Lung Cancer and Þâ²-glucans Review of Potential Therapeutic Applications
from a public wellness perspective, both nutrition and practise are usually the focus of behavioral changes suggested to reduce the risk for some of the major site-specific cancers (12, xiii). Both epidemiological and animal experiments provide insight into the links between nutrition and cancer prevention (thirteen). Dietary fiber, vegetables and fruits, micronutrients, and phytochemicals take all been investigated for their anti-tumor potentiating activity that commonly involves immune system mechanisms (xiii). Lack of practise has been one of the most consistently identified risk factors for all cancer bloodshed (12, 37), besides equally site-specific cancers such equally colorectal cancer (four) and breast cancer (19). However, the strength of the association remains questionable due to the lack of data from controlled experimental studies and the fact that specific mechanisms have not been elucidated. The amount and intensity of do required to reduce the risk of cancer have also not been determined. Express evidence from fauna models typically demonstrates that exercise inhibits the incidence and progression of cancer in a variety of tumor models, including chemically induced tumor models (30, 31, 33), genetically predisposed models (iii), and implantation/transplantation models (vi, 24), although not in all cases (32, 39). Differences in the intensity and duration of practise, the timing of exercise in relation to administration of tumor cells or carcinogen, and specific tumor model are probable to contribute to the inconsistencies.
The part of practise in tumor metastases, perhaps the almost devastating attribute of cancer, has non been widely studied. The lung is one of the major sites of metastases. A recent study in our laboratory found a decrease in the number of lung tumor foci in mice later on intravenous administration of the B16 melanoma cells later on a single tour of prolonged running on a treadmill (half dozen). Similarly, 9 wk of wheel-running activity in mice before administration of CIRAS 1 tumor cells resulted in a lower distribution of tumor metastases in the lungs (22). The mechanisms underlying the exercised-induced inhibition of experimental tumor metastasis are not well understood. Components of the innate immune organization tin play an important role in limiting metastases past altering the early steps of implantation and growth of secondary foci (1, eleven) of various cancer cells, including B16 melanoma. Macrophages and natural killer (NK) cells are cytotoxic to a number of tumor cells in vitro besides every bit in vivo (6, 11, 17, eighteen, 21). Exercise-induced increases in the anti-cancer functions of these cells have been reported (6, 17, 18, 20, 21, 23, 40, 41). Many other potential mechanisms take also been investigated, including steroid hormones, oxygen free radicals, insulin and insulin-similar growth factors, as well as energy residue and body composition, but they are typically investigated in other cancer models involving tumorogenesis that develops over long periods (35).
The dietary cobweb β-glucan, derived from the cell wall of yeast and fungi, has well-documented furnishings in cancer prevention in a multifariousness of syngenic murine tumor models, including B16 melanoma, adenocarcinoma, mammary carcinoma, lymphocytic leukemia, and Lewis lung carcinoma, presumably acting via activation of both nonspecific and specific allowed mechanisms (eight, 27). β-Glucan exerts its furnishings through direct stimulation of macrophage, neutrophil, and NK cells via β-glucan-specific receptor sites on their cell surface membranes (5, 34), such as complement receptor iii and dectin-one (2). The exact mechanisms are at least partially dependent on the route of administration. Protection after oral administration results primarily from ingestion of pocket-sized particles of β-glucan past pinocytic M cells located in Peyer's patches of the small-scale intestine (9). Once activated, these cells can migrate to the lymph nodes and are capable of activating other macrophages, NK cells, and T lymphocytes via the release of cytokines (25, 26, 28). Soluble β-glucan from oats is kickoff to receive greater attention due to its recognition past the Food and Drug Assistants as function of the Heart Healthy Diet and its well-documented health benefits in other pathological conditions, including diabetes and cardiovascular disease (16, 42). Yet, there have been no reports on the specific benefits of soluble oat β-glucan on any grade of cancer.
The purpose of this study was to determine the effects of short-term moderate-practice grooming and oral feedings of soluble oat β-glucan on the metatastic spread of injected tumor cells. The effects on macrophage cytotoxicity were besides studied as a possible mechanism. This was done by using an experimental murine model of lung metastases involving intravenous assistants of B16 melanoma cells in which our laboratory has previously shown a benefit of a unmarried run to fatigue (∼2.5 h), but not a 30-min run, on lung tumor foci (half dozen). Still, the exercise protocol was modified for this experiment to include six consecutive days of treadmill running (i h/day) to better assess the part of brusque-term moderate-exercise training. This exercise protocol can increment macrophage anti-viral function and reduce the risk of respiratory viral infection in mice (7). We hypothesized that both exercise and oat β-glucan would decrease the metatastic spread of injected tumor cells, which would be associated with an increase in macrophage cytotoxicity. Furthermore, nosotros hypothesized that at that place would be an condiment result of exercise and oat β-glucan.
