leptin and Carcinoma--Lewis-Lung

A high energy intake contributes to obesity, a risk factor for cancer. We previously reported that an excessive intake of dietary fat enhances malignant spread in mice. This study tested the hypothesis that consumption of a diet with an excessive amount of sucrose enhances metastasis. In a spontaneous metastasis model of Lewis lung carcinoma (LLC), male C57BL/6 mice were maintained on an AIN93G, a high-fat, or a high-sucrose diet for the duration of the study. Pulmonary metastases from a primary tumor, established by a subcutaneous injection of LLC cells, were quantified. There were no differences in energy intake among the 3 groups. The percent body fat mass of the high-sucrose group, while higher than that of the AIN93G group, was lower than that of the high-fat group. The number and size of lung metastases were significantly higher in the high-fat group than in the AIN93G group; these measurements in the high-sucrose group remained similar to those in the AIN93G group. Hepatic concentrations of triacylglycerols and plasma concentrations of insulin, proinflammatory cytokines (leptin, plasminogen activator inhibitor-1, and monocyte chemotactic protein-1) and angiogenic factors (vascular endothelial growth factor and tissue inhibitor of metalloproteinase-1) in the high-sucrose group were significantly lower than those in the high-fat group. In conclusion, the high-sucrose diet does not enhance spontaneous metastasis of LLC. This null effect may be due to the inadequate production of tumorigenic proinflammatory cytokines and angiogenic factors by the high-sucrose diet compared to the high-fat diet.

Topics: Adipose Tissue; Angiogenesis Inducing Agents; Animals; Carcinoma, Lewis Lung; Chemokine CCL2; Cytokines; Diet; Diet, High-Fat; Dietary Fats; Dietary Sucrose; Energy Intake; Feeding Behavior; Insulin; Leptin; Liver; Lung Neoplasms; Male; Mice, Inbred C57BL; Plasminogen Activator Inhibitor 1; Tissue Inhibitor of Metalloproteinase-1; Triglycerides; Vascular Endothelial Growth Factor A

We investigated the effect of dietary supplementation with selenium on spontaneous metastasis of Lewis lung carcinoma in mice fed a high-fat diet. Mice were fed a low-fat diet or that diet modified with 45% of calories from corn oil and supplemented with 0 or 2.5mg selenium/4029 kcal as methylseleninic acid. After 6 weeks, mice were each injected 2.5 × 10(5) Lewis lung carcinoma cells subcutaneously. The resulting primary tumor was removed surgically 10 days later; the experiment was terminated after an additional 10 days. High-fat feeding increased pulmonary metastases by 17% compared to the low-fat diet (P < 0.01). Selenium supplementation reduced the metastases by 11% compared to nonsupplemented controls (P < 0.05); the reduction was less for animals fed the high-fat diet (5%) than for those fed the low-fat diet (18%). Supplemental Se lowered plasma concentrations of proteases (urokinase plasminogen activator, P < 0.01; matrix metalloproteinase-9, P < 0.05) and angiogenic factors (vascular endothelial growth factor, P < 0.01; tissue inhibitor of metalloproteinase-1, P < 0.01) compared to nonsupplemented controls. High-fat feeding increased plasma concentrations of adipokines plasminogen activator inhibitor-1, monocyte chemotactic protein-1, tumor necrosis factor-α, and leptin regardless of the level of dietary selenium; supplemental selenium lowered plasma concentrations of plasminogen activator inhibitor-1 (P ≤ 0.05) and monocyte chemotactic protein-1 (P ≤ 0.05) in low-fat fed mice but not in high-fat fed mice. These results indicate that consumption of a high-fat diet abrogated the antimetastatic effects of selenium by increasing the expression of adipose-derived inflammatory cytokines.

Topics: Animals; Anticarcinogenic Agents; Body Composition; Carcinoma, Lewis Lung; Diet, High-Fat; Dietary Supplements; Leptin; Male; Matrix Metalloproteinase 9; Mice; Mice, Inbred C57BL; Organoselenium Compounds; Serpin E2; Tissue Inhibitor of Metalloproteinase-1; Vascular Endothelial Growth Factor A

