LAG-3 as a Potent Target for Novel Anticancer Therapies of a Wide Range of Tumors

Sauer, Natalia; Szlasa, Wojciech; Jonderko, Laura; Oślizło, Małgorzata; Kunachowicz, Dominika; Kulbacka, Julita; Karłowicz-Bodalska, Katarzyna

doi:10.3390/ijms23179958

Cited by 40 publications

(29 citation statements)

References 161 publications

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“…Galectin-3 is a multifunctional protein and is involved in various steps in cancer development, progression, and metastasis by binding to a number of galactose-terminated, N- and O -linked cell surface glycans [ 17 , 36 ]. For example, galectin-3 can bind to the galactose-β1,3N-acetyl-galactosamineα-Thr/Ser, an oncofetal carbohydrate antigen (Thomsen-Friedenreich antigen, TF antigen) that occurs in >90 tumour cells [ 37 , 38 ] and can be proteolytically removed by O -glycanase [ 39 ].…”

Section: Discussionmentioning

confidence: 99%

Galectin-3 Is a Natural Binding Ligand of MCAM (CD146, MUC18) in Melanoma Cells and Their Interaction Promotes Melanoma Progression

et al. 2022

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Melanoma cell adhesion molecule (MCAM, CD146, MUC18) is a heavily glycosylated transmembrane protein and a marker of melanoma metastasis. It is expressed in advanced primary melanoma and metastasis but rarely in benign naevi or normal melanocytes. More and more evidence has shown that activation of the MCAM on cell surface plays a vital role in melanoma progression and metastasis. However, the natural MCAM binding ligand that initiates MCAM activation in melanoma so far remains elusive. This study revealed that galectin-3, a galactoside-binding protein that is commonly overexpressed in many cancers including melanoma, is naturally associated with MCAM on the surface of both skin and uveal melanoma cells. Binding of galectin-3 to MCAM, via O-linked glycans on the MCAM, induces MCAM dimerization and clustering on cell surface and subsequent activation of downstream AKT signalling. This leads to the increases of a number of important steps in melanoma progression of cell proliferation, adhesion, migration, and invasion. Thus, galectin-3 is a natural binding ligand of MCAM in melanoma, and their interaction activates MCAM and promotes MCAM-mediated melanoma progression. Targeting the galectin-3–MCAM interaction may potentially be a useful therapeutic strategy for melanoma treatment.

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Section: Discussionmentioning

confidence: 99%

Galectin-3 Is a Natural Binding Ligand of MCAM (CD146, MUC18) in Melanoma Cells and Their Interaction Promotes Melanoma Progression

et al. 2022

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“…12,13 Antigen retrieval was achieved with 10 mmol/l sodium citrate for 24 minutes. The primary antibody was incubated for 16 minutes using rabbit monoclonal antibodies versus primary antibodies against rabbit monoclonal (PYCR1, 1:2000; Proteintech, [14][15][16][17] ) anti-BANF1 antibody [18][19][20][21] (1:100) with mouse anti-STARD8 (1:1,000; [22][23][24][25] Abcam) overnight at 4°C. Tissues were fixed in formalin 10%, and an automated method was used.…”

Section: Methodsmentioning

confidence: 99%

PYCR1, BANF1, and STARD8 Expression in Gastric Carcinoma: A Clinicopathologic, Prognostic, and Immunohistochemical Study

Harb,

Elfeky,

Alabiad

et al. 2023

Applied Immunohistochemistry &Amp; Molecular Morphology

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Background: It will be important to understand the molecular pathways of gastric cancer (GC) occurrence and progression, thus detecting predictive and prognostic biomarkers of GC. Pyrroline-5-carboxylate reductase 1 (PYCR1) was upregulated in many cancers, suggesting its possible roles in carcinogenesis and tumor metastases. Barrier-of-autointegration factor 1 (BANF1) is a protein family that plays essential roles in maintaining the integrity of an intact cellular genome. Rho-GTPs are molecular switches that control many signal transduction pathways in normal cells, including 3 subgroups from 1 to 3 (DLC1-3). DLC-3, known as StAR-related lipid transfer domain protein 8 (STARD8), and its role in cancers were not sufficiently studied. The study aimed to investigate the significance of PYCR1, BANF1, and STARD8 protein expression in GC tissues and normal gastric mucosa retrieved from patients with GC to detect prognostic roles of expression. Patients and Methods: Specimens were collected from 100 patients with gastric carcinoma. After the application of the inclusion criteria of the study, we prepared 100 paraffin blocks from samples of the 100 included patients; each block included samples from gastric carcinoma and adjacent non-neoplastic gastric mucosa. We assessed the expression of PYCR1, BANF1, and STARD8 using immunohistochemistry in all studied samples. We followed patients for the detection of disease progression and survival rates. We correlate PYCR1, BANF1, and STARD8 expression with clinical, pathologic, and prognostic parameters. Results: Overexpression of PYCR1 and BANF1 and decreased expression of STARD8 was found in gastric carcinoma tissues than adjacent non-neoplastic gastric mucosa (P<0.001), and was positively associated with high grade (P=0.006), depth of tumor invasion, presence of lymph nodes metastases and advanced stage (P=0.001), high incidence of GC progression, recurrence, unfavorable disease-free survival (P=0.003) and unfavorable overall survival rates (P<0.001). Thus, it was revealed that; in univariate and multivariate analyses, levels of PYCR1, BANF1, and STARD8 are associated with the overall survival rate of GC patients. Conclusions: We showed that overexpression of PYCR1 and BANF1 and decreased expression of STARD8 in GC tissues was associated with poor prognosis and GC progression.