METHODS
Animals.
Male C57BL/6 mice, 6 wk of age, were purchased from Harlan Sprague-Dawley Laboratories and acclimated to our facility for at least 3 days before any experimentation. Mice were purchased equally pathogen-costless stock, and periodic screening of sentinel mice yielded negative results for common murine viral or bacterial pathogens. Mice were housed 4 per cage and cared for in the beast facility at the University of South Carolina Medical School. Mice were maintained on a 12:12-h calorie-free-night cycle in a low-stress environs (22°C, 50% humidity, low dissonance) and given food (Purina Grub) and water (or oat β-glucan dissolved in water) ad libitum. Separate groups of mice were used for each dependent variable: in vivo lung tumor metastases (due north = eight–11 per group) and peritoneal macrophage cytotoxicity (n = viii per group). All experiments were performed at the cease of the agile dark wheel.
Food treatment.
Mice were randomly assigned to ane of the post-obit four groups: exercise water (Ex-H2O), exercise oat β-glucan (Ex-OβG), control water (Con-H2O), or control oat β-glucan (Con-OβG). Ex-H2O and Con-H2O received tap water for the 10 days before tumor administration or death, whereas Ex-OβG and Con-OβG mice were fed a solution of oat β-glucan dissolved in the drinking water for the 10 days before tumor assistants or expiry and the 14 days after tumor assistants. The oat β-glucan solution was made from an oat bran concentrate enriched to 68% soluble β-glucan (manufactured by Nurture, Devon, PA, and supplied by Quaker Oats, Barrington, IL), which was dissolved in the drinking h2o at a concentration of 0.6 mg/ml and fabricated fresh daily. The balance of the oat bran concentrate included starch, besides as minor quantities of protein, sodium, and fatty. Soluble oat β-glucan is a structural polysaccharide (∼2 × 10half dozen molecular weight) found in the cell walls of the bran layer and endosperm fractions of the whole seed. Structurally, they are linear chains of β-d-glucopyranolsyl units in which ∼70% of the units are linked (1–4), but which also consist of β-d-cellotriosyl and β-d-cellotetraosyl residues separated past (1–3) linkages bundled in a random manner (36). Daily consumption of fluid was measured to ensure that at that place were no differences in fluid ingestion between the h2o and the oat β-glucan solution. Body weight of each animal was monitored throughout supplementation and do menstruation to ensure that no weight loss was experienced past any group.
Treadmill acclimation and exercise protocol.
The University's Institutional Animal Care and Employ Committee approved the protocol described. Get-go on the second twenty-four hours of oat β-glucan or water handling, practice mice (Ex-H2O and Ex-OβG) were acclimated to the treadmill for a period of twenty min a twenty-four hours for iii sequent days. The do protocol consisted of a 1-h tour of treadmill running (performed in the morning, vii AM) for 6 sequent days. Mice ran on the treadmill (2 per lane) at a speed of 36 m/min and a class of viii%, which is estimated to arm-twist ∼75–90% maximal O2 uptake (10, 29), assuming a maximal Oii uptake of 173–206 ml·kg−1·min−ane for mice. Male C57BL/6 mice are capable of running for ∼ii.5 h at this exercise intensity in our hands (6). Electric shock was never used in these experiments, equally mice readily respond to a gentle tap of the tail or hindquarters, encouraging them to maintain pace with the treadmill. Mice rarely require this type of continual prodding during the 1-h practice bout. Mice in the command groups (Con-HtwoO and Con-OβG) remained in their cages in the treadmill room throughout the exercise bouts. These mice were exposed to similar treatment and noise in an attempt to command for extraneous stresses that may be associated with treadmill running. Control mice were deprived of food and water during the exercise sessions.
Tumor metastases.