Epidemiological studies indicate that the risk factors for the development of various cancers are closely associated with metabolic symptoms such as obesity, hyperlipidemia, and insulin resistance caused by the excess consumption of high-calorie diets. However, the mechanisms of tumor growth and metastasis caused by feeding a high-calorie diet have not been clarified yet in tumor-bearing mice. In this study, we examined the effects of a high-fat (HF), a high-sucrose (HS), a high-cholesterol (HC) or a low-fat/low-sucrose (LF/LS) diet on tumor growth and metastasis in tumor-bearing mice. Angiogenic factors such as plasma leptin and monocyte chemoattractant protein-1 (MCP-1) were increased after the implantation of tumors, whereas conversely, an antiangiogenic factor, adiponectin, was reduced after the implantation of tumors in mice fed the HF, the HS, or the HC diet compared to LF/LS diet. Furthermore, we found that vascular endothelial growth factor, hypoxia inducible factor-1alpha and MCP-1 expression levels in tumors of mice fed the HF, the HS, or the HC diet were increased compared to those of mice fed the LF/LS diet. These findings suggest that the acceleration of tumor growth and metastasis by feeding the 3 diets may be due to the increase of angiogenic factors and the reduction of antiangiogenic factors.

Topics: Adiponectin; Animals; Body Weight; Carcinoma, Lewis Lung; Chemokine CCL2; Cholesterol, Dietary; Diet; Dietary Fats; Dietary Sucrose; Disease Progression; Dose-Response Relationship, Drug; Glucose Intolerance; Glucose Tolerance Test; Hyperinsulinism; Hyperlipidemias; Immunohistochemistry; Insulin Resistance; Leptin; Male; Mice; Mice, Inbred C57BL; Neoplasm Metastasis; Neoplasm Transplantation; Neoplasms, Experimental; Obesity; Random Allocation

Although obesity is known as a risk factor for several human cancers, the association of obesity with cancer recurrence and metastasis remains to be characterized. Here, B16-BL6 melanoma and Lewis lung carcinoma cells were intravenously injected into diabetic (db/db) and obese (ob/ob) mice. The number of experimental lung colonies was markedly promoted in these mice when compared with C57BL/6 mice. In contrast, tumor growth at the implanted site was comparable when cells were inoculated orthotopically. The use of B16-BL6 cells stably transfected with the luciferase gene revealed that the increased metastasis reflected a difference mainly within 6 hr after the intravenous inoculation of tumor cells. Administration of recombinant leptin in ob/ob mice abolished the increase in metastasis early on as well as the decrease in the splenic NK cell number. In addition, depletion of NK cells by an anti-asialo-GM1 antibody abrogated the enhanced metastasis in db/db mice. These results demonstrate that metastasis is markedly promoted in diabetic and obese mice mainly because of decreased NK cell function during the early phase of metastasis.

Topics: Animals; Carcinoma, Lewis Lung; Cell Line, Tumor; Hypoglycemic Agents; Killer Cells, Natural; Leptin; Luciferases; Lung; Lung Neoplasms; Lymphocyte Count; Melanoma, Experimental; Mice; Mice, Obese; Pioglitazone; Recombinant Proteins; Thiazolidinediones; Time Factors; Transfection

We have examined the role of leptin in tumor-induced anorexia in 2 different tumor models. In rats bearing the Yoshida AH-130 ascites hepatoma, the reduction in food intake becomes important from day 6 after tumor inoculation. Interestingly, at day 4, when the animals do not show any anorectic behavior, circulating leptin levels were already reduced. Indeed, in all the tumor-bearing groups studied the levels of leptin were lower than in control animals. Moreover, the changes in the circulating levels paralleled changes in adipose tissue leptin mRNA expression, even at early stages following tumor inoculation when neither food intake nor fat stores were modified by the presence of a tumor. Interestingly, 7-day pair-fed controls showed changes similar to those present in tumor-bearing rats. These results agree with previous observations relating fasting to decreased leptin expression. Similar results were observed in another tumor model, the mouse Lewis lung carcinoma; i.e., at day 8 after tumor inoculation (when the animals did not show anorexia) both the circulating levels and the adipose leptin mRNA expression were also reduced. Our results suggest that experimental cancer-induced anorexia is not related to leptin changes.

Topics: Adipose Tissue; Animals; Anorexia; Body Weight; Cachexia; Carcinoma, Lewis Lung; Female; Gene Expression; Insulin; Leptin; Liver Neoplasms, Experimental; Male; Mice; Mice, Inbred C57BL; Organ Size; Proteins; Rats; Rats, Wistar; RNA, Messenger; Time Factors; Tumor Cells, Cultured