The Galectin Family as Molecular Targets: Hopes for Defeating Pancreatic Cancer

Manero-Rupérez, Noemí; Martínez-Bosch, Neus; Barranco, Luis; Visa, Laura; Navarro, Pilar

doi:10.3390/cells9030689

Cited by 25 publications

(32 citation statements)

References 115 publications

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“…Therefore, annexin overexpression is associated with poor patient prognosis and could inspire new therapeutic strategies (128). Galectins, which are a family of carbohydratebinding proteins, are also upregulated during PDAC progression (36,110). Besides galectin-4, which has been described as a tumor suppressor by inhibiting tumor cell migration and invasion, the other galectins favor pancreatic tumor.…”

Section: Ecm-affiliated Proteinsmentioning

confidence: 99%

“…Besides galectin-4, which has been described as a tumor suppressor by inhibiting tumor cell migration and invasion, the other galectins favor pancreatic tumor. Consequently, galectin inhibitors are considered as promising opportunities for pancreatic cancer therapeutic interventions, either alone or combined with current chemo-and/or immunotherapies (110).…”

Section: Ecm-affiliated Proteinsmentioning

confidence: 99%

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Stroma Involvement in Pancreatic Ductal Adenocarcinoma: An Overview Focusing on Extracellular Matrix Proteins

et al. 2021

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Pancreatic cancer is the seventh leading cause of cancer-related deaths worldwide and is predicted to become second in 2030 in industrialized countries if no therapeutic progress is made. Among the different types of pancreatic cancers, Pancreatic Ductal Adenocarcinoma (PDAC) is by far the most represented one with an occurrence of more than 90%. This specific cancer is a devastating malignancy with an extremely poor prognosis, as shown by the 5-years survival rate of 2–9%, ranking firmly last amongst all cancer sites in terms of prognostic outcomes for patients. Pancreatic tumors progress with few specific symptoms and are thus at an advanced stage at diagnosis in most patients. This malignancy is characterized by an extremely dense stroma deposition around lesions, accompanied by tissue hypovascularization and a profound immune suppression. Altogether, these combined features make access to cancer cells almost impossible for conventional chemotherapeutics and new immunotherapeutic agents, thus contributing to the fatal outcomes of the disease. Initially ignored, the Tumor MicroEnvironment (TME) is now the subject of intensive research related to PDAC treatment and could contain new therapeutic targets. In this review, we will summarize the current state of knowledge in the field by focusing on TME composition to understand how this specific compartment could influence tumor progression and resistance to therapies. Attention will be paid to Tenascin-C, a matrix glycoprotein commonly upregulated during cancer that participates to PDAC progression and thus contributes to poor prognosis.

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Section: Ecm-affiliated Proteinsmentioning

confidence: 99%

Section: Ecm-affiliated Proteinsmentioning

confidence: 99%

Stroma Involvement in Pancreatic Ductal Adenocarcinoma: An Overview Focusing on Extracellular Matrix Proteins

et al. 2021

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“…They mediate the crosstalk of tumors and TME [ 114 ]. There is increasing evidence that Gal1, Gal3, and Gal9 play important roles in stromal modulation of ECM, T-cell infiltration, activation, apoptosis, and the formation of the immunosuppressive environment in PDAC in humans [ 115 ]. Upregulation of Gal1 was detected in pancreatic tumors, which activates PSCs, thereby promoting fibrosis in stroma via autocrine signaling [ 114 , 116 ].…”