The tumor cell line B16Fane melanoma (ATCC no. CRL 6323; American Type Culture Collection, Rockville, MD), which is syngeneic to the C57BL/half-dozen mouse strain, was used in all experiments. Tumor cells were maintained in RPMI media (GIBCO BRL, K Island, NY) supplemented with 10% fetal bovine serum and 2% penicillin, streptomycin, and 50-glutamine. The adherent B16 cells were removed from tissue civilization flasks by incubating them for 10 min with trypsin-EDTA (GIBCO BRL). Cells were harvested by centrifugation, washed once, and adapted to concentrations for specific experiments. To appraise the evolution of pulmonary metastases, 0.2 ml of B16 melanoma cells (i × 10half dozen cells/ml) were injected into a tail vein. Mice (n = 8–11 per group) were injected 30 min later the terminal 24-hour interval of exercise or residuum. After tumor assistants, mice were returned to their cages and remained in the animal facility. Mice continued on the oat β-glucan treatment during this period, but exercise stopped. Mice were killed 14 days after tumor administration. The lungs were removed at death and stained with Bouin'due south fixative. The number of tumor foci (pulmonary metastases) on the surface of the lungs was counted nether a dissecting microscope by an investigator blinded to the treatments.
In vitro peritoneal macrophage cytotoxicity.
After the final day of exercise or remainder, mice (n = 8 per grouping) were euthanized in a bell jar by halothane overdose. Death occurred within ane min. Peritoneal macrophages were obtained by lavage of the peritoneal cavity with 5 ml of media. The civilisation medium used was RPMI-1640 (GIBCO BRL). Peritoneal lavage cells were washed once in RPMI-1640, and whatsoever remaining red blood cells were lysed with tris(hydroxymethyl)aminomethane-ammonium chloride, pH seven.ii. Peritoneal cells were seeded in 96-well apartment-bottom microtiter plates at several concentrations (4 × 10v, two × x5, one × 10five, and v × 104) to elicit effector target concentrations of lxxx:1, twoscore:1, 20:1, and 10:1. Cells were maintained at 37°C and five% CO2 for 3 h to allow macrophages to adhere to the plate. Nonadherent cells were and then removed by gentle washing. B16 cells (5 × 104) were then added to each well and to several command wells without macrophages. The plates were so incubated for 48 h at 37°C and 5% COtwo. At this time, 0.25 μCi of [threeH]thymidine (TdR) (ICN Biomedicals, specific activity 6.seven Ci/mmol) were added to each well. The plates were incubated for 24 h, and the amount of TdR incorporated was determined by scintillation counting.
TdR uptakes in the wells containing just B16 tumors were used as control values. This uptake measured "uninhibited" growth of the tumor cells; therefore, whatever TdR uptake less than this represents cytostasis or cytolysis of the tumor cells by the macrophages. Percent cytotoxicity was calculated as follows: (TdR uptake in exam well/TdR uptake in command well) × 100. Macrophages do not proliferate and incorporate TdR in this analysis. Therefore, tumor cell growth is quantified by measuring TdR uptake. This assay measures both macrophage-mediated tumor growth inhibition (cytostasis) and cytolysis, considering lysed cells do non contain TdR.
Statistical analysis.
Statistical analyses were performed past using a commercially bachelor statistical package from SigmaStat (version two.03, SigmaStat, SPSS, Chicago, IL). Fluid consumption, lung tumor foci, and macrophage cytotoxicities were analyzed by two-fashion ANOVA (exercise × oat β-glucan) with Student Newman-Keuls post hoc analysis (P < 0.05).
RESULTS
Food consumption.
There were no differences in the average corporeality of fluid consumed by each group. Over the course of the fluid treatment, Con-HtwoO mice consumed an average of iv.5 ± 0.21 ml/day, which was similar to Ex-HtwoO (4.8 ± 0.60 ml/solar day), Ex-OβG (5.1 ± 0.42 ml/day), and Con-OβG (4.8 ± 0.fifteen ml/day). Therefore, 24-h fluid consumption was not affected by the dissolved oat β-glucan or moderate do. This is also reflected by a lack of departure in torso weight across the groups. Weight gain over the class of the acclimation stage and six-day practice period was 0.95 ± 0.56 one thousand in Ex-H2O, 0.82 ± 0.38 g in Ex-OβG, 0.eight ± 0.44 chiliad in Con-HtwoO, and 0.64 ± 0.74 g in Con-OβG. Food intake was non measured in this study, just it is unlikely that pregnant differences occurred given the like body weights across groups.
Pulmonary metastases.
The number of lung tumor foci was compared across the four groups to determine whether exercise and oat β-glucan, or their combination, altered the metatastic spread of injected B16 melanoma cells. Figure ane illustrates tumor counts fourteen days subsequently intravenous tumor administration of B16 melanoma cells. There were significant primary effects for both exercise (P < 0.05) and oat β-glucan (P < 0.05); however, there were no interactions. Tumor counts were as follows: 95 ± 12.0 in Ex-H2O, 102 ± 12 in Ex-OβG, 189 ± 34 in Con-H2O, and 92 ± 14 in Con-OβG. These were statistically different (P < 0.05, Fig. 1), with Ex-H2O and Ex-OβG mice having fewer tumors than Con-H2O mice (P < 0.001). Similarly, Con-OβG mice had fewer tumors than Con-HiiO (P < 0.001). However, Ex-OβG was not different from Ex-HtwoO or Con-OβG, indicating that at that place were no additive effects of moderate exercise and oat β-glucan.
