Inhibition of galectins in cancer: Biological challenges for their clinical application.

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.

Unraveling How Tumor-Derived Galectins Contribute to Anti-Cancer Immunity Failure.

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.

Polyfunctional KLRG-1CD57 Senescent CD4 T Cells Infiltrate Tumors and Are Expanded in Peripheral Blood From Breast Cancer Patients.

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-1CD57 CD4 and CD8 T cells in peripheral blood. These T cells infiltrate tumors and tumor-draining lymph nodes.

Combining inhibition of galectin-3 with and before a therapeutic vaccination is critical for the prostate-tumor-free outcome.

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.

Galectins as Checkpoints of the Immune System in Cancers, Their Clinical Relevance, and Implication in Clinical Trials.

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.

Regulation of eIF4F Translation Initiation Complex by the Peptidyl Prolyl Isomerase FKBP7 in Taxane-resistant Prostate Cancer.

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. 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.

Endogenous Galectin-1 in T Lymphocytes Regulates Anti-prostate Cancer Immunity.

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.

Stable and high expression of Galectin-8 tightly controls metastatic progression of prostate cancer.

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.

Hemin Conditioning Targets the Vascular and Immunologic Compartments and Restrains Prostate Tumor Development.

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 conditioning model. The stroma of C57BL/6 mice was conditioned by subcutaneous administration of hemin prior to TRAMP-C1 tumor challenge.

Galectin-1 triggers epithelial-mesenchymal transition in human hepatocellular carcinoma cells.

Galectin-1 (Gal1), a β-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.

Regulation of galectins by hypoxia and their relevance in angiogenesis: strategies and methods.

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.

Study of galectins in tumor immunity: strategies and methods.

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.

Glycans and galectins in prostate cancer biology, angiogenesis and metastasis.

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.

Galectin-8: a matricellular lectin with key roles in angiogenesis.

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.

Expression, localization and function of galectin-8, a tandem-repeat lectin, in human tumors.

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 β-galactosides.

Galectins as new prognostic markers and potential therapeutic targets for advanced prostate cancers.

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.

Delineating the "galectin signature" of the tumor microenvironment.

Galectins, a family of glycan-binding proteins, can control tumor progression by promoting transformation, angiogenesis and immune escape. We identified a dynamically regulated 'galectin signature', which delineates the progression of prostate cancer, highlighting galectin-1 as an attractive target for anti-angiogenic therapy in advanced stages of the disease.

A unique galectin signature in human prostate cancer progression suggests galectin-1 as a key target for treatment of advanced disease.

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.

Stemness markers characterize IGR-CaP1, a new cell line derived from primary epithelial prostate cancer.

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.

Modulation of endothelial cell migration and angiogenesis: a novel function for the "tandem-repeat" lectin galectin-8.

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 β-galactosides and a conserved sequence motif, can decipher glycan-containing information and mediate cell-cell communication.

Dissecting the signal transduction pathways triggered by galectin-glycan interactions in physiological and pathological settings.

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.

Dok-4 is a novel negative regulator of T cell activation.

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.

SIRNA-directed in vivo silencing of androgen receptor inhibits the growth of castration-resistant prostate carcinomas.

Background: Prostate carcinomas are initially dependent on androgens, and castration or androgen antagonists inhibit their growth. After some time though, tumors become resistant and recur with a poor prognosis. The majority of resistant tumors still expresses a functional androgen receptor (AR), frequently amplified or mutated.

A partial down-regulation of WASP is sufficient to inhibit podosome formation in dendritic cells.

The Wiskott Aldrich syndrome protein (WASP) is a hematopoietic-specific cytoskeletal regulator that is necessary for induction of normal immunity. In the context of effective gene therapy for WAS, cellular models of human WASP deficiency are important for definition of the threshold of protein expression required for optimal activity. Using lentiviral vector-mediated RNA interference (RNAi), we were able to down-regulate the levels of human WASP in cell lines and primary cells.