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1.
J Cell Physiol ; 230(6): 1298-309, 2015 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-25469885

RESUMO

Galectin-1 (Gal1), a ß-galactoside-binding protein abundantly expressed in tumor microenvironments, is associated with the development of metastasis in hepatocellular carcinomas (HCC). However, the precise roles of Gal1 in HCC cell invasiveness and dissemination are uncertain. Here, we investigated whether Gal1 mediate epithelial-mesenchymal transition (EMT) in HCC cells, a key process during cancer progression. We used the well-differentiated and low invasive HepG2 cells and performed 'gain-of-function' and 'loss-function' experiments by transfecting cells with Gal1 cDNA constructs or by siRNA strategies, respectively. Epithelial and mesenchymal markers expression, changes in apico-basal polarity, independent-anchorage growth, and activation of specific signaling pathways were studied using Western blot, fluorescence microscopy, soft-agar assays, and FOP/TOP flash reporter system. Gal1 up-regulation in HepG2 cells induced down-regulation of the adherens junction protein E-cadherin and increased expression of the transcription factor Snail, one of the main inducers of EMT in HCC. Enhanced Gal1 expression facilitated the transition from epithelial cell morphology towards a fibroblastoid phenotype and favored up-regulation of the mesenchymal marker vimentin in HCC cells. Cells overexpressing Gal1 showed enhanced anchorage-independent growth and loss of apico-basal polarity. Remarkably, Gal1 promoted Akt activation, ß-catenin nuclear translocation, TCF4/LEF1 transcriptional activity and increased cyclin D1 and c-Myc expression, suggesting activation of the Wnt pathway. Furthermore, Gal1 overexpression induced E-cadherin downregulation through a PI3K/Akt-dependent mechanism. Our results provide the first evidence of a role of Gal1 as an inducer of EMT in HCC cells, with critical implications in HCC metastasis.


Assuntos
Caderinas/metabolismo , Carcinoma Hepatocelular/metabolismo , Transição Epitelial-Mesenquimal/fisiologia , Galectina 1/metabolismo , Linhagem Celular Tumoral , Regulação para Baixo/fisiologia , Humanos , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patologia , Fosfatidilinositol 3-Quinases/metabolismo , Regulação para Cima , beta Catenina/metabolismo
2.
Glycobiology ; 24(10): 899-906, 2014 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-24939371

RESUMO

Prostate cancer is the second most common cause of cancer and the sixth leading cause of cancer death among men worldwide. While localized prostate cancer can be cured, advanced and metastatic prostate cancer remains a significant therapeutic challenge. Malignant transformation is associated with important modifications of the cellular glycosylation profile, and it is postulated that these changes have a considerable relevance for tumor biology. Metastasis is a multiphasic process that encompasses angiogenesis, the spread of tumor cells and their growth at distant sites from the primary tumor location. Recognition of glycoconjugates by galectins, among other lectins, plays a fundamental role in the metastatic spread, tumor immune escape and the neovascularization process. Particularly in prostate cancer, both carbohydrates and galectins have been implicated in many cellular processes such as proliferation, apoptosis, migration and invasion. However, a limited number of studies assessed their potential implications in the induction of metastasis in prostate cancer patients or in animal models. Moreover, the role of galectin-glycan interactions in vivo still remains poorly understood; concerted effort should thus be made in order to shed some light on this question. This review summarizes current evidence on both the expression and role of glycans and galectins in prostate cancer, particularly turning our attention to the angiogenic and metastatic processes.


Assuntos
Galectinas/genética , Neovascularização Patológica/genética , Polissacarídeos/genética , Neoplasias da Próstata/genética , Apoptose/genética , Movimento Celular/genética , Proliferação de Células/genética , Galectinas/metabolismo , Regulação Neoplásica da Expressão Gênica , Humanos , Masculino , Metástase Neoplásica , Polissacarídeos/metabolismo , Neoplasias da Próstata/patologia
3.
Glycobiology ; 24(10): 907-14, 2014 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-24939370