Fig. 1.Effects of brusk-term moderate exercise (Ex) and oat β-glucan (OβG) on lung tumor foci after injection of B16 melanoma cells (ii × 105). Values are ways ± SE; n = 8–xi. *Significant difference for Ex-H2O, Ex-OβG, and control (Con)-OβG vs. Con-HiiO: P < 0.001.
Peritoneal macrophage cytotoxicity.
Peritoneal macrophage cytotoxicity, which reflects the ability of the macrophage to destroy tumor cells and/or limit tumor growth, was too measured against B16 melanoma cells. Peritoneal macrophage cytotoxicity was measured in macrophages taken within 30 min after the last exercise bout. Macrophage cytotoxicity was measured at four effector-to-target ratios, equally seen in Fig. 2. There were significant master effects for both exercise (P < 0.05) and oat β-glucan (P < 0.05); however, there were no interactions. Peritoneal macrophages from Ex-H2O mice had significantly enhanced cytotoxicity compared with Con-H2O mice at two effector-to-target ratios (forty:ane and xx:1; P < 0.05). Both OβG groups (Ex-OβG and Con-OβG at 40:1, 20:1, and 10:1; P < 0.05) were too significantly increased over Con-H2O, but there were no additive effects of exercise and oat β-glucan.
Fig. 2.Peritoneal macrophage cytotoxicity after 10 days of OβG feedings and 6 days of short-term moderate exercise at 4 effector-to-target ratios. Values are means ± SE; due north = 8. *Significant differences: Ex-HtwoO vs. Con-H2O: 40:1 (P < 0.01) and xx:1 (P < 0.05); Ex-OβG vs. Con-HiiO: xl:ane (P < 0.001), 20:i (P < 0.01), and 10:i (P < 0.01); Con-OβG vs. Con-H2O: xl:ane (P < 0.001), 20:1 (P < 0.05), and 10:1 (P < 0.01).
Word
Both moderate exercise and a good for you diet have been the focus of behavioral interventions designed to reduce the risk of cancer also equally other chronic diseases. Both exercise and oat β-glucan (as part of a Heart Salubrious Nutrition) take well-documented benefits in the prevention of cardiovascular disease and diabetes, but much less is known virtually their specific part in cancer prevention. Much of the evidence is based on epidemiological and observational studies with trivial data from controlled experimental studies, and the mechanisms are largely unknown. This study used an established experimental tumor metastases model in mice to decide the straight effects of short-term moderate-exercise training and consumption of soluble oat β-glucan on perhaps the well-nigh serious aspect of cancer progression. The information suggest that both moderate exercise and oat β-glucan provide some resistance to the spread of B16 melanoma cells to the lungs, which is a principal site of metastasis for many tumors. These treatments also increased macrophage anti-tumor role, which, along with numerous studies showing the importance of this component of the immune organisation in cancer defence force, suggests that the benefits of practise and oat β-glucan may event, in role, via increased macrophage office. The benefits, still, were not additive, suggesting that different overall mechanisms contribute to each effect or perhaps more than likely that a maximal response (ceiling effect) was accomplished by both treatments independently nether the conditions of this experiment.
Animal models of tumor development typically demonstrate that exercise inhibits tumorigenesis (3, half-dozen, 15, 24, 30, 31, 33), although at that place are a few exceptions to this general finding (32, 39). A recent study in our laboratory using a similar experimental metastasis model establish a decrease in the number of lung tumors after assistants of B16 melanoma cells in response to a single bout of prolonged practise to fatigue on a treadmill (6). Still, this same study establish no benefit of a unmarried 30-min session of running. The beneficial effect of 6 days of moderate exercise in this study, along with related work past others (18, 22, 30, 31), suggests that intensity and duration as well equally the timing of exercise onset are important variables in the protective event of practise.
