute to health and disease. However, dynamic alterations in the O-glycome are poorly understood because current O-glycomic methodologies are not sufficiently sensitive nor quantitative. Here we describe a novel isotope labeling approach termed Isotope-Cellular O-glycome Reporter Amplification (ICORA) to amplify and analyze the O-glycome from cells. In this approach, cells are incubated with Ac3GalNAc-Bn (Ac3GalNAc-[1H7]Bn) or a heavy labeled Ac3GalNAc-BnD7 (Ac3GalNAc-[2D7]Bn) O-glycan precursor (7 Da mass difference), which enters cells and upon de-esterification is modified by Golgi enzymes to generate Bn-O-glycans secreted into the culture media. After recovery, heavy and light Bn-O-glycans from two separate conditions are mixed, analyzed by MS, and statistically interrogated for changes in O-glycan abundance using a semi-automated approach. ICORA enables ~100-1000-fold enhanced sensitivity and increased throughput compared to traditional O-glycomics. We validated ICORA with model cell lines and used it to define alterations in the O-glycome in colorectal cancer. ICORA is a useful tool to explore the dynamic regulation of the O-glycome in health and disease.


Assuntos
Glicômica , Polissacarídeos/análise , Células Cultivadas , Humanos , Marcação por Isótopo , Polissacarídeos/metabolismo
9.
Cancer Med ; 12(6): 6768-6777, 2023 03.
Artigo em Inglês | MEDLINE | ID: mdl-36437732

RESUMO

PURPOSE: Thyroid cancer recurrence following curative thyroidectomy is associated with increased morbidity and mortality, but current surveillance strategies are inadequate for early detection. Prior studies indicate that tissue glycosylation is altered in thyroid cancer, but the utility of serum glycosylation in thyroid cancer surveillance remains unexplored. We therefore assessed the potential utility of altered serum glycomic profile as a tumor-specific target for disease surveillance in recurrent thyroid cancer. EXPERIMENTAL DESIGN: We employed banked serum samples from patients with recurrent thyroid cancer post thyroidectomy and healthy controls. N-glycans were enzymatically released from serum glycoproteins, labeled via permethylation, and analyzed by MALDI-TOF mass spectrometry. Global level and specific subtypes of glycan structures were compared between patients and controls. RESULTS: We evaluated 28 independent samples from 13 patients with cancer recurrence and 15 healthy controls. Global features of glycosylation, including N-glycan class and terminal glycan modifications were similar between groups, but three of 35 individual glycans showed significant differences. The three glycans were biosynthetically related biantennary core fucosylated N-glycans that only varied by the degree of galactosylation (G0F, G1F, and G2F; G: galactose, F: fucose). The ratio of G0F:G1F that captures reduced galactosylation was observed in patients samples but not in healthy controls (p = 0.004) and predicted thyroid cancer recurrence (AUC = 0.82, CI 95% = 0.64-0.99). CONCLUSIONS: Altered N-glycomic profile was associated with thyroid cancer recurrence. This serum-based biomarker would be useful as an effective surveillance tool to improve the care and prognosis of thyroid cancer after prospective validation.


Assuntos
Adenocarcinoma , Neoplasias da Glândula Tireoide , Humanos , Glicômica/métodos , Recidiva Local de Neoplasia , Biomarcadores , Polissacarídeos , Neoplasias da Glândula Tireoide/diagnóstico , Neoplasias da Glândula Tireoide/cirurgia , Espectrometria de Massas por Ionização e Dessorção a Laser Assistida por Matriz
10.
J Gastrointest Oncol ; 14(4): 1878-1886, 2023 Aug 31.
Artigo em Inglês | MEDLINE | ID: mdl-37720425