RESUMO

Galectin-8 (gal-8) is a "tandem-repeat"-type galectin, containing two carbohydrate recognition domains connected by a linker peptide. gal-8 is expressed both in the cytoplasm and nucleus in vascular endothelial cells (ECs) from normal and tumor-associated blood vessels, and in lymphatic endothelial cells. Herein, we describe a novel role for gal-8 in the regulation of vascular and lymphatic angiogenesis and provide evidence of its critical implications in tumor biology. Functional assays revealed central roles for gal-8 in the control of capillary-tube formation, EC migration and in vivo angiogenesis. So far, two endothelial ligands have been described for gal-8, namely podoplanin in lymphatic vessels and CD166 (ALCAM, activated leukocyte cell adhesion molecule) in vascular ECs. Other related gal-8 functions are also summarized here, including cell adhesion and migration, which collectively demonstrate the multi-functionality of this complex lectin. Thus, gal-8 is an important component of the angiogenesis network, and an essential molecule in the extracellular matrix by providing molecular anchoring to this surrounding matrix. The implications of gal-8 in tumor angiogenesis remain to be further explored, but it is exciting to speculate that modulating gal-8-glycan interactions could be used to block lymphatic-vascular connections vital for metastasis.


Assuntos
Carcinogênese/genética , Galectinas/genética , Neoplasias/genética , Neovascularização Patológica/genética , Antígenos CD/genética , Antígenos CD/metabolismo , Adesão Celular/genética , Moléculas de Adesão Celular Neuronais/genética , Moléculas de Adesão Celular Neuronais/metabolismo , Células Endoteliais/metabolismo , Células Endoteliais/patologia , Matriz Extracelular/genética , Proteínas Fetais/genética , Proteínas Fetais/metabolismo , Galectinas/metabolismo , Humanos , Glicoproteínas de Membrana/genética , Glicoproteínas de Membrana/metabolismo , Metástase Neoplásica , Neoplasias/patologia , Neovascularização Patológica/patologia
4.
FASEB J ; 25(1): 242-54, 2011 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-20876211

RESUMO

Angiogenesis, the growth of new capillaries from preexisting blood vessels, is a complex process involving endothelial cell (EC) activation, disruption of vascular basement membranes, and migration and proliferation of ECs. Glycan-mediated recognition has been proposed to play an instrumental role in mediating cell-cell and cell-matrix interactions. Galectins (Gal), a family of glycan-binding proteins with affinity for ß-galactosides and a conserved sequence motif, can decipher glycan-containing information and mediate cell-cell communication. Galectin-8 (Gal-8), a member of this family, is a bivalent "tandem-repeat"-type galectin, which possesses 2 CRDs connected by a linker peptide. Here, we show that Gal-8 is endowed with proangiogeneic properties. Functional assays revealed a critical role for this lectin in the regulation of capillary-tube formation and EC migration. Moreover, Matrigel, either supplemented with Gal-8 or vascular endothelial growth factor (VEGF), injected in mice resulted in induction of in vivo angiogenesis. Remarkably, Gal-8 was expressed both in the cytoplasm and nucleus in ECs of normal and tumor vessels. Furthermore, CD166 [activated leukocyte cell adhesion molecule (ALCAM)] was identified as a specific Gal-8-binding partner in normal vascular ECs. Collectively, these data provide the first evidence demonstrating an essential role for Gal-8 in the regulation of angiogenesis with critical implications in tumor biology.


Assuntos
Movimento Celular/efeitos dos fármacos , Células Endoteliais/efeitos dos fármacos , Galectinas/farmacologia , Neovascularização Fisiológica/efeitos dos fármacos , Molécula de Adesão de Leucócito Ativado/metabolismo , Animais , Linhagem Celular , Núcleo Celular/metabolismo , Colágeno , Citoplasma/metabolismo , Relação Dose-Resposta a Droga , Combinação de Medicamentos , Células Endoteliais/metabolismo , Células Endoteliais/fisiologia , Feminino , Galectinas/genética , Galectinas/metabolismo , Humanos , Immunoblotting , Imuno-Histoquímica , Imunoprecipitação , Cinética , Laminina , Camundongos , Camundongos Endogâmicos BALB C , Neoplasias/irrigação sanguínea , Neoplasias/metabolismo , Neoplasias/patologia , Molécula-1 de Adesão Celular Endotelial a Plaquetas/análise , Ligação Proteica , Proteoglicanas , Ratos , Proteínas Recombinantes/farmacologia , Fator A de Crescimento do Endotélio Vascular/farmacologia
5.
Exp Cell Res ; 317(3): 262-75, 2011 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-20974126