A like focus is being directed to the office of diet every bit a means for reducing the risk of cancer (xiii). Both epidemiological and fauna experiments provide insight into the links betwixt various dietary components in cancer prevention and treatment (thirteen). Vegetables and fruits, dietary fiber, micronutrients, and phytochemicals have all been investigated for their anti-tumor activity (thirteen). Of item contempo involvement has been the potential role of the dietary fiber β-glucan, which is an important component of a Heart Healthy Diet (sixteen). β-Glucan is a polysaccharide that can be derived from the cell wall of yeast, fungi, and oats. About of the anti-tumor data come from experiments involving the insoluble β-glucan from yeast and fungus in a diverseness of murine tumor models, including B16 melanoma, adenocarcinoma, mammary carcinoma, lymphocytic leukemia, and Lewis lung carcinoma, presumably acting via activation of both nonspecific and specific immune mechanisms (viii, 27). However, this is the first experiment on the effects of consuming soluble oat β-glucan in any cancer model. The protective effects shown here are in line with other similar studies. For example, Di Luzio et al. (eight) reported that intravenous administration of β-glucan derived from yeast after subcutaneous injection of B16 melanoma cells resulted in a decrease in tumor growth and prolonged survival fourth dimension in mice. Suzuki et. al. (27) also reported an inhibitory effect of orally administered β-glucan derived from fungus on pulmonary metastases of Lewis lung carcinoma cells.
In the second series of experiments, nosotros sought to explore potential mechanisms that may explain the benefits of moderate practice and oat β-glucan on the reduction in tumor metastases resulting from the intravenous injection of B16 melanoma cells. Various host effector cells, including NK cells, and macrophages tin kill a wide spectrum of tumor cells and do non crave prior antigen priming to exert their cytotoxic furnishings. Both macrophages and NK cells are idea to play a role in limiting metastases by altering the early on steps of implantation and growth of secondary foci (1, 11). Exercise-induced increases in the anti-tumor function of these cells are well documented (6, 17, 18, 20, 21, 23, 40, 41). For example, in addition to the increase in macrophage anti-tumor office shown here with 6 days of moderate-do preparation, nosotros take also shown increases for up to ix h after a single prolonged run to fatigue (half dozen) and after 3 days of both moderate (30 min) and fatiguing exercise (forty). Although the reduction in pulmonary metastasis cannot be directly related to the alveolar macrophage cytotoxicity, it is possible that rather long-lasting effects of macrophage activation might exist responsible through a direct inhibition of infiltration and growth of the tumor cells equally well as the release of antitumor and immunostimulatory cytokines (half dozen, 38). Although NK cytotoxicity was not measured in this written report, we have shown that this same exercise protocol can increase NK cytotoxicity to YAC lymphoma cells in mice (7).
The benefits of oat assistants in this paper may too be attributed to activation of macrophages and NK cells (v, 26, 28, 34). These cells contain receptor sites specific for β-glucan on their cell surface membrane, such as complement receptor-3 and dectin-1 that, when combined with β-glucan, can upregulate macrophage and NK anti-tumor office (2, v, 34). However, the mechanisms of stimulation are dependent on the road of assistants (e.1000., intravenous, intraperitoneal, or oral) and specific characteristics of the β-glucan, including the source (eastward.yard., oats, yeast, fungi, etc.), solubility, molecular mass, degree of branching, and conformation (ratio of 1→3 to 1→4 and i→6 glucopyranolsyl linkages) (nine, 36). Orally administered β-glucan enhances both peritoneal and alveolar macrophage activity through an increase in acid phosphatase activity, phagocytosis, H2O2 product, and IL-ane production (25, 28). This could result from ingestion of β-glucan by pinocytic M cells located in Peyer's patches of the minor intestine, causing a release of cytokines that are responsible for initiating an all-encompassing cascade of systemic immune responses (fourteen, 25, 26, 28). Information technology is also possible for soluble oat β-glucan to be absorbed into the lymphatic and cardiovascular systems and thereby interact directly with circulating immune cells (16, 42). Therefore, it seems reasonable that the soluble oat β-glucan used in this experiment increased macrophage anti-tumor function, and maybe other immune components, via direct activation via β-glucan-specific receptors on their jail cell surface (within the gut-associated lymphoreticular system and peradventure central circulation) and later on through indirect activation via a pour of systemic immune responses involving cytokines.
The results of this study propose that short-term moderate-exercise training and consumption of the soluble cobweb oat β-glucan tin can decrease the metatastic spread of injected B16 melanoma cells to the lungs in this experimental tumor metastasis model. The effects were associated with an increase in macrophage anti-tumor function against the same tumor cells in culture, which suggests a possible role for macrophages every bit mediators of these benefits. However, more than enquiry is required to determine the precise mechanisms of these effects and whether they can contribute to decreased risk of tumor metastasis in other more clinically relevant situations.
FOOTNOTES
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