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1.
Cell ; 156(4): 744-58, 2014 Feb 13.
Artigo em Inglês | MEDLINE | ID: mdl-24529377

RESUMO

The clinical benefit conferred by vascular endothelial growth factors (VEGF)-targeted therapies is variable, and tumors from treated patients eventually reinitiate growth. Here, we identify a glycosylation-dependent pathway that compensates for the absence of cognate ligand and preserves angiogenesis in response to VEGF blockade. Remodeling of the endothelial cell (EC) surface glycome selectively regulated binding of galectin-1 (Gal1), which upon recognition of complex N-glycans on VEGFR2, activated VEGF-like signaling. Vessels within anti-VEGF-sensitive tumors exhibited high levels of α2-6-linked sialic acid, which prevented Gal1 binding. In contrast, anti-VEGF refractory tumors secreted increased Gal1 and their associated vasculature displayed glycosylation patterns that facilitated Gal1-EC interactions. Interruption of ß1-6GlcNAc branching in ECs or silencing of tumor-derived Gal1 converted refractory into anti-VEGF-sensitive tumors, whereas elimination of α2-6-linked sialic acid conferred resistance to anti-VEGF. Disruption of the Gal1-N-glycan axis promoted vascular remodeling, immune cell influx and tumor growth inhibition. Thus, targeting glycosylation-dependent lectin-receptor interactions may increase the efficacy of anti-VEGF treatment.


Assuntos
Inibidores da Angiogênese/uso terapêutico , Neoplasias/irrigação sanguínea , Neoplasias/tratamento farmacológico , Neovascularização Patológica , Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores , Animais , Células Endoteliais/metabolismo , Galectina 1/genética , Galectina 1/metabolismo , Glicosilação , Humanos , Hipóxia , Camundongos , Receptores Mitogênicos/metabolismo
2.
Proc Natl Acad Sci U S A ; 118(21)2021 05 25.
Artigo em Inglês | MEDLINE | ID: mdl-34006646

RESUMO

Colorectal cancer (CRC) represents the third most common malignancy and the second leading cause of cancer-related deaths worldwide. Although immunotherapy has taken center stage in mainstream oncology, it has shown limited clinical efficacy in CRC, generating an urgent need for discovery of new biomarkers and potential therapeutic targets. Galectin-1 (Gal-1), an endogenous glycan-binding protein, induces tolerogenic programs and contributes to tumor cell evasion of immune responses. Here, we investigated the relevance of Gal-1 in CRC and explored its modulatory activity within the CD8+ regulatory T cell (Treg) compartment. Mice lacking Gal-1 (Lgals1-/- ) developed a lower number of tumors and showed a decreased frequency of a particular population of CD8+CD122+PD-1+ Tregs in the azoxymethane-dextran sodium sulfate model of colitis-associated CRC. Moreover, silencing of tumor-derived Gal-1 in the syngeneic CT26 CRC model resulted in reduced number and attenuated immunosuppressive capacity of CD8+CD122+PD-1+ Tregs, leading to slower tumor growth. Moreover, stromal Gal-1 also influenced the fitness of CD8+ Tregs, highlighting the contribution of both tumor and stromal-derived Gal-1 to this immunoregulatory effect. Finally, bioinformatic analysis of a colorectal adenocarcinoma from The Cancer Genome Atlas dataset revealed a particular signature characterized by high CD8+ Treg score and elevated Gal-1 expression, which delineates poor prognosis in human CRC. Our findings identify CD8+CD122+PD-1+ Tregs as a target of the immunoregulatory activity of Gal-1, suggesting a potential immunotherapeutic strategy for the treatment of CRC.


Assuntos
Adenocarcinoma/genética , Linfócitos T CD8-Positivos/imunologia , Colite/genética , Neoplasias Colorretais/genética , Galectina 1/genética , Linfócitos T Reguladores/imunologia , Adenocarcinoma/imunologia , Adenocarcinoma/mortalidade , Adenocarcinoma/patologia , Animais , Atlas como Assunto , Azoximetano/administração & dosagem , Linfócitos T CD8-Positivos/patologia , Linhagem Celular Tumoral , Colite/induzido quimicamente , Colite/imunologia , Colite/mortalidade , Neoplasias Colorretais/imunologia , Neoplasias Colorretais/mortalidade , Neoplasias Colorretais/patologia , Biologia Computacional , Sulfato de Dextrana/administração & dosagem , Modelos Animais de Doenças , Galectina 1/deficiência , Galectina 1/imunologia , Regulação Neoplásica da Expressão Gênica , Humanos , Subunidade beta de Receptor de Interleucina-2/genética , Subunidade beta de Receptor de Interleucina-2/imunologia , Camundongos , Camundongos Knockout , Receptor de Morte Celular Programada 1/genética , Receptor de Morte Celular Programada 1/imunologia , Transdução de Sinais , Análise de Sobrevida , Linfócitos T Reguladores/patologia , Carga Tumoral
3.
Glycobiology ; 33(11): 855-860, 2023 Dec 25.
Artigo em Inglês | MEDLINE | ID: mdl-37584473