RESUMO

Background: Less than two percent of pancreatic neuroendocrine tumors (NETs) produce serotonin. Serotonin can cause carcinoid syndrome and less commonly carcinoid heart disease (CHD). CHD is associated with increased mortality and requires a more aggressive approach. Here we present a rare case of a serotonin-producing pancreatic NET complicated by CHD at presentation and discuss timing of systemic therapy, liver-directed therapy, and heart failure management. Case Description: A 36-year-old white man presented with diarrhea, lower extremity edema, and exertional dyspnea. He was found to have a well-differentiated serotonin-producing pancreatic NETs grade three with bilobar liver metastasis complicated by carcinoid syndrome and CHD. His symptoms and disease burden improved with somatostatin analog and liver-directed therapy with bland embolization to control carcinoid symptoms and obtain rapid hormonal control to prevent progression of CHD. He concurrently received diuretics to manage his heart failure and was considered for valvular replacement surgery, which was deferred for optimal hormonal control. Conclusions: Our case highlights the importance of multidisciplinary care for patients with pancreatic NETs and early identification and management of CHD. Although uncommon, serotonin-producing pancreatic NETs can present with CHD and require combination of somatostatin analogs, liver-directed therapy, and heart failure management.

11.
Curr Protoc ; 1(6): e142, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-34101390

RESUMO

Mucin-type O-glycosylation (O-glycans, O-glycome) is among the most biologically important post-translational modification in glycoproteins but O-glycan structural diversity and expression are poorly understood due to the inadequacy of current analytical methods. We recently developed a new tool termed cellular O-glycome reporter/amplification (CORA), which uses O-glycan precursors, benzyl-α-GalNAc (Bn-α-GalNAc) or azido-Bn-α-GalNAc (N3 -Bn-α-GalNAc), as surrogates of protein O-glycosylation. Living cells metabolically convert these precursors to all types of O-GalNAc glycans representative of the cells' capabilities. The amplification and secretion of the O-glycome products greatly facilitates their analysis and functional studies. Here we describe protocols for analytical and preparative applications. © 2021 The Authors. Current Protocols published by Wiley Periodicals LLC. This article is a U.S. Government work and is in the public domain in the USA. Basic Protocol 1: Cellular O-glycome reporter/amplification for the analysis of mucin-type O-glycans from living cells Basic Protocol 2: Preparation of cellular O-glycans from living cells for functional glycomics and glycan microarrays Basic Protocol 3: Conjugation of cellular O-glycans with a bifunctional fluorescent tag Basic Protocol 4: 2D-HPLC purification and MALDI-TOF/MS identification of individual PYAB-Bn-O-glycan.


Assuntos
Glicômica , Mucinas , Glicoproteínas , Glicosilação , Polissacarídeos
12.
Cell Chem Biol ; 28(4): 567-582.e4, 2021 04 15.
Artigo em Inglês | MEDLINE | ID: mdl-33378651

RESUMO

The pleiotropic functions of macrophages in immune defense, tissue repair, and maintenance of tissue homeostasis are supported by the heterogeneity in macrophage sub-populations that differ both in ontogeny and polarization. Although glycans and glycan-binding proteins (GBPs) are integral to macrophage function and may contribute to macrophage diversity, little is known about the factors governing their expression. Here, we provide a resource for characterizing the N-/O-glycomes of various murine peritoneal macrophage sub-populations, demonstrating that glycosylation primarily reflects developmental origin and, to a lesser degree, cellular polarization. Furthermore, comparative analysis of GBP-coding genes in resident and elicited macrophages indicated that GBP expression is consistent with specialized macrophage functions and correlates with specific types of displayed glycans. An integrated, semi-quantitative approach was used to confirm distinct expression patterns of glycans and their binding proteins across different macrophages. The data suggest that regulation of glycan-protein complexes may be central to macrophage residence and recruitment.


Assuntos
Proteínas de Transporte/genética , Glicômica , Macrófagos/metabolismo , Polissacarídeos/genética , Animais , Proteínas de Transporte/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Polissacarídeos/metabolismo
13.
Nat Rev Gastroenterol Hepatol ; 17(10): 597-617, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32710014