RESUMO

Deciphering molecular pathways involved in the early steps of prostate oncogenesis requires both in vitro and in vivo models derived from human primary tumors. However the few recognized models of human prostate epithelial cancer originate from metastases. To date, very few models are proposed from primary tumors and immortalizing normal human prostate cells does not recapitulate the natural history of the disease. By culturing human prostate primary tumor cells onto human epithelial extra-cellular matrix, we successfully selected a new prostate cancer cell line, IGR-CaP1, and clonally-derived subclones. IGR-CaP1 cells, that harbor a tetraploid karyotype, high telomerase activity and mutated TP53, rapidly induced subcutaneous xenografts in nude mice. Furthermore, IGR-CaP1 cell lines, all exhibiting negativity for the androgen receptor and PSA, express the specific prostate markers alpha-methylacyl-CoA racemase and a low level of the prostate-specific membrane antigen PSMA, along with the prostate basal epithelial markers CK5 and CK14. More importantly, these clones express high CD44, CD133, and CXCR4 levels associated with high expression of α2ß1-integrin and Oct4 which are reported to be prostate cancer stemness markers. RT-PCR data also revealed high activation of the Sonic Hedgehog signalling pathway in these cells. Additionally, the IGR-CaP1 cells possess a 3D sphere-forming ability and a renewal capacity by maintaining their CSC potential after xenografting in mice. As a result, the hormone-independent IGR-CaP1 cellular clones exhibit the original features of both basal prostate tissue and cancer stemness. Tumorigenic IGR-CaP1 clones constitute invaluable human models for studying prostate cancer progression and drug assessment in vitro as well as in animals specifically for developing new therapeutic approaches targeting prostate cancer stem cells.


Assuntos
Matriz Extracelular/patologia , Neoplasias da Próstata/patologia , Células Tumorais Cultivadas , Animais , Antígenos de Superfície/análise , Biomarcadores Tumorais/análise , Células Clonais/patologia , Humanos , Imunofenotipagem , Masculino , Camundongos , Camundongos Nus , Transplante de Neoplasias , Transplante Heterólogo
6.
Front Immunol ; 13: 1104625, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36703969

RESUMO

Galectins play relevant roles in tumor development, progression and metastasis. Accordingly, galectins are certainly enticing targets for medical intervention in cancer. To date, however, clinical trials based on galectin inhibitors reported inconclusive results. This review summarizes the galectin inhibitors currently being evaluated and discusses some of the biological challenges that need to be addressed to improve these strategies for the benefit of cancer patients.


Assuntos
Antineoplásicos , Galectinas , Neoplasias , Humanos , Galectinas/antagonistas & inibidores , Neoplasias/tratamento farmacológico , Neoplasias/metabolismo , Antineoplásicos/uso terapêutico
7.
J Immunol ; 182(12): 7681-9, 2009 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-19494292

RESUMO

Dok-4 (downstream of tyrosine kinase-4) is a recently identified member of the Dok family of adaptor proteins, which are characterized by an amino-terminal pleckstrin homology domain, a phosphotyrosine-binding domain, and a carboxyl-terminal region containing several tyrosines and poly-proline-rich motifs. Two members of the Dok family, Dok-1 and Dok-2, have already been described as negative regulators in T cells. However, the function of Dok-4, which is also expressed in T cells, remains unknown. In this study, we report that Dok-4 is phosphorylated after TCR engagement and shuttled within the cytoplasm of T cells before being recruited to the polarized microtubule organizing center after the formation of the immunological synapse. Loss-of-function experiments using RNA interference constructs show that Dok-4 is a negative regulator of ERK phosphorylation, IL-2 promoter activity, and T cell proliferation. Exogenous expression of wild-type Dok-4 induces a significant activation of Rap1, which is involved in the regulation of ERK. The pleckstrin homology domain of Dok-4 is required both for its cytoplasmic shuttling and relocalization as well as for its inhibitory properties on T cell activation. Thus, Dok-4 represents a novel negative regulator of T cells.


