RESUMEN
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.
Asunto(s)
Galectinas/metabolismo , Neoplasias/metabolismo , Biomarcadores de Tumor/análisis , Humanos , Neoplasias/patologíaRESUMEN
Galectins, a family of glycan-binding proteins, influence tumor progression by modulating interactions between tumor, endothelial, stromal, and immune cells. Despite considerable progress in identifying the roles of individual galectins in tumor biology, an integrated portrait of the galectin network in different tumor microenvironments is still missing. We undertook this study to analyze the "galectin signature" of the human prostate cancer microenvironment with the overarching goal of selecting novel-molecular targets for prognostic and therapeutic purposes. In examining androgen-responsive and castration-resistant prostate cancer cells and primary tumors representing different stages of the disease, we found that galectin-1 (Gal-1) was the most abundantly expressed galectin in prostate cancer tissue and was markedly upregulated during disease progression. In contrast, all other galectins were expressed at lower levels: Gal-3, -4, -9, and -12 were downregulated during disease evolution, whereas expression of Gal-8 was unchanged. Given the prominent regulation of Gal-1 during prostate cancer progression and its predominant localization at the tumor-vascular interface, we analyzed the potential role of this endogenous lectin in prostate cancer angiogenesis. In human prostate cancer tissue arrays, Gal-1 expression correlated with the presence of blood vessels, particularly in advanced stages of the disease. Silencing Gal-1 in prostate cancer cells reduced tumor vascularization without altering expression of other angiogenesis-related genes. Collectively, our findings identify a dynamically regulated "galectin-specific signature" that accompanies disease evolution in prostate cancer, and they highlight a major role for Gal-1 as a tractable target for antiangiogenic therapy in advanced stages of the disease.
Asunto(s)
Galectina 1/metabolismo , Terapia Molecular Dirigida , Neovascularización Patológica/metabolismo , Neoplasias de la Próstata/metabolismo , Neoplasias de la Próstata/patología , Anciano , Progresión de la Enfermedad , Galectina 1/genética , Humanos , Immunoblotting , Inmunohistoquímica , Masculino , Persona de Mediana Edad , Neovascularización Patológica/genética , Neoplasias de la Próstata/tratamiento farmacológico , Neoplasias de la Próstata/genética , Reacción en Cadena en Tiempo Real de la Polimerasa , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Análisis de Matrices Tisulares , Transcriptoma , Microambiente Tumoral/fisiologíaRESUMEN
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.