RESUMO

Cell surface glycans play essential roles in diverse physiological and pathological processes and their assessment has important implications in biomedicine and biotechnology. Here we present a rapid, versatile, and single-step multicolor flow cytometry method for evaluation of cell surface glycan signatures using a panel of selected fluorochrome-conjugated lectins. This procedure allows simultaneous detection of cell surface glycans with a 10-fold reduction in the number of cells required compared with traditional multistep lectin staining methods. Interestingly, we used this one-step lectin array coupled with dimension reduction algorithms in a proof-of-concept application for discrimination among different tumor and immune cell populations. Moreover, this procedure was also able to unveil T-, B-, and myeloid cell subclusters exhibiting differential glycophenotypes. Thus, we report a rapid and versatile lectin cytometry method to simultaneously detect a particular repertoire of surface glycans on living cells that can be easily implemented in different laboratories and core facilities.


Assuntos
Corantes Fluorescentes , Lectinas , Lectinas/metabolismo , Polissacarídeos/metabolismo , Membrana Celular/metabolismo
4.
Biochem J ; 478(3): 597-617, 2021 02 12.
Artigo em Inglês | MEDLINE | ID: mdl-33600595

RESUMO

A sequence of interconnected events known as the metastatic cascade promotes tumor progression by regulating cellular and molecular interactions between tumor, stromal, endothelial, and immune cells both locally and systemically. Recently, a new concept has emerged to better describe this process by defining four attributes that metastatic cells should undergo. Every individual hallmark represents a unique trait of a metastatic cell that impacts directly in the outcome of the metastasis process. These critical features, known as the hallmarks of metastasis, include motility and invasion, modulation of the microenvironment, cell plasticity and colonization. They are hierarchically regulated at different levels by several factors, including galectins, a highly conserved family of ß-galactoside-binding proteins abundantly expressed in tumor microenvironments and sites of metastasis. In this review, we discuss the role of galectins in modulating each hallmark of metastasis, highlighting novel therapeutic opportunities for treating the metastatic disease.


Assuntos
Galectinas/fisiologia , Metástase Neoplásica/prevenção & controle , Proteínas de Neoplasias/fisiologia , Imunidade Adaptativa , Animais , Anticorpos Neutralizantes/farmacologia , Aptâmeros de Nucleotídeos/farmacologia , Carboidratos/farmacologia , Movimento Celular , Ensaios Clínicos Fase I como Assunto , Transição Epitelial-Mesenquimal/fisiologia , Matriz Extracelular/metabolismo , Galectinas/antagonistas & inibidores , Humanos , Imunidade Inata , Camundongos , Invasividade Neoplásica , Metástase Neoplásica/imunologia , Metástase Neoplásica/fisiopatologia , Proteínas de Neoplasias/antagonistas & inibidores , Células Neoplásicas Circulantes , Neovascularização Patológica/metabolismo , Oligopeptídeos/farmacologia , Peptídeos/farmacologia , Polissacarídeos/fisiologia , RNA Interferente Pequeno/farmacologia , Células Estromais/metabolismo , Microambiente Tumoral/fisiologia
5.
Nat Immunol ; 10(9): 981-91, 2009 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-19668220

RESUMO

Despite their central function in orchestrating immunity, dendritic cells (DCs) can respond to inhibitory signals by becoming tolerogenic. Here we show that galectin-1, an endogenous glycan-binding protein, can endow DCs with tolerogenic potential. After exposure to galectin-1, DCs acquired an interleukin 27 (IL-27)-dependent regulatory function, promoted IL-10-mediated T cell tolerance and suppressed autoimmune neuroinflammation. Consistent with its regulatory function, galectin-1 had its highest expression on DCs exposed to tolerogenic stimuli and was most abundant from the peak through the resolution of autoimmune pathology. DCs lacking galectin-1 had greater immunogenic potential and an impaired ability to halt inflammatory disease. Our findings identify a tolerogenic circuit linking galectin-1 signaling, IL-27-producing DCs and IL-10-secreting T cells, which has broad therapeutic implications in immunopathology.


Assuntos
Células Dendríticas/fisiologia , Galectina 1/fisiologia , Tolerância Imunológica , Interleucina-10/fisiologia , Linfócitos T/imunologia , Animais , Antígenos CD40/fisiologia , Encefalomielite Autoimune Experimental/etiologia , Feminino , Galectina 1/genética , Regulação da Expressão Gênica , Glicoproteínas/imunologia , Interleucinas/fisiologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Glicoproteína Mielina-Oligodendrócito , Fragmentos de Peptídeos/imunologia , Fator de Transcrição STAT3/fisiologia
6.
J Immunol ; 194(7): 3452-62, 2015 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-25740944

