Galectin-3: A factotum in carcinogenesis bestowing an archery for prevention

Kim

Proc. Natl. Acad. Sci. U.S.A.

et al. 2022

The major challenges in pancreatic ductal adenocarcinoma (PDAC) management are local or distant metastasis and limited targeted therapeutics to prevent it. To identify a druggable target in tumor secretome and to explore its therapeutic intervention, we performed a liquid chromatography–tandem mass spectrometry (LC-MS/MS)–based proteomic analysis of tumors obtained from a patient-derived xenograft model of PDAC. Galectin-3 binding protein (Gal-3BP) is identified as a highly secreted protein, and its overexpression is further validated in multiple PDAC tumors and primary cells. Knockdown and exogenous treatment of Gal-3BP showed that it is required for PDAC cell proliferation, migration, and invasion. Mechanistically, we revealed that Gal-3BP enhances galectin-3–mediated epidermal growth factor receptor signaling, leading to increased cMyc and epithelial-mesenchymal transition. To explore the clinical impact of these findings, two antibody clones were developed, and they profoundly abrogated the metastasis of PDAC cells in vivo. Altogether, our data demonstrate that Gal-3BP is an important therapeutic target in PDAC, and we propose its blockade by antibody as a therapeutic option for suppressing PDAC metastasis.

Section: Discussionmentioning

confidence: 99%

Antibody-mediated blockade for galectin-3 binding protein in tumor secretome abrogates PDAC metastasis

Kim

Proc. Natl. Acad. Sci. U.S.A.

et al. 2022

“…FGL-1 directly downregulates the secretion of IL-2, thus conveying a negative regulatory signal 79 , whereas Gal-3 binds oncoproteins and elicits tumor cell proliferative effects. For example, binding of N-Ras to Gal-3 leads to transformation of the former into K-Ras, which in turn increases the number of breast cancer cells 80 .…”

Section: Emerging Immune Checkpoint Inhibitorsmentioning

confidence: 99%

Immune checkpoint inhibitors: breakthroughs in cancer treatment

Kong,

Zhang,

Chen

et al. 2024

Cancer Biol Med

Over the past two decades, immunotherapies have increasingly been considered as first-line treatments for most cancers. One such treatment is immune checkpoint blockade (ICB), which has demonstrated promising results against various solid tumors in clinical trials. Monoclonal antibodies (mAbs) are currently available as immune checkpoint inhibitors (ICIs). These ICIs target specific immune checkpoints, including cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) and programmed cell death protein 1 (PD-1). Clinical trial results strongly support the feasibility of this immunotherapeutic approach. However, a substantial proportion of patients with cancer develop resistance or tolerance to treatment, owing to tumor immune evasion mechanisms that counteract the host immune response. Consequently, substantial research focus has been aimed at identifying additional ICIs or synergistic inhibitory receptors to enhance the effectiveness of anti-PD-1, anti-programmed cell death ligand 1 (anti-PD-L1), and anti-CTLA-4 treatments. Recently, several immune checkpoint molecular targets have been identified, such as T cell immunoreceptor with Ig and ITIM domains (TIGIT), mucin domain containing-3 (TIM-3), lymphocyte activation gene-3 (LAG-3), V-domain immunoglobulin suppressor of T cell activation (VISTA), B and T lymphocyte attenuator (BTLA), and signal-regulatory protein α (SIRPα). Functional mAbs targeting these molecules are under development. CTLA-4, PD-1/PD-L1, and other recently discovered immune checkpoint proteins with distinct structures are at the forefront of research. This review discusses these structures, as well as clinical progress in mAbs targeting these immune checkpoint molecules and their potential applications.

“…Moreover, in diabetic patients, diabetic nephropathy, diabetic foot, diabetic microvascular complications, and diabetic cardiomyopathy have been all related to changes in Gal-3 serum levels [125]. In particular, Galectin 1 (Gal-1) and Galectin 3 (Gal-3) seem to initiate the inflammatory response by acting as chemotactic agents towards the inflammatory site for the neutrophils, facilitating their binding to the endothelium and their trafficking through the extracellular matrix [126].…”

Section: Galectins and Ersmentioning

confidence: 99%

Inhibition of Galectins and the P2X7 Purinergic Receptor as a Therapeutic Approach in the Neurovascular Inflammation of Diabetic Retinopathy

Lepre

Russo

Trotta

et al. 2023

IJMS

Diabetic retinopathy (DR) is the most frequent microvascular retinal complication of diabetic patients, contributing to loss of vision. Recently, retinal neuroinflammation and neurodegeneration have emerged as key players in DR progression, and therefore, this review examines the neuroinflammatory molecular basis of DR. We focus on four important aspects of retinal neuroinflammation: (i) the exacerbation of endoplasmic reticulum (ER) stress; (ii) the activation of the NLRP3 inflammasome; (iii) the role of galectins; and (iv) the activation of purinergic 2X7 receptor (P2X7R). Moreover, this review proposes the selective inhibition of galectins and the P2X7R as a potential pharmacological approach to prevent the progression of DR.