Assuntos
Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Ativação Linfocitária/imunologia , Linfócitos T/imunologia , Linfócitos T/metabolismo , Proteínas Adaptadoras de Transdução de Sinal , Motivos de Aminoácidos , Células Apresentadoras de Antígenos/imunologia , Células Apresentadoras de Antígenos/metabolismo , Comunicação Celular/imunologia , Linhagem Celular , Regulação da Expressão Gênica , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/química , Peptídeos e Proteínas de Sinalização Intracelular/genética , Centro Organizador dos Microtúbulos/imunologia , Centro Organizador dos Microtúbulos/metabolismo , Fosfotirosina/metabolismo , Regiões Promotoras Genéticas/genética , Receptores de Antígenos de Linfócitos T/imunologia , Transdução de Sinais/imunologia
8.
Cancers (Basel) ; 13(18)2021 Sep 09.
Artigo em Inglês | MEDLINE | ID: mdl-34572756

RESUMO

Current data indicates that anti-tumor T cell-mediated immunity correlates with a better prognosis in cancer patients. However, it has widely been demonstrated that tumor cells negatively manage immune attack by activating several immune-suppressive mechanisms. It is, therefore, essential to fully understand how lymphocytes are activated in a tumor microenvironment and, above all, how to prevent these cells from becoming dysfunctional. Tumors produce galectins-1, -3, -7, -8, and -9 as one of the major molecular mechanisms to evade immune control of tumor development. These galectins impact different steps in the establishment of the anti-tumor immune responses. Here, we carry out a critical dissection on the mechanisms through which tumor-derived galectins can influence the production and the functionality of anti-tumor T lymphocytes. This knowledge may help us design more effective immunotherapies to treat human cancers.

9.
Front Immunol ; 12: 713132, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34386013

RESUMO

Senescent T cells have been described during aging, chronic infections, and cancer; however, a comprehensive study of the phenotype, function, and transcriptional program of this T cell population in breast cancer (BC) patients is missing. Compared to healthy donors (HDs), BC patients exhibit an accumulation of KLRG-1+CD57+ CD4+ and CD8+ T cells in peripheral blood. These T cells infiltrate tumors and tumor-draining lymph nodes. KLRG-1+CD57+ CD4+ and CD8+ T cells from BC patients and HDs exhibit features of senescence, and despite their inhibitory receptor expression, they produce more effector cytokines and exhibit higher expression of Perforin, Granzyme B, and CD107a than non-senescent subsets. When compared to blood counterparts, tumor-infiltrating senescent CD4+ T cells show similar surface phenotype but reduced cytokine production. Transcriptional profiling of senescent CD4+ T cells from the peripheral blood of BC patients reveals enrichment in genes associated with NK or CD8+-mediated cytotoxicity, TCR-mediated stimulation, and cell exhaustion compared to non-senescent T cells. Comparison of the transcriptional profile of senescent CD4+ T cells from peripheral blood of BC patients with those of HDs highlighted marked similarities but also relevant differences. Senescent CD4+ T cells from BC patients show enrichment in T-cell signaling, processes involved in DNA replication, p53 pathways, oncogene-induced senescence, among others compared to their counterparts in HDs. High gene expression of CD4, KLRG-1, and B3GAT1 (CD57), which correlates with increased overall survival for BC patients, underscores the usefulness of the evaluation of the frequency of senescent CD4+ T cells as a biomarker in the follow-up of patients.


Assuntos
Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/metabolismo , Senescência Celular , Linfócitos do Interstício Tumoral/imunologia , Linfócitos do Interstício Tumoral/metabolismo , Neoplasias da Mama/etiologia , Antígenos CD57/metabolismo , Estudos de Casos e Controles , Senescência Celular/genética , Senescência Celular/imunologia , Citotoxicidade Imunológica , Feminino , Perfilação da Expressão Gênica , Humanos , Imunofenotipagem , Lectinas Tipo C/metabolismo , Contagem de Linfócitos , Linfócitos do Interstício Tumoral/patologia , Receptores Imunológicos/metabolismo , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismo , Subpopulações de Linfócitos T/patologia
10.
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
11.
Biomolecules ; 10(5)2020 05 12.
Artigo em Inglês | MEDLINE | ID: mdl-32408492

RESUMO

Galectins are small proteins with pleiotropic functions, which depend on both their lectin (glycan recognition) and non-lectin (recognition of other biomolecules besides glycans) interactions. Currently, 15 members of this family have been described in mammals, each with its structural and ligand recognition particularities. The galectin/ligand interaction translates into a plethora of biological functions that are particular for each cell/tissue type. In this sense, the cells of the immune system are highly sensitive to the action of these small and essential proteins. While galectins play central roles in tumor progression, they are also excellent negative regulators (checkpoints) of the immune cell functions, participating in the creation of a microenvironment that promotes tumor escape. This review aims to give an updated view on how galectins control the tumor's immune attack depending on the tumor microenvironment, because determining which galectins are essential and the role they play will help to develop future clinical trials and benefit patients with incurable cancer.