RESUMO

Myeloid-derived suppressor cells (MDSCs) are key regulatory cells that control inflammation and promote tumor-immune escape. To date, no specific immunomodulatory drug has proven efficacy in targeting the expansion and/or function of these cells in different pathophysiologic settings. In this study, we identified a context-dependent effect of the nonsteroidal anti-inflammatory drug indomethacin (IND) on MDSCs, depending on whether they were derived from tumor microenvironments (TME) or from tumor-free microenvironments (TFME). Treatment of mice bearing the LP07 lung adenocarcinoma with IND inhibited the suppressive activity of splenic MDSCs, which restrained tumor growth through mechanisms involving CD8(+) T cells. The same effect was observed when MDSCs were treated with IND and conditioned media from LP07 tumor cells in vitro. However, in the absence of a tumor context, IND enhanced the intrinsic suppressive function of MDSCs and amplified their protumoral activity. In a model of autoimmune neuroinflammation, IND-treated MDSCs differentiated in TFME attenuated inflammation, whereas IND-treated MDSCs differentiated in TME aggravated clinical symptoms and delayed resolution of the disease. Mechanistically, IND reduced arginase activity as well as NO and reactive oxygen species production in MDSCs differentiated in TME but not in TFME. Moreover, expression of the C/EBP-ß transcription factor isoforms correlated with the suppressive activity of IND-treated MDSCs. Our study unveils the dual and context-dependent action of IND, a drug that serves both as an anti-inflammatory and anticancer agent, which differentially affects MDSC activity whether these cells are derived from TME or TFME. These results have broad clinical implication in cancer, chronic inflammation and autoimmunity.


Assuntos
Anti-Inflamatórios não Esteroides/farmacologia , Microambiente Celular/efeitos dos fármacos , Microambiente Celular/imunologia , Indometacina/farmacologia , Células Mieloides/efeitos dos fármacos , Células Mieloides/imunologia , Microambiente Tumoral/efeitos dos fármacos , Microambiente Tumoral/imunologia , Animais , Autoimunidade/efeitos dos fármacos , Modelos Animais de Doenças , Encefalomielite Autoimune Experimental/imunologia , Encefalomielite Autoimune Experimental/metabolismo , Feminino , Imunofenotipagem , Camundongos , Modelos Biológicos , Células Mieloides/metabolismo , Neoplasias/imunologia , Neoplasias/patologia , Óxido Nítrico/metabolismo , Fenótipo , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais/efeitos dos fármacos , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismo , Carga Tumoral/efeitos dos fármacos , Carga Tumoral/imunologia
7.
Cancer Immunol Immunother ; 62(12): 1781-95, 2013 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-24114144

RESUMO

The progesterone analog medroxyprogesterone acetate (MPA) is widely used as a hormone replacement therapy in postmenopausal women and as contraceptive. However, prolonged administration of MPA is associated with increased incidence of breast cancer through ill-defined mechanisms. Here, we explored whether exposure to MPA during mammary tumor growth affects myeloid-derived suppressor cells (MDSCs; CD11b(+)Gr-1(+), mostly CD11b(+)Ly6G(+)Ly6C(int) and CD11b(+)Ly6G(-)Ly6C(high) cells) and natural killer (NK) cells, potentially restraining tumor immunosurveillance. We used the highly metastatic 4T1 breast tumor (which does not express the classical progesterone receptor and expands MDSCs) to challenge BALB/c mice in the absence or in the presence of MPA. We observed that MPA promoted the accumulation of NK cells in spleens of tumor-bearing mice, but with reduced degranulation ability and in vivo cytotoxic activity. Simultaneously, MPA induced a preferential expansion of CD11b(+)Ly6G(+)Ly6C(int) cells in spleen and bone marrow of 4T1 tumor-bearing mice. In vitro, MPA promoted nuclear mobilization of the glucocorticoid receptor (GR) in 4T1 cells and endowed these cells with the ability to promote a preferential differentiation of bone marrow cells into CD11b(+)Ly6G(+)Ly6C(int) cells that displayed suppressive activity on NK cell degranulation. Sorted CD11b(+)Gr-1(+) cells from MPA-treated tumor-bearing mice exhibited higher suppressive activity on NK cell degranulation than CD11b(+)Gr-1(+) cells from vehicle-treated tumor-bearing mice. Thus, MPA, acting through the GR, endows tumor cells with an enhanced capacity to expand CD11b(+)Ly6G(+)Ly6C(int) cells that subsequently display a stronger suppression of NK cell-mediated anti-tumor immunity. Our results describe an alternative mechanism by which MPA may affect immunosurveillance and have potential implication in breast cancer incidence.


Assuntos
Antígenos Ly/imunologia , Neoplasias da Mama/imunologia , Antígeno CD11b/imunologia , Células Matadoras Naturais/imunologia , Acetato de Medroxiprogesterona/farmacologia , Células Mieloides/imunologia , Animais , Antígenos Ly/metabolismo , Antineoplásicos Hormonais/farmacologia , Western Blotting , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Antígeno CD11b/metabolismo , Diferenciação Celular , Proliferação de Células , Citotoxicidade Imunológica , Feminino , Citometria de Fluxo , Imunofluorescência , Humanos , Células Matadoras Naturais/efeitos dos fármacos , Células Matadoras Naturais/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Células Mieloides/efeitos dos fármacos , Células Mieloides/metabolismo , Receptores de Glucocorticoides/metabolismo , Fator de Transcrição STAT3/metabolismo , Células Tumorais Cultivadas
8.
Int J Cancer ; 131(5): 1131-41, 2012 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-22020795