Section: Inhibitory Receptorsmentioning

confidence: 99%

Mechanisms of T-Cell Exhaustion in Pancreatic Cancer

Saka

Gökalp

Piyade

et al. 2020

Cancers

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T-cell exhaustion is a phenomenon that represents the dysfunctional state of T cells in chronic infections and cancer and is closely associated with poor prognosis in many cancers. The endogenous T-cell immunity and genetically edited cell therapies (CAR-T) failed to prevent tumor immune evasion. The effector T-cell activity is perturbed by an imbalance between inhibitory and stimulatory signals causing a reprogramming in metabolism and the high levels of multiple inhibitory receptors like programmed cell death protein-1 (PD-1), cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), T cell immunoglobulin and mucin domain-containing protein 3 (TIM-3), and Lymphocyte-activation gene 3 (Lag-3). Despite the efforts to neutralize inhibitory receptors by a single agent or combinatorial immune checkpoint inhibitors to boost effector function, PDAC remains unresponsive to these therapies, suggesting that multiple molecular mechanisms play a role in stimulating the exhaustion state of tumor-infiltrating T cells. Recent studies utilizing transcriptomics, mass cytometry, and epigenomics revealed a critical role of Thymocyte selection-associated high mobility group box protein (TOX) genes and TOX-associated pathways, driving T-cell exhaustion in chronic infection and cancer. Here, we will review recently defined molecular, genetic, and cellular factors that drive T-cell exhaustion in PDAC. We will also discuss the effects of available immune checkpoint inhibitors and the latest clinical trials targeting various molecular factors mediating T-cell exhaustion in PDAC.

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“…galectin-1, -2, -5, -7, -10, -11, -13, -14, -15), chimera (i.e., galectin-3), and tandem repeat (viz. galectin-4, -6, -8, -9, -12) [22][23][24]. These three groups of galectins possess a well-defined carbohydrate recognition domain (CRD) constituting highly evolutionary conserved amino acid sequences and a β-sandwich structure that confers their ability to bind with β-galactoside-rich glycoconjugates.…”

Section: Introductionmentioning

confidence: 99%

Structure-based identification of galectin-1 selective modulators in dietary food polyphenols: a pharmacoinformatics approach

et al. 2021

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In this study, a set of dietary polyphenols was comprehensively studied for the selective identification of the potential inhibitors/modulators for galectin-1. Galectin-1 is a potent prognostic indicator of tumor progression and a highly regarded therapeutic target for various pathological conditions. This indicator is composed of a highly conserved carbohydrate recognition domain (CRD) that accounts for the binding affinity of β-galactosides. Although some small molecules have been identified as galectin-1 inhibitors/modulators, there are limited studies on the identification of novel compounds against this attractive therapeutic target. The extensive computational techniques include potential drug binding site recognition on galectin-1, binding affinity predictions of ~ 500 polyphenols, molecular docking, and dynamic simulations of galectin-1 with selective dietary polyphenol modulators, followed by the estimation of binding free energy for the identification of dietary polyphenol-based galectin-1 modulators. Initially, a deep neural network-based algorithm was utilized for the prediction of the druggable binding site and binding affinity. Thereafter, the intermolecular interactions of the polyphenol compounds with galectin-1 were critically explored through the extra-precision docking technique. Further, the stability of the interaction was evaluated through the conventional atomistic 100 ns dynamic simulation study. The docking analyses indicated the high interaction affinity of different amino acids at the CRD region of galectin-1 with the proposed five polyphenols. Strong and consistent interaction stability was suggested from the simulation trajectories of the selected dietary polyphenol under the dynamic conditions. Also, the conserved residue (His44, Asn46, Arg48, Val59, Asn61, Trp68, Glu71, and Arg73) associations suggest high affinity and selectivity of polyphenols toward galectin-1 protein. Graphic Abstract

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The Galectin Family as Molecular Targets: Hopes for Defeating Pancreatic Cancer

Cited by 25 publications

References 115 publications

Stroma Involvement in Pancreatic Ductal Adenocarcinoma: An Overview Focusing on Extracellular Matrix Proteins

Stroma Involvement in Pancreatic Ductal Adenocarcinoma: An Overview Focusing on Extracellular Matrix Proteins

Mechanisms of T-Cell Exhaustion in Pancreatic Cancer

Structure-based identification of galectin-1 selective modulators in dietary food polyphenols: a pharmacoinformatics approach

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