Assuntos
Ensaios Clínicos como Assunto , Galectinas/metabolismo , Sistema Imunitário/metabolismo , Neoplasias/metabolismo , Animais , Humanos , Inibidores de Checkpoint Imunológico/farmacologia , Inibidores de Checkpoint Imunológico/uso terapêutico , Sistema Imunitário/efeitos dos fármacos , Neoplasias/diagnóstico , Prognóstico
12.
J Immunother Cancer ; 8(2)2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-33293356

RESUMO

BACKGROUND: Prostate cancer (PCa) is a major health problem worldwide. Taxol derivatives-based chemotherapies or immunotherapies are usually proposed depending on the symptomatic status of the patient. In the case of immunotherapy, tumors develop robust immune escape mechanisms that abolish any protective response, and to date why prostate cancer is one of the most resistant diseases remains unresolved. METHODS: By using a combination of clinical data to study the transcriptome of metastasis samples from patients with castration-refractory prostate cancer, and state of the art cellular and molecular biology assays in samples from tumor-bearing mice that have been submitted to surgical resection of the tumor before receiving a vaccination, we answered several essential questions in the field of immunotherapy for prostate cancer. We also used two different methods to inhibit the expression of galectin-3 (Gal-3) in tumor cells: a stable RNA interference method to control the expression of this galectin efficiently only in tumor cells, and low and non-cytotoxic doses of docetaxel to easily transfer our findings to clinical settings. RESULTS: Herein, we show for the first time that Gal-3 expressed by prostate tumor cells is the main immune checkpoint responsible for the failure of vaccine-based immunotherapy. Our results show that low and non-cytotoxic doses of docetaxel lead to the inhibition of Gal-3 expression in PCa cells as well as in clinical samples of patients with metastatic and castration-resistant PCa promoting a Th1 response. We thus optimized a prostate cancer animal model that undergoes surgical resection of the tumor to mimic prostatectomy usually performed in patients. Importantly, using Gal-3-knocked down-PCa cells or low and non-cytotoxic doses of taxane before vaccination, we were able to highly control tumor recurrence through a direct impact on the proliferation and infiltration of CD8+ cytotoxic T. CONCLUSIONS: Thus, Gal-3 expression by PCa cells is a crucial inhibitor for the success of immunotherapy, and low doses of docetaxel with non-cytotoxic effect on leukocyte survival could be used before immunotherapy for all patients with PCa to reduce the expression of this critical negative immune checkpoint, pre-conditioning the tumor-microenvironment to activate an antitumor immune response and promote tumor-free outcome.


Assuntos
Galectina 3/antagonistas & inibidores , Imunoterapia/métodos , Neoplasias da Próstata/tratamento farmacológico , Vacinação/métodos , Animais , Galectina 3/farmacologia , Galectina 3/uso terapêutico , Humanos , Masculino , Camundongos , Neoplasias da Próstata/patologia , Resultado do Tratamento
13.
Clin Cancer Res ; 25(2): 710-723, 2019 01 15.
Artigo em Inglês | MEDLINE | ID: mdl-30322877

RESUMO

PURPOSE: Targeted therapies that use the signaling pathways involved in prostate cancer are required to overcome chemoresistance and improve treatment outcomes for men. Molecular chaperones play a key role in the regulation of protein homeostasis and are potential targets for overcoming chemoresistance.Experimental Design: We established 4 chemoresistant prostate cancer cell lines and used image-based high-content siRNA functional screening, based on gene-expression signature, to explore mechanisms of chemoresistance and identify new potential targets with potential roles in taxane resistance. The functional role of a new target was assessed by in vitro and in vivo silencing, and mass spectrometry analysis was used to identify its downstream effectors. RESULTS: We identified FKBP7, a prolyl-peptidyl isomerase overexpressed in docetaxel-resistant and in cabazitaxel-resistant prostate cancer cells. This is the first study to characterize the function of human FKBP7 and explore its role in cancer. We discovered that FKBP7 was upregulated in human prostate cancers and its expression correlated with the recurrence observed in patients receiving docetaxel. FKBP7 silencing showed that FKBP7 is required to maintain the growth of chemoresistant cell lines and chemoresistant tumors in mice. Mass spectrometry analysis revealed that FKBP7 interacts with eIF4G, a component of the eIF4F translation initiation complex, to mediate the survival of chemoresistant cells. Using small-molecule inhibitors of eIF4A, the RNA helicase component of eIF4F, we were able to kill docetaxel- and cabazitaxel-resistant cells. CONCLUSIONS: Targeting FKBP7 or the eIF4G-containing eIF4F translation initiation complex could be novel therapeutic strategies to eradicate taxane-resistant prostate cancer cells.