RESUMO

The immunosuppressive strategies devised by neuroblastoma (NB), the most common solid extracranial childhood cancer, are poorly understood. Here, we identified an immunoevasive program triggered by NB through secretion of galectin-1 (Gal-1), a multifunctional glycan-binding protein. Human and mouse NB cells express and secrete Gal-1, which negatively regulates T cell and dendritic cell function. When injected subcutaneously in syngeneic A/J mice, knockdown transfectants expressing low amounts of Gal-1 (NXS2/L) showed reduction of primary tumor growth by 83-90% and prevented spontaneous liver metastases in contrast to NXS2 cell variants (NXS2/H, NXS2 wildtype) expressing high amounts of Gal-1. Splenocytes from mice receiving Gal-1 knockdown NXS2/L cells secreted higher amounts of IFN-γ and displayed enhanced cytotoxic T-cell function compared to NXS2/H or NXS2 controls. Immunohistochemical analysis revealed a six- to tenfold increase in the frequency of CD4+ and CD8+ T cells infiltrating tumors from mice receiving knockdown transfectants. This effect was confirmed by in vitro migration assays. Finally, supernatants of NXS2/H or NXS2 cells suppressed dendritic cell (DC) maturation and induce T cell apoptosis, whereas these effects were only marginal on DCs and T cells exposed to supernatants from NXS2/L cells. These results demonstrate a novel immunoinhibitory role of the Gal-1-glycan axis in NB, highlighting an alternative target for novel immunotherapeutic modalities.


Assuntos
Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Células Dendríticas/imunologia , Galectina 1/metabolismo , Neoplasias Pulmonares/imunologia , Neuroblastoma/imunologia , Linfócitos T Citotóxicos/imunologia , Animais , Células Apresentadoras de Antígenos/imunologia , Células Apresentadoras de Antígenos/metabolismo , Células Apresentadoras de Antígenos/patologia , Apoptose , Western Blotting , Linfócitos T CD4-Positivos/metabolismo , Linfócitos T CD4-Positivos/patologia , Linfócitos T CD8-Positivos/metabolismo , Linfócitos T CD8-Positivos/patologia , Adesão Celular , Movimento Celular , Proliferação de Células , Células Dendríticas/metabolismo , Células Dendríticas/patologia , Feminino , Citometria de Fluxo , Galectina 1/genética , Terapia Genética , Humanos , Técnicas Imunoenzimáticas , Interferon gama/metabolismo , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/prevenção & controle , Neoplasias Pulmonares/secundário , Camundongos , Camundongos Endogâmicos A , Neuroblastoma/metabolismo , Neuroblastoma/patologia , Neuroblastoma/prevenção & controle , Linfócitos T Citotóxicos/metabolismo , Linfócitos T Citotóxicos/patologia , Células Tumorais Cultivadas
9.
Cancer Immunol Immunother ; 61(4): 469-80, 2012 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-21947259

RESUMO

Although lymphomas account for almost half of blood-derived cancers that are diagnosed each year, the causes of new cases are poorly understood, as reflected by the relatively few risk factors established. Galectin-1, an immunoregulatory ß-galactoside-binding protein, has been widely associated with tumor-immune escape. The aim of the present work was to study the relationship between tumor growth rate, aggressiveness, and response to cyclophosphamide (Cy) therapy with regard to Gal-1 expression in murine T-cell lymphoma models. By means of a disruptive selection process for tumor growth rate, we generated two lymphoma variants from a parental T-cell lymphoma, which have unique characteristics in terms of tumor growth rate, spontaneous regression, metastatic capacity, Gal-1 expression and sensitivity to Cy therapy. Here, we show that Gal-1 expression strongly correlates with tumor growth rate, metastatic capacity and response to single-dose Cy therapy in T-cell lymphoma models; this association might have important consequences for evaluating prognosis and treatments of this type of tumors.


Assuntos
Galectina 1/metabolismo , Linfoma de Células T/patologia , Linfócitos T Reguladores/metabolismo , Animais , Antígenos CD4/metabolismo , Proliferação de Células/efeitos dos fármacos , Ciclofosfamida/administração & dosagem , Feminino , Fatores de Transcrição Forkhead/metabolismo , Galectina 1/genética , Galectina 1/imunologia , Regulação Neoplásica da Expressão Gênica , Humanos , Terapia de Imunossupressão , Subunidade alfa de Receptor de Interleucina-2/metabolismo , Linfoma de Células T/tratamento farmacológico , Linfoma de Células T/imunologia , Camundongos , Metástase Neoplásica , Linfócitos T Reguladores/efeitos dos fármacos , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/patologia
10.
Methods Mol Biol ; 2442: 635-653, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35320550

RESUMO

Development of an aberrant vascular network is a hallmark of the multistep pathological process of tumor growth and metastasis. In response to hypoxia, several pro-angiogenic factors are synthesized to support vascularization programs required for cancer progression. Emerging data indicate the involvement of glycans and glycan-binding proteins as critical regulators of vascular circuits in health and disease. Galectins may be regulated by hypoxic conditions and control angiogenesis in different physiopathological settings. These ß-galactoside-binding proteins may promote sprouting angiogenesis by interacting with different glycosylated receptors and triggering distinct signaling pathways. Understanding the role of galectins in tumor neovascularization will contribute to the design of novel anti-angiogenic therapies aimed at complementing current anti-cancer modalities and overcoming resistance to these treatments. Here we describe selected strategies and methods used to study the role of hypoxia-regulated galectins in the regulation of blood vessel formation.


