Obesity increases the risk of many cancers in both males and females. This study describes a link between obesity, obesity-associated metabolic alterations, and the risk of developing cancer in male and female mice. The goal of this study was to evaluate the relationship between gender and obesity and to determine the role of estrogen status in obese females and its effect on tumor growth. We examined the susceptibility of C57BL/6 mice to diet-induced obesity, insulin resistance/glucose intolerance, and tumors. Mice were injected sc with one of two tumorigenic cell lines, Lewis lung carcinoma, or mouse colon 38-adenocarcinoma. Results show that tumor growth rate was increased in obese mice vs. control mice irrespective of the tumor cell type. To investigate the effect of estrogen status on tumor development in obese females, we compared metabolic parameters and tumor growth in ovariectomized (ovx) and intact obese female mice. Obese ovx female mice developed insulin resistance and glucose intolerance similar to that observed in obese males. Our results demonstrate that body adiposity increased in ovx females irrespective of the diet administered and that tumor growth correlated positively with body adiposity. Overall, these data point to more rapid tumor growth in obese mice and suggest that endogenous sex steroids, together with diet, affect adiposity, insulin sensitivity, and tumor growth in female mice.

Mesothelial cells, the progenitor cell of the asbestos-induced tumor mesothelioma, are particularly sensitive to the toxic effects of asbestos, although the molecular mechanisms by which asbestos induces injury in mesothelial cells are not known. We asked whether asbestos induced apoptosis in mesothelial cells and whether reactive oxygen species were important. Pleural mesothelial cells (rabbit or human) were exposed to asbestos (crocidolite, amosite, or chrysotile) or control particles at moderate doses (1-10 g/cm 2 ) over 24 h and evaluated for oligonucleosomal DNA fragmentation, loss of membrane phospholipid asymmetry, and nuclear condensation.

The establishment of an effective pulmonary alveolar-capillary interface occurs during mid to late gestation. This requires an expansion of endothelial, epithelial, and air space compartments with relative thinning of the interstitial compartment. Traditionally, these changes have been attributed to differences in the rate of cell growth in the respective compartments. We hypothesized that apoptosis also participates in this lung remodeling. Using light and electron microscopy, the nucleosomal ladder pattern of DNA digestion, and the detection of apoptotic cells in situ by the TUNEL method (Gavrieli, et al. J. Cell Biol. 1992;119:493-501), we demonstrated the occurrence of apoptosis in fetal lungs in vivo and in explant culture. In the rat fetal lung (RFL) in vivo we detected apoptosis from 16 through 22 d gestation. There was variation in the amount of DNA digestion between fetal lungs, but no correlation with gestational age. The findings in human fetal lungs (HFL) from 15 through 24 wk gestation were similar to those of the RFL; the apoptotic indices for both were about 2 apoptotic cells per thousand, suggesting that a significant percentage of cells are eliminated by this mechanism. In the HFL explant culture system, a rapid and massive wave of apoptosis occurred. In all samples of RFL and HFL examined, apoptosis was restricted to interstitial cells. This work has demonstrated for the first time that apoptosis is a feature of normal fetal lung development and that the process is accelerated in lung explant culture.

Insulin is known to regulate adipocyte differentiation and lipid accumulation, but the specific mechanism by which precursor cells differentiate into adipocytes is not clearly understood. This study evaluated the role of the IGF-I receptor in the process of adipocyte differentiation in bone marrow-derived human mesenchymal stem cells (HMSCs). The results demonstrated that nanomolar concentrations of IGF-I adequately replaced micromolar concentrations of insulin in supporting differentiation and lipid accumulation in HMSCs. The addition of IGF-I specifically increased cell proliferation and lipid accumulation in HMSCs, but a mixture of differentiation factors including dexamethasone, indomethacin, and 3-isobutyl-1-methylxanthine did not. These effects were blocked by the alphaIR-3 antibody, which inhibits IGF-I receptor activity. We also describe the pattern of differentiation with regard to cell growth, lipid accumulation, and morphologic changes and define the changes in these parameters that are influenced by IGF-I. Finally, peroxisome proliferator activating receptor-gamma immunoreactivity was also increased in response to IGF-I, and this effect was blocked in cells treated with the alphaIR-3 antibody. Taken together, these findings suggest that IGF-I plays a critical role in adipocyte differentiation and lipid accumulation.