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“…CTLA-4 and Tim-3 were expressed as brownish cytoplasmic/membranous staining and were assessed in TILs and cancer cells and scored as follows: 2,26 A scale from 0 to 3 was used to grade the degree of CRC cell staining (0 = negative, 1 = mild staining, 2 = moderate staining, and 3 = strong staining. To arrive at the final score, the epithelial intensity score was split into low (0, 1) and High (2, 3), while the stromal H score was split into low (mean) and high ( > mean).…”

Section: Immunohistochemical Evaluationmentioning

confidence: 99%

Immunohistochemical Expression of Immune Checkpoints; CTLA-4, LAG3, and TIM-3 in Cancer Cells and Tumor-infiltrating Lymphocytes (TILs) in Colorectal Carcinoma

Abdelrahman,

Elhasadi,

Anbaig

et al. 2023

Applied Immunohistochemistry &Amp; Molecular Morphology

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Background: Colorectal cancer is considered the third most prevalent cancer in both sexes. Immune checkpoint receptors that regulate T-cell response, stimulation, and development include lymphocyte activating gene 3 (LAG-3), cytotoxic T lymphocyte-associated antigen-4 (CTLA-4), and T-cell immunoglobulin and mucin domain 3 (Tim-3). In addition, they are crucial for the advancement of cancer and tumor immune escape. Objective: This work’s aim was to assess the immunohistochemistry expression of Tim-3, CTLA-4, and LAG-3 in cancer cells and tumor-infiltrating lymphocytes (TILs) in colorectal cancer (CRC) and the correlation between these markers and clinicopathological variables and survival data. Methods: This study involved 206 CRC specimens processed for CTLA-4, LAG3, and TIM-3 immunohistochemistry and correlated with the clinicopathological and survival parameters of the patients. Results: High CTLA-4 epithelial expression was highly related to the old age group, large tumor size, low tumor-stroma ratio (TSR), high grade, advanced stage, the presence of distant metastasis (DM), perineural invasion (PNI), necrosis, lymphovascular invasion (LVI), relapse, mortality, overall survival (OS), and disease-free survival (DFS), while negative CTLA-4 TILs expression was highly linked with the presence of gross perforation, low TSR, high tumor budding (TB) score, high grade, advanced stage, the existence of lymph node (LN) metastasis, DM, necrosis, LVI, PNI, DFS, mortality, and OS. Positive LAG-3 TILs expression was highly correlated with large tumor size, gross perforation, low TSR, high TB score, high grade, advanced phase, the presence of LN, necrosis, LVI, PNI, relapse DFS, mortality, and OS. High Tim-3 epithelial expression was extremely linked with low TSR, advanced phase, the presence of LN, LVI, PNI, relapse, DFS, mortality, and OS, while positive Tim-3 TILs expression was related to gross perforation, low TSR, high TB score, advanced stage, the presence of LN, DM, necrosis, relapse, DFS, mortality, and OS. Conclusions: The patients’ poor prognosis may be related to the immunohistochemistry expression of LAG-3, Tim-3, and CTLA-4 in CRC cancer tissue and TILs. Poor patient consequences can result from the CTLA-4, Tim-3, and LAG-3 co-expression, but CTLA-4 TILs’ expression of these proteins may inhibit the growth of tumors.

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LAG-3 as a Potent Target for Novel Anticancer Therapies of a Wide Range of Tumors

Cited by 40 publications

References 161 publications

Galectin-3 Is a Natural Binding Ligand of MCAM (CD146, MUC18) in Melanoma Cells and Their Interaction Promotes Melanoma Progression

Galectin-3 Is a Natural Binding Ligand of MCAM (CD146, MUC18) in Melanoma Cells and Their Interaction Promotes Melanoma Progression

PYCR1, BANF1, and STARD8 Expression in Gastric Carcinoma: A Clinicopathologic, Prognostic, and Immunohistochemical Study

Immunohistochemical Expression of Immune Checkpoints; CTLA-4, LAG3, and TIM-3 in Cancer Cells and Tumor-infiltrating Lymphocytes (TILs) in Colorectal Carcinoma

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