Assuntos
Galectinas , Hipóxia , Neoplasias , Neovascularização Patológica , Galectinas/metabolismo , Humanos , Hipóxia/fisiopatologia , Neoplasias/irrigação sanguínea , Neovascularização Patológica/fisiopatologia , Transdução de Sinais
11.
Cancer Res ; 81(5): 1375-1387, 2021 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-33268529

RESUMO

The role of active antitumor immunity in hormone receptor-positive (HR+) breast cancer has been historically underlooked. The aim of this study was to determine the contribution of the immune system to antiprogestin-induced tumor growth inhibition using a hormone-dependent breast cancer model. BALB/c-GFP+ bone marrow (BM) cells were transplanted into immunodeficient NSG mice to generate an immunocompetent NSG/BM-GFP+ (NSG-R) mouse model. Treatment with the antiprogestin mifepristone (MFP) inhibited growth of 59-2-HI tumors with similar kinetics in both animal models. Interestingly, MFP treatment reshaped the tumor microenvironment, enhancing the production of proinflammatory cytokines and chemokines. Tumors in MFP-treated immunocompetent mice showed increased infiltration of F4/80+ macrophages, natural killer, and CD8 T cells, displaying a central memory phenotype. Mechanistically, MFP induced immunogenic cell death (ICD) in vivo and in vitro, as depicted by the expression and subcellular localization of the alarmins calreticulin and HMGB-1 and the induction of an ICD gene program. Moreover, MFP-treated tumor cells efficiently activated immature dendritic cells, evidenced by enhanced expression of MHC-II and CD86, and induced a memory T-cell response, attenuating tumor onset and growth after re-challenge. Finally, MFP treatment increased the sensitivity of HR+ 59-2-HI tumor to PD-L1 blockade, suggesting that antiprogestins may improve immunotherapy response rates. These results contribute to a better understanding of the mechanisms underlying the antitumor effect of hormonal treatment and the rational design of therapeutic combinations based on endocrine and immunomodulatory agents in HR+ breast cancer. SIGNIFICANCE: Antiprogestin therapy induces immunogenic tumor cell death in PRA-overexpressing tumors, eliciting an adaptive immune memory response that protects mice from future tumor recurrence and increases sensitivity to PD-L1 blockade. GRAPHICAL ABSTRACT: http://cancerres.aacrjournals.org/content/canres/81/5/1375/F1.large.jpg.


Assuntos
Inibidores de Checkpoint Imunológico/farmacologia , Neoplasias Mamárias Experimentais/tratamento farmacológico , Neoplasias Mamárias Experimentais/imunologia , Animais , Antígeno B7-H1/antagonistas & inibidores , Morte Celular/efeitos dos fármacos , Morte Celular/imunologia , Linhagem Celular Tumoral , Células Dendríticas/imunologia , Feminino , Humanos , Memória Imunológica/efeitos dos fármacos , Neoplasias Mamárias Experimentais/patologia , Camundongos Endogâmicos BALB C , Camundongos Transgênicos , Mifepristona/farmacologia , Microambiente Tumoral/efeitos dos fármacos , Microambiente Tumoral/imunologia
12.
IUBMB Life ; 62(1): 1-13, 2010 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-20014236

RESUMO

Galectins are a family of evolutionarily conserved animal lectins with pleiotropic functions and widespread distribution. Fifteen members have been identified in a wide variety of cells and tissues. Through recognition of cell surface glycoproteins and glycolipids, these endogenous lectins can trigger a cascade of intracellular signaling pathways capable of modulating cell differentiation, proliferation, survival, and migration. These cellular events are critical in a variety of biological processes including embryogenesis, angiogenesis, neurogenesis, and immunity and are substantially altered during tumorigenesis, neurodegeneration, and inflammation. In addition, galectins can modulate intracellular functions and this effect involves direct interactions with distinct signaling pathways. In this review, we discuss current knowledge on the intracellular signaling pathways triggered by this multifunctional family of beta-galactoside-binding proteins in selected physiological and pathological settings. Understanding the "galectin signalosome" will be essential to delineate rational therapeutic strategies based on the specific control of galectin expression and function.


Assuntos
Galectinas/metabolismo , Hematopoese/fisiologia , Neoplasias/fisiopatologia , Polissacarídeos/metabolismo , Transdução de Sinais , Animais , Humanos
13.
Cytokine Growth Factor Rev ; 18(1-2): 57-71, 2007.
Artigo em Inglês | MEDLINE | ID: mdl-17321195

RESUMO

Several families of endogenous glycan-binding proteins have been implicated in a wide variety of immunological functions including first-line defence against pathogens, cell trafficking, and immune regulation. These include, among others, the C-type lectins (collectins, selectins, mannose receptor, and others), S-type lectins (galectins), I-type lectins (siglecs and others), P-type lectins (phosphomannosyl receptors), pentraxins, and tachylectins. This review will concentrate on the immunoregulatory roles of galectins (particularly galectin-1) and collectins (mannose-binding lectins and surfactant proteins) to illustrate the ability of endogenous glycan-binding proteins to act as cytokines, chemokines or growth factors, and thereby modulating innate and adaptive immune responses under physiological or pathological conditions. Understanding the pathophysiologic relevance of endogenous lectins in vivo will reveal novel targets for immunointervention during chronic infection, autoimmunity, transplantation and cancer.


