RESUMO
The microenvironment of a tumor is a highly complex milieu, primarily characterized by immunosuppression, abnormal angiogenesis, and hypoxic regions. These features promote tumor progression and metastasis, resulting in poor prognosis and greater resistance to existing cancer therapies. Galectin-1 is a ß-galactoside binding protein that is abundantly secreted by almost all types of malignant tumor cells. The expression of galectin-1 is regulated by hypoxia-inducible factor-1 (HIF-1) and it plays vital pro-tumorigenic roles within the tumor microenvironment. In particular, galectin-1 suppresses T cell-mediated cytotoxic immune responses and promotes tumor angiogenesis. However, since galectin-1 displays many different activities by binding to a number of diverse N- or O-glycan modified target proteins, it has been difficult to fully understand how galectin-1 supports tumor growth and metastasis. This review explores the importance of galectin-1 and glycan expression patterns in the tumor microenvironment and the potential effects of inhibiting galectin-1 as a therapeutic target for cancer treatment.
Assuntos
Galectina 1/antagonistas & inibidores , Galectina 1/fisiologia , Neoplasias/tratamento farmacológico , Microambiente Tumoral , Animais , Hipóxia Celular , Galectina 1/química , Humanos , Tolerância Imunológica , Metástase Neoplásica , Neoplasias/imunologia , Neovascularização Patológica/etiologia , Linfócitos T/imunologia , Tiogalactosídeos/farmacologiaRESUMO
High level galectin-1 expression results in cancer cell evasion of the immune response, increased tumour survival and aggressive metastases. Using a galectin-1 polyclonal antibody, high levels of galectin-1 protein were shown to be expressed by breast cancer cells established from FVB/N MMTV-c-neu mice as well as by the B16F10 melanoma cell line. In mixed lymphocyte cultures using tumour cells as antigenic stimulators, addition of recombinant galectin-1 dose-dependently inhibited lymphocyte production. Disaccharides were identified that inhibited galectin-1 function and increased growth and activation of CD8(+) CTL's killing cancer cells. X-ray crystallographic structures of human galectin-1 in complex with inhibitory disaccharides revealed their mode of binding. Combining galectin-blocking carbohydrates as adjuvants with vaccine immunotherapy in vivo to promote immune responses significantly decreased tumour progression and improved the outcomes for tumour challenged mice. This is the first report showing that suitably selected galectin-1 blocking disaccharides will act as adjuvants promoting vaccine stimulated immune responses against tumours in vivo.
Assuntos
Dissacarídeos/farmacologia , Galectinas/metabolismo , Imunidade/efeitos dos fármacos , Neoplasias Mamárias Experimentais/imunologia , Animais , Western Blotting , Linfócitos T CD8-Positivos/imunologia , Vacinas Anticâncer/administração & dosagem , Vacinas Anticâncer/imunologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Cristalografia por Raios X , Citotoxicidade Imunológica/efeitos dos fármacos , Dissacarídeos/química , Dissacarídeos/metabolismo , Feminino , Galectina 1/química , Galectina 1/genética , Galectina 1/metabolismo , Galectina 3/química , Galectina 3/genética , Galectina 3/metabolismo , Galectinas/química , Galectinas/genética , Humanos , Imunoterapia/métodos , Neoplasias Mamárias Experimentais/patologia , Neoplasias Mamárias Experimentais/terapia , Camundongos , Camundongos Endogâmicos , Modelos Moleculares , Ligação Proteica , Tiogalactosídeos/química , Tiogalactosídeos/metabolismo , Tiogalactosídeos/farmacologia , Carga Tumoral/efeitos dos fármacosRESUMO
OBJECTIVE: IL-12 is involved in immune surveillance and response that links the innate and adaptive arms of the immune system. Among its many effects, IL-12 increases the cell surface expression of the CCR5 co-receptor for R5 strains of HIV-1, which are predominantly involved in HIV-1 transmission and spread. In the present study we investigated the effect of epistasis between allelic variants of CCR5 and IL12B on the susceptibility to HIV-1 infection and HIV-1 disease progression. METHODS: HIV-1-positive patients were genotyped for IL12Bpro from two groups of HIV-1 seroincident patients from Western Australia (n = 101 and 200), longitudinal clinical data were available for one of the Western Australian cohorts for a period of over 12 years and a group of seroprevalent individuals from Sydney (n = 112). A group of ethnically matched healthy volunteers (n = 200) was also genotyped as controls. Comparison of allele frequencies between HIV-1 patients and controls was performed to determine the influence on susceptibility to HIV-1 infection, and regression analysis was used to determine the influence on disease progression. RESULTS: Individuals positive for CCR5Delta32 and who carry the IL12Bpro1.1 genotype were underrepresented across all three independent HIV-1-positive cohorts [odds ratio 0.5; 95% confidence interval (CI) 0.28-0.97; P = 0.038]. CCR5wt/wt and IL12Bpro2.2 individuals progressed to AIDS at a significantly faster rate than other CCR5 and IL12Bpro groups (hazards ratio 3.24; 95% CI 1.9-15.1; P = 0.002). CONCLUSION: Epistatic interaction between allelic variants of CCR5 and IL12Bpro exert a significant influence on the clinical outcome of HIV-1 infection.
