epiglucan and Carcinoma--Lewis-Lung

Myeloid-derived suppressor cells (MDSC) are a heterogeneous population of immature myeloid cells that promote tumor progression. In this study, we demonstrated that activation of a C-type lectin receptor, dectin-1, in MDSC differentially modulates the function of different MDSC subsets. Yeast-derived whole β-glucan particles (WGP; a ligand to engage and activate dectin-1, oral treatment in vivo) significantly decreased tumor weight and splenomegaly in tumor-bearing mice with reduced accumulation of polymorphonuclear MDSC but not monocytic MDSC (M-MDSC), and decreased polymorphonuclear MDSC suppression in vitro through the induction of respiratory burst and apoptosis. On a different axis, WGP-treated M-MDSC differentiated into F4/80(+)CD11c(+) cells in vitro that served as potent APC to induce Ag-specific CD4(+) and CD8(+) T cell responses in a dectin-1-dependent manner. Additionally, Erk1/2 phosphorylation was required for the acquisition of APC properties in M-MDSC. Moreover, WGP-treated M-MDSC differentiated into CD11c(+) cells in vivo with high MHC class II expression and induced decreased tumor burden when inoculated s.c. with Lewis lung carcinoma cells. This effect was dependent on the dectin-1 receptor. Strikingly, patients with non-small cell lung carcinoma that had received WGP treatment for 10-14 d prior to any other treatment had a decreased frequency of CD14(-)HLA-DR(-)CD11b(+)CD33(+) MDSC in the peripheral blood. Overall, these data indicate that WGP may be a potent immune modulator of MDSC suppressive function and differentiation in cancer.

Topics: Adult; Aged; Aged, 80 and over; Animals; Antigen-Presenting Cells; Apoptosis; beta-Glucans; Blotting, Western; Carcinoma, Lewis Lung; Carcinoma, Non-Small-Cell Lung; Cell Differentiation; Cell Separation; Disease Models, Animal; Female; Flow Cytometry; Humans; Lectins, C-Type; Lung Neoplasms; Lymphocyte Culture Test, Mixed; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Middle Aged; Monocytes; Myeloid Cells; Neutrophils; Real-Time Polymerase Chain Reaction; Yeasts

Candida albicans (C. albicans) cell wall beta-glucan has been considered as a potential agent in the treatment of cancers due to its anti-tumor properties. Therefore, in the present study, we investigated the anti-cancer effects of Candida cell wall beta-glucan on Lewis lung carcinoma cell line (LL/2) cells. Beta-glucan of C. albicans cell wall was extracted. LL/2 cell line was cultured, then sphere cells and parental cells were exposed to the different concentrations of beta-glucan extracted from C. albicans (10-6000 μg/ml), for 24, 48 and 72 h. Cytotoxicity of beta-glucan was assayed by MTT test, then RNA extracted from cells population (treated and untreated cells), cDNA synthetized and expression level of Sox2, Oct4, C-myc, Nanog genes were also investigated using Real-time methods. At optimal concentrations of 800 and 1000 μg/ml, the extracted beta-glucan showed a significant cytotoxic effect on both parental and sphere cell populations (p < 0.05). Real-time PCR analysis revealed a decreased expression of Oct4 and Sox2 genes in treatment of cells with beta-glucan compared with control group. Since the extracted beta-glucan showed an inhibitory effect on the expression of Oct4 and Sox2 genes involved in LL/2 metastasis, therefore, beta-glucan can be considered as an anti-tumor agent because of its anti-metastatic properties, however, more in vitro and in vivo studies are needed to provide further evidence on this topic in the future.