Assuntos
Colectinas/imunologia , Citocinas/imunologia , Galectina 1/imunologia , Polissacarídeos/imunologia , Animais , Autoimunidade , Doença Crônica , Humanos , Infecções/imunologia , Infecções/patologia , Infecções/fisiopatologia , Inflamação/imunologia , Inflamação/patologia , Inflamação/fisiopatologia , Neoplasias/imunologia , Neoplasias/patologia , Neoplasias/fisiopatologia , Transplante de Órgãos
14.
J Exp Med ; 217(2)2020 02 03.
Artigo em Inglês | MEDLINE | ID: mdl-31873723

RESUMO

Hanahan and Weinberg have proposed 10 organizing principles that enable growth and metastatic dissemination of cancer cells. These distinctive and complementary capabilities, defined as the "hallmarks of cancer," include the ability of tumor cells and their microenvironment to sustain proliferative signaling, evade growth suppressors, resist cell death, promote replicative immortality, induce angiogenesis, support invasion and metastasis, reprogram energy metabolism, induce genomic instability and inflammation, and trigger evasion of immune responses. These common features are hierarchically regulated through different mechanisms, including those involving glycosylation-dependent programs that influence the biological and clinical impact of each hallmark. Galectins, an evolutionarily conserved family of glycan-binding proteins, have broad influence in tumor progression by rewiring intracellular and extracellular circuits either in cancer or stromal cells, including immune cells, endothelial cells, and fibroblasts. In this review, we dissect the role of galectins in shaping cellular circuitries governing each hallmark of tumors, illustrating relevant examples and highlighting novel opportunities for treating human cancer.


Assuntos
Carcinogênese/metabolismo , Galectinas/metabolismo , Neoplasias/metabolismo , Animais , Biomarcadores Tumorais/metabolismo , Morte Celular , Proliferação de Células , Metabolismo Energético , Instabilidade Genômica , Glicosilação , Humanos , Inflamação/metabolismo , Metástase Neoplásica , Neovascularização Patológica/metabolismo , Telomerase/metabolismo , Evasão Tumoral
15.
Mol Cell Biol ; 25(12): 4826-40, 2005 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-15923602

RESUMO

Interactions between steroid hormone receptors and signal transducer and activator of transcription (Stat)-mediated signaling pathways have already been described. In the present study, we explored the capacity of progestins to modulate Stat3 transcriptional activation in an experimental model of hormonal carcinogenesis in which the synthetic progestin medroxyprogesterone acetate (MPA) induced mammary adenocarcinomas in BALB/c mice and in the human breast cancer cell line T47D. We found that C4HD epithelial cells, from the MPA-induced mammary tumor model, expressed Stat3 and that MPA treatment of C4HD cells up-regulated Stat3 protein expression. In addition, MPA induced rapid, nongenomic Stat3, Jak1, and Jak2 tyrosine phosphorylation in C4HD and T47D cells. MPA treatment of C4HD cells also resulted in rapid c-Src tyrosine phosphorylation. These effects were completely abolished by the progestin antagonist RU486. Abrogation of Jak1 and Jak2 activity by transient transfection of C4HD cells with dominant negative (DN) Jak1 or DN Jak2 vectors, or inhibition of Src activity by preincubation of cells with the Src family kinase inhibitor PP2, blocked the capacity of MPA to induce Stat3 phosphorylation. Treatment of C4HD cells with MPA induced Stat3 binding to DNA. In addition, MPA promoted strong Stat3 transcriptional activation in C4HD and T47D cells that was inhibited by RU486 and by blockage of Jak1, Jak2, and Src activities. To investigate the correlation between MPA-induced Stat3 activation and cell growth, C4HD cells were transiently transfected with a DN Stat3 expression vector, Stat3Y705-F, or with a constitutively activated Stat3 mutant, Stat3-C. While expression of Stat3Y705-F mutant had an inhibitory effect on MPA-induced growth of C4HD cells, transfection with the constitutively activated Stat3-C vector resulted in MPA-independent proliferation. Finally, we addressed the effect of targeting Stat3 in in vivo growth of C4HD breast tumors. Blockage of Stat3 activation by transfection of C4HD cells with the DN Stat3Y705-F expression vector significantly inhibited these cells' ability to form tumors in syngeneic mice. Our results have for the first time demonstrated that progestins are able to induce Stat3 transcriptional activation, which is in turn an obligatory requirement for progestin stimulation of both in vitro and in vivo breast cancer growth.