RESUMO

Inflammatory bowel disease (IBD) affects 6.8 million people globally. A variety of factors have been implicated in IBD pathogenesis, including host genetics, immune dysregulation and gut microbiota alterations. Emerging evidence implicates intestinal epithelial glycosylation as an underappreciated process that interfaces with these three factors. IBD is associated with increased expression of truncated O-glycans as well as altered expression of terminal glycan structures. IBD genes, glycosyltransferase mislocalization, altered glycosyltransferase and glycosidase expression and dysbiosis drive changes in the glycome. These glycan changes disrupt the mucus layer, glycan-lectin interactions, host-microorganism interactions and mucosal immunity, and ultimately contribute to IBD pathogenesis. Epithelial glycans are especially critical in regulating the gut microbiota through providing bacterial ligands and nutrients and ultimately determining the spatial organization of the gut microbiota. In this Review, we discuss the regulation of intestinal epithelial glycosylation, altered epithelial glycosylation in IBD and mechanisms for how these alterations contribute to disease pathobiology. We hope that this Review provides a foundation for future studies on IBD glycosylation and the emergence of glycan-inspired therapies for IBD.


Assuntos
Microbioma Gastrointestinal/fisiologia , Doenças Inflamatórias Intestinais/metabolismo , Doenças Inflamatórias Intestinais/microbiologia , Mucosa Intestinal/metabolismo , Mucosa Intestinal/microbiologia , Polissacarídeos/metabolismo , Biomarcadores/metabolismo , Microbioma Gastrointestinal/imunologia , Glicosilação , Humanos , Doenças Inflamatórias Intestinais/imunologia , Mucosa Intestinal/imunologia
14.
Clin Lymphoma Myeloma Leuk ; 20(11): 757-767.e3, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-32703750

RESUMO

BACKGROUND: Treatment of cutaneous T-cell lymphoma (CTCL) with total skin electron beam (TSEB) therapy has been associated with deep responses but short progression-free intervals. Maintenance therapy might prolong the response duration; however, limited data assessing the outcomes with maintenance therapy after TSEB are available. We evaluated the effect of maintenance therapy on the outcomes for patients with CTCL receiving TSEB therapy. MATERIALS AND METHODS: We conducted a single-center retrospective analysis of 101 patients with CTCL who had received TSEB therapy from 1998 to 2018 at the Winship Cancer Institute of Emory University and compared the overall survival (OS) and progression-free survival (PFS) for patients had received maintenance therapy, including retinoids, interferon, ultraviolet therapy, nitrogen mustard, and extracorporeal photopheresis compared with those who had not. RESULTS: We found that pooled maintenance therapies improved PFS (hazard ratio [HR], 0.60; P = .026) but not OS (median HR, 0.73; P = .264). The median PFS and OS was 7.2 months versus 9.6 months and 2.4 years versus 4.2 years for the no maintenance and maintenance groups, respectively. On exploratory analysis of the individual regimens, ultraviolet therapy was associated with improved OS (HR, 0.21; P = .034) and PFS (HR, 0.26; P = .002) compared with no maintenance. CONCLUSION: Among the patients with CTCL who had received TSEB therapy, maintenance therapy improved PFS for all patients, and ultraviolet-based maintenance improved both PFS and OS in a subset of patients.


Assuntos
Linfoma Cutâneo de Células T/radioterapia , Neoplasias Cutâneas/radioterapia , Pele/efeitos da radiação , Terapia Ultravioleta/métodos , Irradiação Corporal Total/métodos , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Linfoma Cutâneo de Células T/mortalidade , Masculino , Pessoa de Meia-Idade , Dosagem Radioterapêutica , Estudos Retrospectivos , Neoplasias Cutâneas/mortalidade , Adulto Jovem
15.
Nat Commun ; 11(1): 3990, 2020 08 10.
Artigo em Inglês | MEDLINE | ID: mdl-32778659

RESUMO

The molecular mechanisms regulating lymphocyte homing into lymph nodes are only partly understood. Here, we report that B cell-specific deletion of the X-linked gene, Cosmc, and the consequent decrease of protein O-glycosylation, induces developmental blocks of mouse B cells. After transfer into wild-type recipient, Cosmc-null B cells fail to home to lymph nodes as well as non-lymphoid organs. Enzymatic desialylation of wild-type B cells blocks their migration into lymph nodes, indicating a requirement of sialylated O-glycans for proper trafficking. Mechanistically, Cosmc-deficient B cells have normal rolling and firm arrest on high endothelium venules (HEV), thereby attributing their inefficient trafficking to alterations in the subsequent transendothelial migration step. Finally, Cosmc-null B cells have defective chemokine signaling responses. Our results thus demonstrate that Cosmc and its effects on O-glycosylation are important for controlling B cell homing.