Topics: Animals; beta-Glucans; Candida; Candida albicans; Carcinoma, Lewis Lung; Cell Line, Tumor; Cell Wall; Host-Pathogen Interactions; Humans

β-Glucans are well-established immunomodulators with strong effects across all immune reactions. Due to the extensive amount of studies, glucans are steadily progressing from a non-specific immunomodulator to a licensed drug. However, direct comparisons of higher numbers of different glucans are rare.. In this study, we used 16 different glucans isolated from yeasts, mushroom, algae, and oat and compared their effects on phagocytosis, IL-2 production, antibody secretion, and inhibition of three experimental cancer models.. Our results showed significant differences among tested glucans, showing that despite the fact that glucans in general have strong stimulating effects on most aspects of the immune system, it is necessary to choose the right glucan.. Based on our studies, we can conclude that highly purified and active glucans have significant pleiotropic effects.

Topics: Agaricales; Animals; Antibody Formation; Avena; beta-Glucans; Carcinoma, Lewis Lung; Cell Line, Tumor; Disease Models, Animal; Female; Humans; Interleukin-2; Mammary Neoplasms, Experimental; Mice, Inbred BALB C; Phagocytosis; Spleen; Yeasts

Tumor-elicited immunosuppression is one of the essential mechanisms for tumor evasion of immune surveillance. It is widely thought to be one of the main reasons for the failure of tumor immunotherapy. Myeloid-derived suppressor cells (MDSCs) comprise a heterogeneous population of cells that play an important role in tumor-induced immunosuppression. These cells expand in tumor-bearing individuals and suppress T cell responses via various mechanisms. Curdlan, the linear (1 → 3)-β-glucan from Agrobacterium, has been applied in the food industry and other sectors. The anti-tumor property of curdlan has been recognized for a long time although the underlying mechanism still needs to be explored. In this study, we investigated the effect of curdlan on MDSCs and found that curdlan could promote MDSCs to differentiate into a more mature state and then significantly reduce the suppressive function of MDSCs, decrease the MDSCs in vivo and down-regulate the suppression in tumor-bearing mice, thus leading to enhanced anti-tumor immune responses. We, therefore, increase the understanding of further mechanisms by which curdlan achieves anti-tumor effects.

Topics: Agrobacterium; Animals; Antineoplastic Agents; beta-Glucans; Carcinoma, Lewis Lung; Cell Differentiation; Immunity; Immunosuppression Therapy; Immunotherapy; Lung Neoplasms; Male; Mice; Mice, Inbred C57BL; Myeloid-Derived Suppressor Cells; Neoplasms, Experimental; T-Lymphocytes; Tumor Burden; Tumor Escape

Myeloid-derived suppressor cells (MDSCs) play a critical role in tumor-associated immunosuppression, thus affecting effective immunotherapies for cancers. However, the molecular mechanisms involved in regulating the differentiation and function of MDSCs remain largely unclear. In this study, we found that inhibition of microRNA (miR)-9 promoted the differentiation of MDSCs with significantly reduced immunosuppressive function whereas overexpression of miR-9 markedly enhanced the function of MDSCs. Notably, knockdown of miR-9 significantly impaired the activity of MDSCs and inhibited the tumor growth of Lewis lung carcinoma in mice. Moreover, miR-9 regulated MDSCs differentiation by targeting the runt-related transcription factor 1, an essential transcription factor in regulating MDSC differentiation and function. Furthermore, the CREB was found to regulate miR-9 expression in MDSCs. Taken together, our findings have identified a critical role of miR-9 in regulating the differentiation and function of MDSCs.

Topics: Animals; beta-Glucans; Carcinoma, Lewis Lung; Cell Differentiation; Cell Line; Core Binding Factor Alpha 2 Subunit; Cyclic AMP Response Element-Binding Protein; HEK293 Cells; Humans; Male; Mice; Mice, Inbred BALB C; MicroRNAs; Myeloid Cells; Promoter Regions, Genetic

The present study showed that oral mushroom beta-glucan treatment significantly increased IFN-γ mRNA expression but significantly reduced COX-2 mRNA expression within the lung. For LLC tumor model, oral Ganoderma lucidum or Antrodia camphorata polysaccharides treatments significantly reduced TGF-β production in serum. In addition, IL-12 and IFN-γ mRNA expression were significantly increased, but IL-6, IL-10, COX-2, and TGF-β mRNA expression were substantially following oral mushroom polysaccharides treatments. The study highlights the efficacious effect of mushroom polysaccharides for ameliorating the immune suppression in the tumor microenvironment. Increased M1 phenotype of tumor-associated macrophages and attenuated M2 phenotype of tumor-associated macrophages could be achieved by ingesting mushroom polysaccharides.