Assuntos
Hidrocarbonetos Aromáticos com Pontes/farmacologia , Proteínas de Ligação ao Cálcio/metabolismo , Resistencia a Medicamentos Antineoplásicos , Fator de Iniciação 4F em Eucariotos/metabolismo , Regulação Neoplásica da Expressão Gênica , Neoplasias da Próstata/genética , Neoplasias da Próstata/metabolismo , Proteínas de Ligação a Tacrolimo/metabolismo , Taxoides/farmacologia , Animais , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Biologia Computacional , Modelos Animais de Doenças , Progressão da Doença , Resistencia a Medicamentos Antineoplásicos/genética , Perfilação da Expressão Gênica , Inativação Gênica , Humanos , Masculino , Camundongos , Neoplasias da Próstata/tratamento farmacológico , Neoplasias da Próstata/patologia , Ligação Proteica , RNA Interferente Pequeno/genética , Transcriptoma , Ensaios Antitumorais Modelo de Xenoenxerto
14.
Front Immunol ; 9: 2190, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30319642

RESUMO

The identification of effective new therapies for prostate cancer (PCa) requires a better understanding of the multiple molecular interactions between tumor cells and their associated microenvironment. In this context, galectin-1 (Gal-1) is a key molecule in the determination of the prostatic carcinoma microenviroment; therefore, it is essential to understand all the molecular processes in which this protein is involved. Most of the previous studies found in the literature have focused on the microenvironment remodeling properties of tumor-secreted Gal-1, through its interactions with the glyco-receptors at the cell membrane and the extracellular matrix. This report shows original aspects of the lectin by focusing on the role of lymphocyte endogenous Gal-1 in controlling anti-prostate tumor immunity. Using a murine preclinical model of prostate cancer, our results demonstrate that endogenous Gal-1 in lymphocytes modulates their proliferative rate and cytotoxic function in conditions of high extracellular Gal-1 concentration, mainly derived from tumor cells. In such conditions, the absence of Gal-1 in T lymphocytes potentiates anti-tumor immune responses. Further studies demonstrated that endogenous Gal-1 in CD4+, but mainly in CD8+T cells, acts as a negative regulator of anti-tumor immunity. In conclusion, prostate tumors require Gal-1 in lymphocytes to evade immune responses. This report lays the foundation for an original immunotherapy strategy for prostate cancer.


Assuntos
Galectina 1/imunologia , Neoplasias da Próstata/imunologia , Linfócitos T/imunologia , Microambiente Tumoral/imunologia , Animais , Linhagem Celular Tumoral/transplante , Proliferação de Células , Modelos Animais de Doenças , Galectina 1/genética , Galectina 1/metabolismo , Humanos , Imunoterapia/métodos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Nus , Neoplasias da Próstata/patologia , Neoplasias da Próstata/terapia , Linfócitos T/metabolismo
15.
Oncotarget ; 8(27): 44654-44668, 2017 Jul 04.
Artigo em Inglês | MEDLINE | ID: mdl-28591719

RESUMO

Two decades ago, Galectin-8 was described as a prostate carcinoma biomarker since it is only expressed in the neoplastic prostate, but not in the healthy tissue. To date, no biological function has been attributed to Galectin-8 that could explain this differential expression. In this study we silenced Galectin-8 in two human prostate cancer cell lines, PC3 and IGR-CaP1, and designed a pre-clinical experimental model that allows monitoring the pathology from its early steps to the long-term metastatic stages. We show for the first time that the natural and conserved expression of Gal-8 in tumour cells is responsible for the metastatic evolution of prostate cancer. In fact, Gal-8 controls the rearrangement of the cytoskeleton and E-Cadherin expression, with a major impact on anoikis and homotypic aggregation of tumour cells, both being essential processes for the survival of circulating tumour cells during metastasis. While localized prostate cancer can be cured, metastatic and advanced disease remains a significant therapeutic challenge, urging for the identification of prognostic markers of the metastatic process. Collectively, our results highlight Galectin-8 as a potential target for anti-metastatic therapy against prostate cancer.