Assuntos
Proteínas de Ligação a DNA/metabolismo , Progestinas/metabolismo , Proteínas Tirosina Quinases/metabolismo , Proteínas Proto-Oncogênicas/metabolismo , Transativadores/metabolismo , Ativação Transcricional , Quinases da Família src/metabolismo , Transporte Ativo do Núcleo Celular , Animais , Antineoplásicos Hormonais/metabolismo , Neoplasias da Mama , Linhagem Celular Tumoral , DNA/metabolismo , Proteínas de Ligação a DNA/genética , Células Epiteliais/citologia , Células Epiteliais/metabolismo , Feminino , Humanos , Janus Quinase 1 , Janus Quinase 2 , Acetato de Medroxiprogesterona/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Proteínas Tirosina Quinases/genética , Proteínas Proto-Oncogênicas/genética , Receptores de Progesterona/metabolismo , Fator de Transcrição STAT3 , Transativadores/genética , Quinases da Família src/genética
16.
Mol Endocrinol ; 21(6): 1335-58, 2007 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-17440047

RESUMO

Accumulating evidence indicates that progestins are involved in controlling mammary gland tumorigenesis. Here, we assessed the molecular mechanisms of progestin action in breast cancer models with different phenotypes. We examined C4HD cells, an estrogen (ER) and progesterone (PR) receptor-positive murine breast cancer model in which progestins exert sustained proliferative response, the LM3 murine metastatic mammary tumor cell line, which lacks PR and ER expression, and human PR null T47D-Y breast cancer cells. In addition to acting as a transcription factor, PR can also function as an activator of signaling pathways. To explore which of these two functions were involved in progestin responses, reconstitution experiments in the PR-negative models were performed with wild-type PR-B, with a DNA binding mutant C587A-PR, and with mutant PR-BmPro, which lacks the ability to activate cytoplasm signaling pathways. We found that in a cell context either ER-positive or -negative, progestins induced cell growth and modulation of matrix metalloproteinases-9 (MMP-9) and -2 (MMP-2), and urokinase-type plasminogen activator (uPA) activities, via MAPK and phosphatidylinositol 3-kinase/Akt pathways, in cells expressing wild-type PR-B or DNA binding mutant C587A-PR. In contrast, in cells expressing mutant PR-BmPro, progestins did not induce growth. We also found that unliganded PR expression conferred breast cancer cells an in vitro less proliferative phenotype, as compared with cells lacking PR expression. Modulation of this behavior occurred when PR was functioning either as transcription factor or as signaling activator. Finally, we for the first time demonstrated that progestins favor development of breast tumor metastasis via PR function as activator of signaling pathways. Our present findings provide mechanistic support to the design of a novel therapeutic intervention in PR-positive breast tumors involving blockage of PR capacity to activate cytoplasmic signaling.


Assuntos
Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Peptídeo Hidrolases/metabolismo , Progestinas/farmacologia , Receptores de Progesterona/metabolismo , Animais , Neoplasias da Mama/genética , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Citoplasma/metabolismo , Metaloproteinase 2 da Matriz/metabolismo , Metaloproteinase 9 da Matriz/metabolismo , Camundongos , Quinases de Proteína Quinase Ativadas por Mitógeno/antagonistas & inibidores , Quinases de Proteína Quinase Ativadas por Mitógeno/metabolismo , Metástase Neoplásica , Fosfatidilinositol 3-Quinases/metabolismo , Inibidores de Fosfoinositídeo-3 Quinase , Receptores de Progesterona/genética , Transdução de Sinais , Ativador de Plasminogênio Tipo Uroquinase/metabolismo
17.
Cancer Cell ; 33(2): 155-157, 2018 02 12.
Artigo em Inglês | MEDLINE | ID: mdl-29438689

RESUMO

The clinical efficacy of therapies targeting the PD-1/PD-L1 pathway is still limited. In this issue of Cancer Cell, Li and colleagues identify a PD-L1 glycosylation-based mechanism in triple-negative breast cancer that fosters immunosuppression by enhancing interactions with PD-1. Targeting glycosylated PD-L1 with a drug-conjugated antibody opens new avenues for treatment.


Assuntos
Antígeno B7-H1 , Neoplasias de Mama Triplo Negativas , Humanos , Imunoterapia , Polissacarídeos
19.
Mol Cell Biol ; 23(3): 1095-111, 2003 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-12529413