Topics: Agaricales; Animals; beta-Glucans; Carcinoma, Lewis Lung; Cytokines; Gene Expression Regulation, Neoplastic; Immunologic Factors; Macrophages; Mice; RNA, Messenger; Tumor Microenvironment

Natural immunomodulators are getting more and more popular. The popularity, however, often brings over-optimistic claims and mediocre effects. The purpose of the present study was to directly compare eleven most commonly used immunomodulators. Through testing both cellular and humoral branches of immune reactions, we found that most of the immunomodulators tested have limited, if any, effects, with glucan being consistently the most active molecule strongly stimulating every reaction evaluated. These data were also confirmed using a Lewis lung cancer model, where only glucan and resveratrol lowered the number of metastases.

Topics: Animals; beta-Glucans; Carcinoma, Lewis Lung; Female; Humans; Immune System; Immunologic Factors; Mice; Mice, Inbred BALB C; Resveratrol; Stilbenes

Myeloid-derived suppressor cells (MDSCs) accumulate in tumor-bearing hosts and play a major role in tumor-induced immunosuppression, which hampers effective immuno-therapeutic approaches. β-Glucans have been reported to function as potent immuno-modulators to stimulate innate and adaptive immune responses, which contributes to their antitumor property. Here, we investigated the effect of particulate β-glucans on MDSCs and found that β-glucan treatment could promote the differentiation of M-MDSCs (monocytic MDSCs) into a more mature CD11c(+) F4/80(+) Ly6C(low) population via dectin-1 pathway in vitro, which is NF-κB dependent, and the suppressive function of M-MDSCs was significantly decreased. Treatment of orally administered yeast-derived particulate β-glucan drastically downregulated MDSCs but increased the infiltrated DCs and macrophages in tumor-bearing mice, thus eliciting CTL and Th1 responses, inhibiting the suppressive activity of regulatory T cells, thereby leading to the delayed tumor progression. We show here for the first time that β-glucans induce the differentiation of MDSCs and inhibit the regulatory function of MDSCs, therefore revealing a novel mechanism for β-glucans in immunotherapy and suggesting their potential clinical benefit.

Topics: Administration, Oral; Animals; beta-Glucans; Carcinoma, Lewis Lung; CD11c Antigen; Cell Differentiation; Cell Movement; Dendritic Cells; Fungal Polysaccharides; Gene Expression Regulation, Neoplastic; Immunologic Factors; Immunosuppression Therapy; Lectins, C-Type; Macrophages; Mice; Myeloid Cells; NF-kappa B; Saccharomyces cerevisiae; Spleen; T-Lymphocytes, Cytotoxic; T-Lymphocytes, Regulatory

β-Glucans are naturally occurring carbohydrates found in plants, fungi and some bacterial species, and currently are well-established and powerful immunomodulators with beneficial properties in cancer therapy. Recent studies suggested that some additional bioactive molecules have synergistic effects when combined with glucan. In the current study, we evaluated the anticancer properties of glucan, resveratrol, vitamin C combination. We found that compared to the individual components, the combination was the strongest activator of phagocytosis and antibody formation. Using two different models of cancer treatment, our results demonstrated that the combination strongly suppressed the growth of breast and lung tumors, most likely due to the stimulation of apoptosis.

