Gal 9

Genomic alteration can reshape tumor microenvironment to drive tumor malignancy. However, how PTEN deficiency influences microenvironment-mediated cell-cell interactions in glioblastoma (GBM) remains unclear. Here, we show that PTEN deficiency induces a symbiotic glioma-M2 macrophage interaction to support glioma progression. Mechanistically, PTEN-deficient GBM cells secrete high levels of galectin-9 (Gal-9) via the AKT-GSK3β-IRF1 pathway. The secreted Gal-9 drives macrophage M2 polarization by activating its receptor Tim-3 and downstream pathways in macrophages. These macrophages, in turn, secrete VEGFA to stimulate angiogenesis and support glioma growth. Furthermore, enhanced Gal-9/Tim-3 expression predicts poor outcome in glioma patients. In GBM models, blockade of Gal-9/Tim-3 signaling inhibits macrophage M2 polarization and suppresses tumor growth. Moreover, α-lactose attenuates glioma angiogenesis by down-regulating macrophage-derived VEGFA, providing a novel antivascularization strategy. Therefore, our study suggests that blockade of Gal-9/Tim-3 signaling is effective to impair glioma progression by inhibiting macrophage M2 polarization, specifically for PTEN-null GBM.

Generally considered as a potent pro‑inflammatory signal, β‑galactosidelectin suppresses T cell receptor activation, can both promote and inhibit integrin‑mediated adhesion and is required in nuclear pre‑mRNA splicing. Galectin‑9 (Gal‑9), a member of β‑galactoside lectin, is involved many processes of T cell‑mediated diseases (such as autoimmune diseases and asthma) and immunomodulation of macrophages. Macrophages are involved in the occurrence of inflammation, development and digestion and other stages. At different stages of the inflammatory response, macrophages exhibit different phenotypes, but mainly two subtypes, classically (M1) or alternatively (M2) polarization. The purpose of this work is to investigate the effect of overexpression or knockdown of Gal‑9 on the macrophage polarization. Macrophage polarization was detected by flow cytometric profiling of secreted cytokines and specific surface markers expression, including nitric oxide synthase 2 (NOS2) and mannose receptor 1 (CD206). Protein and mRNA expression levels of TNF‑α, TGF‑β, IL‑6, IL‑10, NF‑κB, signal transducer and activator of transcription (Stat)1 and Stat3 were determined by ELISA, western blot analysis or qRT‑PCR. Our results implied that differentiation of the mouse macrophage line RAW264.7 into M1‑type and M2‑type macrophages is followed by marked variations of Gal‑9 expression. Furthermore, its overexpression and secretion are tightly associated with M2‑type macrophages, whereas its downregulation promotes macrophages to polarize into M1‑type macrophages, which confirmed by elevated CD206 and NOS2, respectively. In response to the changes of Gal‑9 expression, cytokines, transcription factors and regulators, including TNF‑α, IL‑6, NF‑κB, Stat1, TGF‑β, IL‑10, and Stat3, were tightly regulated and significantly associated with classically and alternatively activated macrophages. Consistent with characteristics of M1‑type macrophages, the transcriptional or translational expression levels or activity of TNF‑α, IL‑6, Stat1 and NF‑κB were markedly increased with knockdown of Gal‑9 in macrophages. By contrast, the expression levels or activity of TGF‑β, IL‑10 and Stat3 were clearly elevated in macrophages with Gal‑9 overexpression, which is closely related with M2‑type macrophages. Specific expression and secretion patterns of cytokines, transcription factors and regulators in M1‑type and M2‑type macrophages contribute to better understanding the role of Gal‑9 in regulation in macrophages. This study provides a new insight that Gal‑9 may be a new immunomodulatory target for macrophages.

Galectin-9 (Gal-9) is a β-galactoside binding lectin known for its immunomodulatory role in various microbial infections. Gal-9 is expressed in all organ systems and localized in the nucleus, cell surface, cytoplasm and the extracellular matrix. It mediates host-pathogen interactions and regulates cell signalling via binding to its receptors. Gal-9 is involved in many physiological functions such as cell growth, differentiation, adhesion, communication and death. However, recent studies have emphasized on the elevated levels of Gal-9 in autoimmune disorders, viral infections, parasitic invasion, cancer, acute liver failure, atopic dermatitis, chronic kidney disease, type-2 diabetes, coronary artery disease, atherosclerosis and benign infertility-related gynecological disorders. In this paper we have reviewed the potential of Gal-9 as a reliable, sensitive and non-invasive biomarker of disease severity. Tracking changes in Gal-9 levels and its implementation as a biomarker in clinical practice will be an important tool to monitor disease activity and facilitate personalized treatment decisions.