epiglucan and Neoplasm-Metastasis

Beta-glucans (β-glucans), naturally occurring polysaccharides, are present as constituents of the cell wall of cereal grains, mushrooms, algae, or microbes including bacteria, fungi, and yeast. Since Pillemer et al. first prepared and investigated zymosan in the 1940s and others followed with the investigation of β-glucans in the 1960s and 1970s, researchers have well established the significant role of β-glucans on the immune system relative to cancer treatment, infection immunity, and restoration of damaged bone marrow. However, information on their biological role in anti-metastatic activity remains limited. As an immunomodulating agent, β-glucan acts through the activation of innate immune cells such as macrophages, dendritic cells, granulocytes, and natural killer cells. This activation triggers the responses of adaptive immune cells such as CD4(+) or CD8(+) T cells and B cells, resulting in the inhibition of tumor growth and metastasis. Reports have shown that β-glucans exert multiple effects on cancer cells and cancer prevention. However the mechanisms of their actions appear complex due to differences in source, chemical structure, insufficiently defined preparation, and molecular weight, hence the inconsistent and often contradictory results obtained. This review is focused on the potential of β-glucans as anti-metastatic agents and the known mechanisms underlying their biological effects.

Topics: Animals; beta-Glucans; Clinical Trials as Topic; Humans; Neoplasm Metastasis; Neoplasms; Signal Transduction; Treatment Outcome

Common genetic alteration in cancer genomes is implicated for embracing an aberrant cancer gene participated in tumor progression. In this study, we identified a somatic mutated LIM and cysteine-rich domains-1 (LMCD1) as a putative metastatic oncogene in human hepatocellular carcinoma (HCC) using integrated genomic approaches. In addition to revealing genomic amplification and gene upregulation, we identified recurrent E135K (3/48 cases) mutations in HCC tissues and K237R mutation in the PLC/PRF/5 HCC cell line. Expression of mutant LMCD1 E135K or K237R reduced the stress fiber assembly, increased cortical actin accumulation and induced lamellipodial extension. Consistently, these mutations enhanced cell migration and showed activation of the Rac1-signaling pathway. Inhibition of the LMCD1/Rac1 pathway by an LMCD1 short-hairpin RNA (shLMCD1) or the Rac1 inhibitor NSC23766 suppressed the mutation-mediated lamellipodial protrusion and cell migration. In PLC/PRF/5 cells with endogenous K237R mutation, cell migration was enhanced by estrogen-induced LMCD1 expression but reversed by shLMCD1 treatment. Moreover, overexpression of LMCD1 E135K mutation significantly promoted systemic lung metastasis in a murine tail vein injection model. Together, our results suggest that LMCD1 mutations are potential oncogenic events in HCC metastasis to promote cell migration through the Rac1-signaling pathway.

Topics: Animals; beta-Glucans; Carcinoma, Hepatocellular; Cell Line, Tumor; Cell Movement; Co-Repressor Proteins; Gene Amplification; Gene Knockdown Techniques; Humans; LIM Domain Proteins; Liver Neoplasms; Lung Neoplasms; Mice; Neoplasm Metastasis; Neoplasm Transplantation; Point Mutation; Pseudopodia; rac1 GTP-Binding Protein; Signal Transduction; Up-Regulation

Sparassis crispa (SC), Hanabiratake in Japanese, is an edible mushroom with medicinal properties, that contains more than 40% beta-D-glucan. It was concluded from results of the methylation study that beta-D-glucan from SC (SBG) was composed of a backbone of beta-(1-->3)-linked D-glucopyranosyl residues, and had beta-D-glucopyranosyl groups joined through O-6 and O-2 of D-glucose of the backbone. We purified SBG and investigated its anti-angiogenic functions and anti-metastatic effects on neoplasm using different animal models. The oral administration of the purified SBG suppressed B16-F10 cell-induced angiogenesis in the dorsal air sac assay using female ICR mice as well as vascular endothelial growth factor induced neovascularization in the Matrigel plug assay using female C57BL/6J mice. Furthermore, it suppressed the growth and numbers of the metastatic tumor foci in lung, along with the primary tumor growth in the spontaneous metastatic model using female C57BL/6J mice. From these results, it is apparent that the oral administration of SBG results in suppressive effect on tumor growth and metastasis in lung through the inhibition of tumor induced-angiogenesis. These effects are not a result of direct action on the endothelial cells because cell growth, migration and capillary-like tube formation were not affected in the human umbilical vein endothelial cells by SBG application. This is the first report showing that the oral administration of SBG is capable of suppressing angiogenesis and metastasis.

Topics: Agaricales; Angiogenesis Inhibitors; Animals; Antineoplastic Agents; beta-Glucans; Capillaries; Cell Line; Cell Movement; Cell Proliferation; Female; Humans; Lung Neoplasms; Melanoma, Experimental; Methylation; Mice; Mice, Inbred ICR; Neoplasm Metastasis; Neoplasm Transplantation; Neovascularization, Pathologic; Proteoglycans; Structure-Activity Relationship; Vascular Endothelial Growth Factor A

Beta-1,3-glucans enhance immune reactions such as antitumor, antibacterial, antiviral, anticoagulatory, and wound healing activities. beta-1,3-Glucans have various functions depending on the molecular weight, degree of branching, conformation, water solubility, and intermolecular association. The molecular weight of the soluble glucan was about 15,000 as determined by a high-performance size exclusion chromatography. From the infrared (IR) and 13C NMR analytical data, the purified soluble glucan was found to exclusively consist of beta-D-glucopyranose with 1,3 linkage. We tested the immunestimulating activities of the soluble beta-1,3-glucan extracted from Agrobacterium sp. R259 KCTC 1019 and confirmed the following activities. IFN-gamma and each cytokines were induced in the spleens and thymus of mice treated with soluble beta-1,3-glucan. Adjuvant effect was observed on antibody production. Nitric oxide was synthesized in monocytic cell lines treated with beta-1,3-glucan. The cytotoxic and antitumor effects were observed on various cancer cell lines and ICR mice. These results strongly suggested that this soluble beta-1,3-glucan could be a good candidate for an immune-modulating agent.

Topics: Animals; Antineoplastic Agents; beta-Glucans; Cell Line, Tumor; Cell Proliferation; Disease Models, Animal; Magnetic Resonance Spectroscopy; Mice; Mice, Inbred ICR; Neoplasm Metastasis; Rhizobium; Solubility; Water

The purpose of this study was to investigate the combined antitumor effect of aminated beta-1,3-D-glucan (AG) and interferon-gamma (IFN-gamma) in an experimental liver metastasis model. Liver metastases were established by inoculation of C-26 colon carcinoma cells into the superior mesenteric vein of syngeneic mice. Treatment of mice started 24 hours after inoculation of tumor cells by daily intravenous injections of either AG, IFN-gamma, or a combination of both for a duration of 6 days. The resultant liver metastases were then quantified after an additional period of 11 days. Combination of IFN-gamma and AG inhibited the growth of liver metastases almost entirely. IFN-gamma was also very efficient, while AG alone did not exert any significant antitumor effect. These results, along with histological studies from mice receiving AG and IFN-gamma, indicated that activation and recruitment of liver macrophages may be a part of the mechanism responsible for the inhibition of metastatic growth observed in this study.

Topics: Animals; Antineoplastic Agents; beta-Glucans; Carcinoma; Colonic Neoplasms; Drug Synergism; Female; Glucans; Interferon-gamma; Liver Neoplasms; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Neoplasm Metastasis; Recombinant Proteins