Topics: Animals; Antibody Formation; Antioxidants; Ascorbic Acid; beta-Glucans; Carcinoma, Lewis Lung; Drug Therapy, Combination; Female; Granulocytes; Immunologic Factors; Mammary Neoplasms, Experimental; Mice; Mice, Inbred BALB C; Ovalbumin; Phagocytosis; Resveratrol; Stilbenes

β-Glucans have been shown to function as a potent immunomodulator to stimulate innate and adaptive immune responses, which contributes to their anti-tumor property. However, their mechanisms of action are still elusive. Glucocorticoid-induced TNF receptor ligand (GITRL), a member of the TNF superfamily, binds to its receptor, GITR, on both effector and regulatory T cells, generates a positive co-stimulatory signal implicated in a wide range of T cell functions, which is important for the development of immune responses.. In this study, we found that whole β-glucan particles (WGPs) could activate dendritic cells (DCs) via dectin-1 receptor, and increase the expression of GITRL on DCs in vitro and in vivo. Furthermore, we demonstrated that the increased GITRL on DCs could impair the regulartory T cell (Treg)-mediated suppression and enhance effector T cell proliferation in a GITR/GITRL dependent way. In tumor models, DCs with high levels of GITRL were of great potential to prime cytotoxic T lymphocyte (CTL) responses and down-regulate the suppressive activity of Treg cells, thereby leading to the delayed tumor progression.. These findings suggest that particulate β-glucans can be used as an immunomodulator to stimulate potent T cell-mediated adaptive immunity while down-regulate suppressive immune activity via GITR/GITRL interaction, leading to a more efficient defense mechanism against tumor development.

Topics: Animals; beta-Glucans; Carcinoma, Lewis Lung; Dendritic Cells; Gene Expression Regulation, Neoplastic; Immunity, Cellular; Immunologic Factors; Lectins, C-Type; Lung; Male; Mice; Mice, Inbred C57BL; Saccharomyces cerevisiae; T-Lymphocytes, Regulatory; Tumor Necrosis Factors; Up-Regulation

The beneficial properties of β-glucans have been recognized for centuries. Their proposed mechanisms of action in cancer therapy occur via stimulation of macrophages and priming of innate neutrophil complement receptor 3 for eliciting complement receptor 3-dependent cellular cytotoxicity of iC3b-opsonized tumor cells. The current study is to investigate whether β-glucan therapy has any effect on antitumor adaptive T-cell responses.. We first examined the trafficking of orally administered particulate yeast-derived β-glucan and its interaction with dendritic cells (DC) that captured tumor materials. Antigen-specific T cells were adoptively transferred into recipient mice to determine whether oral β-glucan therapy induces augmented T-cell responses. Lewis lung carcinoma and RAM-S lymphoma models were used to test oral β-glucan therapeutic effect. Further mechanistic studies including tumor-infiltrating T cells and cytokine profiles within the tumor milieu were determined.. Orally administered particulate β-glucan trafficked into spleen and lymph nodes and activated DCs that captured dying tumor cells in vivo, leading to the expansion and activation of antigen-specific CD4 and CD8 T cells. In addition, IFN-γ production of tumor-infiltrating T cells and CTL responses were significantly enhanced on β-glucan treatment, which ultimately resulted in significantly reduced tumor burden. Moreover, β-glucan-treated tumors had significantly more DC infiltration with the activated phenotype and significant levels of Th1-biased cytokines within the tumor microenvironment.. These data highlight the ability of yeast-derived β-glucan to bridge innate and adaptive antitumor immunity and suggest that it can be used as an adjuvant for tumor immunotherapy.

Topics: Adjuvants, Immunologic; Administration, Oral; Animals; beta-Glucans; Carcinoma, Lewis Lung; Cells, Cultured; Dendritic Cells; Dosage Forms; Drug Evaluation, Preclinical; Immunity, Cellular; Mice; Mice, Inbred C57BL; Mice, Transgenic; Neoplasms; Phagocytosis; Powders; T-Lymphocytes