Assuntos
Galectinas/genética , Expressão Gênica , Neoplasias da Próstata/genética , Neoplasias da Próstata/patologia , Animais , Anoikis/genética , Caderinas/genética , Caderinas/metabolismo , Adesão Celular , Linhagem Celular Tumoral , Movimento Celular/genética , Proliferação de Células , Transformação Celular Neoplásica/genética , Transformação Celular Neoplásica/metabolismo , Modelos Animais de Doenças , Progressão da Doença , Galectinas/metabolismo , Inativação Gênica , Humanos , Masculino , Metástase Neoplásica , Estadiamento de Neoplasias , Microambiente Tumoral/genética , Ensaios Antitumorais Modelo de Xenoenxerto
16.
Clin Cancer Res ; 23(17): 5135-5148, 2017 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-28512172

RESUMO

Purpose: Conditioning strategies constitute a relatively unexplored and exciting opportunity to shape tumor fate by targeting the tumor microenvironment. In this study, we assessed how hemin, a pharmacologic inducer of heme oxygenase-1 (HO-1), has an impact on prostate cancer development in an in vivo conditioning model.Experimental Design: The stroma of C57BL/6 mice was conditioned by subcutaneous administration of hemin prior to TRAMP-C1 tumor challenge. Complementary in vitro and in vivo assays were performed to evaluate hemin effect on both angiogenesis and the immune response. To gain clinical insight, we used prostate cancer patient-derived samples in our studies to assess the expression of HO-1 and other relevant genes.Results: Conditioning resulted in increased tumor latency and decreased initial growth rate. Histologic analysis of tumors grown in conditioned mice revealed impaired vascularization. Hemin-treated human umbilical vein endothelial cells (HUVEC) exhibited decreased tubulogenesis in vitro only in the presence of TRAMP-C1-conditioned media. Subcutaneous hemin conditioning hindered tumor-associated neovascularization in an in vivo Matrigel plug assay. In addition, hemin boosted CD8+ T-cell proliferation and degranulation in vitro and antigen-specific cytotoxicity in vivo A significant systemic increase in CD8+ T-cell frequency was observed in preconditioned tumor-bearing mice. Tumors from hemin-conditioned mice showed reduced expression of galectin-1 (Gal-1), key modulator of tumor angiogenesis and immunity, evidencing persistent remodeling of the microenvironment. We also found a subset of prostate cancer patient-derived xenografts and prostate cancer patient samples with mild HO-1 and low Gal-1 expression levels.Conclusions: These results highlight a novel function of a human-used drug as a means of boosting the antitumor response. Clin Cancer Res; 23(17); 5135-48. ©2017 AACR.


Assuntos
Galectina 1/genética , Heme Oxigenase-1/genética , Hemina/administração & dosagem , Neoplasias da Próstata/tratamento farmacológico , Animais , Linfócitos T CD8-Positivos/efeitos dos fármacos , Linfócitos T CD8-Positivos/patologia , Proliferação de Células/efeitos dos fármacos , Modelos Animais de Doenças , Galectina 1/antagonistas & inibidores , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Heme Oxigenase-1/antagonistas & inibidores , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Humanos , Masculino , Camundongos , Neovascularização Patológica/tratamento farmacológico , Neovascularização Patológica/genética , Neovascularização Patológica/patologia , Neoplasias da Próstata/genética , Neoplasias da Próstata/patologia , Ensaios Antitumorais Modelo de Xenoenxerto
17.
Methods Mol Biol ; 1207: 249-68, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-25253145

RESUMO

During the past decade, a better understanding of the cellular and molecular mechanisms underlying tumor immunity has provided the appropriate framework for the development of therapeutic strategies for cancer immunotherapy. Under this complex scenario, galectins have emerged as promising molecular targets for cancer therapy responsible of creating immunosuppressive microenvironments at sites of tumor growth and metastasis. Galectins, expressed in tumor, stromal, and endothelial cells, contribute to thwart the development of immune responses by favoring the expansion of T regulatory cells and contributing to their immunosuppressive activity, driving the differentiation of tolerogenic dendritic cells, limiting T cell viability, and maintaining T cell anergy. The emerging data promise a future scenario in which the selective blockade of individual members of the galectin family, either alone or in combination with other therapeutic regimens, will contribute to halt tumor progression by counteracting tumor-immune escape. Here we describe a selection of methods used to investigate the role of galectin-1 in tumor-immune escape.