RESUMO

The present study addresses the capacity of heregulin (HRG), a ligand of type I receptor tyrosine kinases, to transactivate the progesterone receptor (PR). For this purpose, we studied, on the one hand, an experimental model of hormonal carcinogenesis in which the synthetic progestin medroxyprogesterone acetate (MPA) induced mammary adenocarcinomas in female BALB/c mice and, on the other hand, the human breast cancer cell line T47D. HRG was able to exquisitely regulate biochemical attributes of PR in a way that mimicked PR activation by progestins. Thus, HRG treatment of primary cultures of epithelial cells of the progestin-dependent C4HD murine mammary tumor line and of T47D cells induced a decrease of protein levels of PRA and -B isoforms and the downregulation of progesterone-binding sites. HRG also promoted a significant increase in the percentage of PR localized in the nucleus in both cell types. DNA mobility shift assay revealed that HRG was able to induce PR binding to a progesterone response element (PRE) in C4HD and T47D cells. Transient transfections of C4HD and T47D cells with a plasmid containing a PRE upstream of a chloramphenicol acetyltransferase (CAT) gene demonstrated that HRG promoted a significant increase in CAT activity. In order to assess the molecular mechanisms underlying PR transactivation by HRG, we blocked ErbB-2 expression in C4HD and T47D cells by using antisense oligodeoxynucleotides to ErbB-2 mRNA, which resulted in the abolishment of HRG's capacity to induce PR binding to a PRE, as well as CAT activity in the transient-transfection assays. Although the inhibition of HRG binding to ErbB-3 by an anti-ErbB-3 monoclonal antibody suppressed HRG-induced PR activation, the abolishment of HRG binding to ErbB-4 had no effect on HRG activation of PR. To investigate the role of mitogen-activated protein kinases (MAPKs), we used the selective MEK1/MAPK inhibitor PD98059. Blockage of MAPK activation resulted in complete abrogation of HRG's capacity to induce PR binding to a PRE, as well as CAT activity. Finally, we demonstrate here for the first time that HRG-activated MAPK can phosphorylate both human and mouse PR in vitro.


Assuntos
Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Neoplasias Mamárias Experimentais/genética , Neoplasias Mamárias Experimentais/metabolismo , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Neuregulina-1/farmacologia , Receptor ErbB-2/metabolismo , Receptores de Progesterona/genética , Animais , Neoplasias da Mama/patologia , Divisão Celular/efeitos dos fármacos , Núcleo Celular/efeitos dos fármacos , Núcleo Celular/metabolismo , Inibidores Enzimáticos/farmacologia , Feminino , Flavonoides/farmacologia , Genes erbB-2 , Antagonistas de Hormônios/farmacologia , Humanos , Neoplasias Mamárias Experimentais/patologia , Camundongos , Camundongos Endogâmicos BALB C , Mifepristona/farmacologia , Proteínas Quinases Ativadas por Mitógeno/antagonistas & inibidores , Fosforilação , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , RNA Neoplásico/genética , RNA Neoplásico/metabolismo , Receptor ErbB-2/genética , Receptores de Progesterona/metabolismo , Ativação Transcricional/efeitos dos fármacos , Células Tumorais Cultivadas
20.
Oncogene ; 23(30): 5161-74, 2004 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-15122317

RESUMO

The present study addresses the effect of targeting type I insulin-like growth factor receptor (IGF-IR) with antisense strategies in in vivo growth of breast cancer cells. Our research was carried out on C4HD tumors from an experimental model of hormonal carcinogenesis in which the synthetic progestin medroxyprogesterone acetate (MPA) induced mammary adenocarcinomas in Balb/c mice. We employed two different experimental strategies. With the first one we demonstrated that direct intratumor injection of phosphorothioate antisense oligodeoxynucleotides (AS[S]ODNs) to IGF-IR mRNA resulted in a significant inhibition of C4HD tumor growth. In the second experimental strategy, we assessed the effect of intravenous (i.v.) injection of AS [S]ODN on C4HD tumor growth. This systemic treatment also resulted in significant reduction in tumor growth. The antitumor effect of IGF-IR AS[S]ODNs in both experimental protocols was due to a specific antisense mechanism, since growth inhibition was dose-dependent and no abrogation of tumor proliferation was observed in mice treated with phosphorothioate sense ODNs (S[S]ODNs). In addition, IGF-IR expression was inhibited in tumors from mice receiving AS[S]ODNs, as compared to tumors from control groups. We then investigated signal transduction pathways modulated in vivo by AS[S]ODNs treatment. Tumors from AS[S]ODN-treated mice of both intratumoral and intravenous protocols showed a significant decrease in the degree of insulin receptor substrate-1 (IRS-1) tyrosine phosphorylation. Activation of two of the main IGF-IR signaling pathways, phosphatidylinositol 3-kinase (PI-3K)/Akt and p42/p44 mitogen-activated protein kinases (MAPK) was abolished in tumors growing in AS[S]ODN-treated animals. Moreover, ErbB-2 tyrosine phosphorylation was blocked by in vivo administration of AS[S]ODNs. On the other hand, we found no regulation of either progesterone receptor expression or activity by in vivo AS[S]ODNs administration. Our results for the first time demonstrated that breast cancer growth can be inhibited by direct in vivo administration of IGF-IR AS[S]ODNs.


Assuntos
Neoplasias Mamárias Experimentais/terapia , Proteína Quinase 1 Ativada por Mitógeno/metabolismo , Oligodesoxirribonucleotídeos Antissenso/farmacologia , Fosfatidilinositol 3-Quinases/metabolismo , Receptor IGF Tipo 1/metabolismo , Receptores de Progesterona/metabolismo , Animais , Divisão Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ativação Enzimática , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/metabolismo , Células Epiteliais/patologia , Feminino , Genes erbB-1/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos BALB C , Proteína Quinase 1 Ativada por Mitógeno/antagonistas & inibidores , Transplante de Neoplasias , Inibidores de Fosfoinositídeo-3 Quinase , RNA Mensageiro/efeitos dos fármacos , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Receptor IGF Tipo 1/antagonistas & inibidores , Receptor IGF Tipo 1/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Células Tumorais Cultivadas
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