During the photodynamic treatment, complement system is activated and tumor cells are opsonized with iC3b fragment. beta-glucans can enhance cytotoxicity of iC3b-opsonized cells due to their specific interaction with complement receptor 3 (CR3; CD11b/CD18) on the surface of the effector cells. In contrast to microorganisms, tumor cells lack beta-glucan as a surface component and cannot trigger complement receptor 3-dependent cellular cytotoxicity and initiate tumor-killing activity. This mechanism could be induced in the presence of beta-glucans. This study aimed at determining the influence of coadministration of beta-glucan from barley on the efficacy of photodynamic tumor therapy (PDT).. C57 Bl/6 female mice bearing Lewis lung carcinoma were used throughout the study. Mice were randomized into groups (15 in each group) and exposed to the treatment with intravenous Photofrin injection (dose, 10 mg/kg) and after 24 h following laser illumination, or with oral administration of beta-glucan from barley at a dose of 400 microg/mouse per day up to 5 days, or with their combination. Tumor growth dynamics and survival of the treated and untreated mice were monitored.. Tumor volume in all treated groups was significantly lower (P<0.001) than that in the control group. The most effective tumor growth suppression (P=0.033) was achieved in mice treated with combination of PDT and beta-glucan from barley as compared with PDT alone. The best survival was achieved in the same group, but difference was not significant as compared to the control group (P=0.143) and to PDT alone group (P=0.319).. The present study demonstrates that coadministration of beta-glucan from barley can enhance efficacy of photodynamic therapy.

Topics: Administration, Oral; Animals; beta-Glucans; Carcinoma, Lewis Lung; Data Interpretation, Statistical; Drug Therapy, Combination; Female; Hordeum; Kaplan-Meier Estimate; Mice; Mice, Inbred C57BL; Photochemotherapy; Random Allocation; Receptors, Complement; Time Factors

(1-->3)-beta-D-Glucans represent highly conserved structural components of cell walls in yeast, fungi, or seaweed. However, it is still unknown how they mediate their effects. The aim of this study was to evaluate both intraperitoneal and oral application of seaweed-derived (1-->3)-beta-D-glucan Phycarine. Phycarine showed significant stimulation of phagocytosis by peripheral blood cells. In addition, the efficiency of chemotherapy of Lewis lung carcinoma with cyclophosphamide was potentiated by Phycarine administration. Phycarine also strongly shortened the recovery of leucopenia caused either by chemotherapy or irradiation. Besides the role in stimulation of cellular immunity, we also found a significant increase of antibody formation. Using a suckling rat model for evaluation of the absorption and tissues distribution of enterally administered (125)I-Phycarine, we found that the majority of Phycarine was detected in the stomach and duodenum 5 min after the administration. This amount sharply decreased during first 30 min. A significant amount of Phycarine entered proximal intestine in a shortly after the gavage. Its transit through proximal intestine was decreasing with time and simultaneously increasing in the ileum. Systemic blood levels were very low (less than 0.5%). Taken together, these observations suggest that Phycarine is similarly effective both after i.p. and oral application, has very strong stimulating effects on three types of experimentally induced leucopenia and stimulates both humoral and cellular branch of immune reactions. The majority of Phycarine can be detected throughout the gastrointestinal tract, supporting the feasibility of enteral administration of Phycarine in the treatment of gastrointestinal diseases.

Topics: Administration, Oral; Animals; Antibody Formation; Apoptosis; beta-Glucans; Bone Marrow Cells; Carcinoma, Lewis Lung; Cell Count; Cyclophosphamide; Immunity, Cellular; Injections, Intraperitoneal; Iodine Radioisotopes; Killer Cells, Natural; Leukopenia; Mice; Mice, Inbred BALB C; Microspheres; Phagocytosis; Proteoglycans; Rats; Rats, Sprague-Dawley; Seaweed; Spleen; Thymus Gland; Tissue Distribution