Assuntos
Linfócitos B/metabolismo , Linfonodos/metabolismo , Chaperonas Moleculares/metabolismo , Animais , Movimento Celular , Feminino , Glicosilação , Humanos , Imunidade Humoral/fisiologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Chaperonas Moleculares/genética , Polissacarídeos/metabolismo , Transcriptoma , Vênulas
16.
Front Immunol ; 9: 2857, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30619255

RESUMO

Germinal centers (GC) are microanatomical niches where B cells proliferate, undergo antibody affinity maturation, and differentiate to long-lived memory B cells and antibody-secreting plasma cells. For decades, GC B cells have been defined by their reactivity to the plant lectin peanut agglutinin (PNA), which binds serine/threonine (O-linked) glycans containing the asialylated disaccharide Gal-ß1,3-GalNAc-Ser/Thr (also called T-antigen). In T cells, acquisition of PNA binding by activated T cells and thymocytes has been linked with altered tissue homing patterns, cell signaling, and survival. Yet, in GC B cells, the glycobiological basis and significance of PNA binding remains surprisingly unresolved. Here, we investigated the basis for PNA reactivity of GC B cells. We found that GC B cell binding to PNA is associated with downregulation of the α2,3 sialyltransferase, ST3GAL1 (ST3Gal1), and overexpression of ST3Gal1 was sufficient to reverse PNA binding in B cell lines. Moreover, we found that the primary scaffold for PNA-reactive O-glycans in B cells is the B cell receptor-associated receptor-type tyrosine phosphatase CD45, suggesting a role for altered O-glycosylation in antigen receptor signaling. Consistent with similar reports in T cells, ST3Gal1 overexpression in B cells in vitro induced drastic shortening in O-glycans, which we confirmed by both antibody staining and mass spectrometric O-glycomic analysis. Unexpectedly, ST3Gal1-induced changes in O-glycan length also correlated with altered binding of two glycosylation-sensitive CD45 antibodies, RA3-6B2 (more commonly called B220) and MEM55, which (in humans) have previously been reported to favor binding to naïve/GC subsets and memory/plasmablast subsets, respectively. Analysis of primary B cell binding to B220, MEM55, and several plant lectins suggested that B cell differentiation is accompanied by significant loss of O-glycan complexity, including loss of extended Core 2 O-glycans. To our surprise, decreased O-glycan length from naïve to post-GC fates best correlated not with ST3Gal1, but rather downregulation of the Core 2 branching enzyme GCNT1. Thus, our data suggest that O-glycan remodeling is a feature of B cell differentiation, dually regulated by ST3Gal1 and GCNT1, that ultimately results in expression of distinct O-glycosylation states/CD45 glycoforms at each stage of B cell differentiation.


Assuntos
Linfócitos B/imunologia , Diferenciação Celular/imunologia , Polissacarídeos/imunologia , Transdução de Sinais/imunologia , Linfócitos B/citologia , Linfócitos B/metabolismo , Diferenciação Celular/genética , Linhagem Celular Tumoral , Células Cultivadas , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Centro Germinativo/citologia , Centro Germinativo/imunologia , Centro Germinativo/metabolismo , Glicosilação , Humanos , Lectinas/imunologia , Lectinas/metabolismo , Aglutinina de Amendoim/imunologia , Aglutinina de Amendoim/metabolismo , Polissacarídeos/metabolismo , Sialiltransferases/genética , Sialiltransferases/imunologia , Sialiltransferases/metabolismo , Transdução de Sinais/genética , beta-Galactosídeo alfa-2,3-Sialiltransferase
17.
Adv Cancer Res ; 126: 53-135, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-25727146

RESUMO

Mucin-type O-glycans are a class of glycans initiated with N-acetylgalactosamine (GalNAc) α-linked primarily to Ser/Thr residues within glycoproteins and often extended or branched by sugars or saccharides. Most secretory and membrane-bound proteins receive this modification, which is important in regulating many biological processes. Alterations in mucin-type O-glycans have been described across tumor types and include expression of relatively small-sized, truncated O-glycans and altered terminal structures, both of which are associated with patient prognosis. New discoveries in the identity and expression of tumor-associated O-glycans are providing new avenues for tumor detection and treatment. This chapter describes mucin-type O-glycan biosynthesis, altered mucin-type O-glycans in primary tumors, including mechanisms for structural changes and contributions to the tumor phenotype, and clinical approaches to detect and target altered O-glycans for cancer treatment and management.