Assuntos
Galectinas/metabolismo , Neoplasias/imunologia , Neoplasias/metabolismo , Transferência Adotiva , Animais , Antígenos de Neoplasias/imunologia , Western Blotting , Células da Medula Óssea/citologia , Complexo CD3/metabolismo , Proliferação de Células , Separação Celular , Citocinas/metabolismo , Células Dendríticas/citologia , Células Dendríticas/metabolismo , Ensaio de Imunoadsorção Enzimática , Citometria de Fluxo , Galectina 1/metabolismo , Inativação Gênica , Vetores Genéticos/genética , Humanos , Interleucina-27/metabolismo , Lentivirus/genética , Linfonodos/imunologia , Camundongos , Neoplasias/patologia , Fosforilação , Fator de Transcrição STAT3/metabolismo , Baço/imunologia , Linfócitos T Reguladores/citologia , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/metabolismo , Transdução Genética , Microambiente Tumoral
18.
Methods Mol Biol ; 1207: 293-304, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-25253148

RESUMO

Formation of an aberrant and heterogeneous vascular network is a key pathological event in the multistep process of tumor growth and metastasis. Pro-angiogenic factors are synthesized and released from tumor, stromal, endothelial, and myeloid cells in response to hypoxic and immunosuppressive microenvironments which are commonly found during cancer progression. Emerging data indicate key roles for galectins, particularly galectin-1, -3, -8, and -9 in the regulation of angiogenesis in different pathophysiologic settings. Each galectin interacts with a preferred set of glycosylated receptors, triggers different signaling pathway, and promotes sprouting angiogenesis through different mechanisms. Understanding the role of galectins in tumor neovascularization will contribute to the design of novel anti-angiogenic therapies aimed at complementing current clinical approaches. Here we describe selected strategies and methods used to study the galectin-1 regulation by hypoxia and its role in blood vessel formation.


Assuntos
Galectina 1/metabolismo , Neovascularização Patológica/metabolismo , Western Blotting , Hipóxia Celular , Movimento Celular , Células Endoteliais da Veia Umbilical Humana/citologia , Células Endoteliais da Veia Umbilical Humana/metabolismo , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Solubilidade , Microambiente Tumoral , Fator A de Crescimento do Endotélio Vascular/química , Fator A de Crescimento do Endotélio Vascular/metabolismo
19.
Histol Histopathol ; 29(9): 1093-105, 2014 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-24696431

RESUMO

Galectin-8 (Gal-8) is a 'tandem-repeat'-type galectin, which possesses two carbohydrate recognition domains connected by a linker peptide. Gal-8 complexity is related to the alternative splicing of its mRNA precursor, which is known to generate isoforms. Regarding its carbohydrate-binding specificity, Gal-8 has a unique feature among galectins, since its C-terminal domain has higher affinity for N-glycan-type branched oligosaccharides, while its N-terminal domain shows strong affinity for α2-3-sialylated or 3'-sulfated ß-galactosides. We integrate here the available information on Gal-8 expression in different tumor types and attempt to elucidate associations of its expression and localization with tumor progression with the overarching goal of analyzing its potential applications in diagnosis and prognosis. Differential diagnosis is still a prime concern in tumor pathology, and Gal-8 could be of great value in some types of primary or secondary tumors (i.e. papillary thyroid carcinoma, advanced colon carcinoma from patients with distant metastases, or metastases from primary lung carcinoma). The prognostic value of Gal-8 has been described for laryngeal carcinoma as well as advanced colon carcinoma. Further studies are needed to explain the relevance of Gal-8 and its isoforms in tumor pathology and their different intra- or extracellular roles (cytoplasmic, nuclear or extracellular) in tumor biology.


Assuntos
Galectinas/metabolismo , Neoplasias/metabolismo , Biomarcadores Tumorais/análise , Humanos , Neoplasias/patologia
20.
Prostate Cancer ; 2013: 519436, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-24205440

RESUMO

A better understanding of multimolecular interactions involved in tumor dissemination is required to identify new effective therapies for advanced prostate cancer (PCa). Several groups investigated protein-glycan interactions as critical factors for crosstalk between prostate tumors and their microenvironment. This review both discusses whether the "galectin-signature" might serve as a reliable biomarker for the identification of patients with high risk of metastasis and assesses the galectin-glycan lattices as potential novel targets for anticancer therapies. The ultimate goal of this review is to convey how basic findings related to galectins could be in turn translated into clinical settings for patients with advanced PCa.

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