The Basidiomycete fungus Agaricus blazei Murill has traditionally been used as a health food for the prevention of cancer.. We examined whether beta-(1-6)-D: -glucan extracted from A. blazei is a potential anticancer agent in an in vitro and in vivo animal model.. Here we show that (1) beta-glucan had cytotoxic effect against human ovarian cancer HRA cells, but not against murine Lewis lung cancer 3LL cells, in vitro; (2) beta-glucan promotes p38 MAPK activity for suppressing HRA cell proliferation and amplifying the apoptosis cascade; (3) beta-glucan stimulates translocation of the proapoptotic protein, Bax, from the cytosol to mitochondria, cytochrome c release, and subsequent caspase-9 activation; (4) treatment with SB203580, a p38 MAPK-specific inhibitor, suppresses beta-glucan-induced effects, indicating that activation of p38 MAPK is involved in the suppression of cell proliferation and mitochondrial activation-mediated cell death pathway; (5) in mice, oral supplementation with beta-glucan reduces pulmonary metastasis of 3LL cells and peritoneal disseminated metastasis of HRA cells and inhibits the growth of these metastatic tumors in lung or peritoneal cavity, in part, by suppressing uPA expression; and (6) in an in vivo experimental metastasis assay, however, the oral supplementation with beta-glucan after i.v. tumor cell inoculation did not reduce the number of lung tumor colonies.. Treatment with beta-glucan may be beneficial for cancer patients with or at risk for metastasis. The beta-glucan-dependent signaling pathways are critical for our understanding of anticancer events and development of cancer therapeutic agents.

Topics: Administration, Oral; Agaricus; Animals; Antineoplastic Agents; Apoptosis; beta-Glucans; Carcinoma, Lewis Lung; Cell Proliferation; Drug Administration Schedule; Enzyme Activation; Female; Humans; Mice; Ovarian Neoplasms; p38 Mitogen-Activated Protein Kinases; Peritoneal Neoplasms; Signal Transduction; Tumor Cells, Cultured

The efficiency of chemotherapy of Lewis lung carcinoma with cyclophosphamide was affected by administration of the water-soluble yeast polysaccharide derivative--carboxymethylated (1 --> 3)-beta-D-glucan (CMG)-a well-known macrophage stimulator. It was found that while cyclophosphamide showed 57% growth inhibition of the intramuscular tumor implants in comparison with the control group, its combined administration with CMG led to 75-90% inhibition. Similarly, increased inhibition of occurrence of lung metastases (up to 92-94%) was observed using the combined application of the two compounds. The stimulatory effect of CMG is not associated with the changed cellularity of peripheral blood, but is rather due to the obviously increased concentration of the intracellular inhibitor of cysteine proteases-stefin A and cystatin C in tumor tissue.

Topics: Animals; beta-Glucans; Carcinoma, Lewis Lung; Cyclophosphamide; Cysteine Endopeptidases; Cysteine Proteinase Inhibitors; Drug Therapy, Combination; Glucans; Leukocytes; Lung Neoplasms; Macrophages; Male; Mice; Mice, Inbred C57BL; Mice, Inbred CBA; Saccharomyces cerevisiae; Xenograft Model Antitumor Assays

We studied the effect of macrophage stimulator water-soluble beta-(1-->3)-D-carboxymethylglucan on the efficiency of cyclophosphamide chemotherapy in Lewis lung carcinoma. Cyclophosphamide inhibited the growth of primary tumor nodes by 57%. The preparation possessed pronounced antimetastatic activity: metastases were found in 40.9% animals. Combination therapy with cyclophosphamide and (1-->3)-beta;-D-glucan inhibited the growth of intramuscular tumors by 75-89% and reduced the incidence of metastases into the lungs by 92-94%. The therapeutic effect was most pronounced after simultaneous administration of these preparations: tumor growth was suppressed by 89.3% and metastases were found in only 7.5% animals (vs. 100% in the control). The potentiating effect of beta-(1-->3)-D-carboxymethylglucan is related to accumulation of cysteine proteinase inhibitors in the tumor tissue and plasma, but not to changes in blood cell composition.

Topics: Animals; Antineoplastic Agents, Alkylating; Antineoplastic Combined Chemotherapy Protocols; beta-Glucans; Body Weight; Carcinoma, Lewis Lung; Cathepsin B; Cathepsin L; Cathepsins; Cyclophosphamide; Cystatin A; Cystatin C; Cystatins; Cysteine Endopeptidases; Drug Synergism; Glucans; Injections, Intraperitoneal; Lung Neoplasms; Macrophages; Male; Mice; Mice, Inbred C57BL; Mice, Inbred CBA; Neoplasm Transplantation