Assuntos
Neoplasias/metabolismo , Neoplasias/patologia , Polissacarídeos/química , Polissacarídeos/metabolismo , Animais , Progressão da Doença , Glicosilação , Humanos
18.
Cancer Biomark ; 14(1): 63-81, 2014 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-24643043

RESUMO

The Tn antigen is a tumor-associated carbohydrate antigen that is not normally expressed in peripheral tissues or blood cells. Expression of this antigen, which is found in a majority of human carcinomas of all types, arises from a blockage in the normal O-glycosylation pathway in which glycans are extended from the common precursor GalNAcα1-O-Ser/Thr (Tn antigen). This precursor is generated in the Golgi apparatus on newly synthesized glycoproteins by a family of polypeptide α-N-acetylgalactosaminyltransferases (ppGalNAcTs) and then extended to the common core 1 O-glycan Galß1-3GalNAcα1-O-Ser/Thr (T antigen) by a single enzyme termed the T-synthase (core 1 ß3-galactosyltransferase or C1GalT). Formation of the active form of the T-synthase requires a unique molecular chaperone termed Cosmc, encoded by Cosmc on the X-chromosome (Xq24 in humans, Xc3 in mice). Cosmc resides in the endoplasmic reticulum (ER) and prevents misfolding, aggregation, and proteasome-dependent degradation of newly synthesized T-synthase. Loss of expression of active T-synthase or Cosmc can lead to expression of the Tn antigen, along with its sialylated version Sialyl Tn antigen as observed in several cancers. Both genetic and epigenetic pathways, in addition to potential metabolic regulation, can result in abnormal expression of the Tn antigen. Engineered expression of the Tn antigen by disruption of either C1GalT (T-syn) or Cosmc in mice is associated with a tremendous range of pathologies and engineered expression of the Tn antigen in mouse embryos leads to embryonic death. Studies indicate that many membrane glycoproteins expressing the Tn antigen and/or truncated O-glycans may be dysfunctional, due to degradation and/or misfolding. Thus, expression of normal O-glycans is associated with health and homeostasis whereas truncation of O-glycans, e.g. the Tn and/or Sialyl Tn antigens is associated with cancer and other pathologies.


Assuntos
Antígenos Glicosídicos Associados a Tumores/biossíntese , Neoplasias/metabolismo , Polissacarídeos/metabolismo , Animais , Antígenos Glicosídicos Associados a Tumores/genética , Sequência de Carboidratos , Glicosilação , Humanos , Camundongos , Neoplasias/genética
19.
Expert Rev Ophthalmol ; 8(5): 475-484, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-30613209

RESUMO

Neovascular ('wet') age-related macular degeneration (AMD) is the leading cause of blindness among Caucasians over the age of 55 in the USA and is an important cause of ocular morbidity worldwide. Progress in oncology, and more recently ophthalmology, led to the development of VEGF antagonists, three of which are now approved for the treatment of wet AMD. Recent discoveries in ophthalmology and vascular biology, however, suggest that combined inhibition of VEGF and platelet-derived growth factor (PDGF) may be more beneficial than inhibition of VEGF alone. Accordingly, numerous studies are underway to evaluate the role of anti-VEGF/PDGF combination therapies for the treatment of wet AMD. This review discusses the biology of VEGF and PDGF and current preclinical and clinical data exploring the use of combined VEGF/PDGF inhibitors in the treatment of neovascular age-related macular degeneration.

20.
Dis Markers ; 2013 Mar 11.
Artigo em Inglês | MEDLINE | ID: mdl-23478278

RESUMO

Ahead of Print article withdrawn by publisher. At request of the authors, this article will be published in the journal Cancer Biomarkers (ISSN 1574-0153).

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