Establishment of a complex inflammatory and protumorigenic microenvironment in mouse pancreas through cyclooxygenase-2 overexpression

Chronic inflammation is an established risk factor in the pathogenesis of many cancers. Pancreatic ductal adenocarcinoma, a malignancy with a particularly dismal prognosis, is no exception. Cyclooxygenase-2, a key enzyme induced by tissue injury, has a critical role in the generation of bioactive lipids known as prostaglandins. COX-2 overexpression is a frequent finding in pancreatic cancer, chronic pancreatitis and pancreatic intraepithelial neoplasias. To explore mechanisms through which chronic inflammation establishes and maintains a protumorigenic environment, we designed a mouse model overexpressing COX-2 in pancreatic parenchyma (BK5.COX-2 mice). We discovered that constitutive expression of COX-2 has a number of important sequelae, including upregulation of additional eicosanoid-generating enzymes and proinflammatory cytokines. Many of these molecular alterations precede the onset of significant histopathological changes. Increased levels of prostaglandins E2, D2, and F2α, 5-, 12-, and 15-hydroxyeiosatetraenoic acid (HETEs) were documented in tumors and pancreata of younger transgenic mice. Using a TaqMan™ Mouse Immune Panel, we detected elevated mRNAs for a number of proinflammatory cytokines (e.g., TNFα, IL-1β, IL-6). ^ Histological examination revealed early changes in the pancreas with similarities to human chronic pancreatitis, including loss of acinar cells, appearance of metaplastic ducts, and increased deposition of stroma. As the lesions progress, features typical of dysplastic and neoplastic cells emerged within the metaplastic ductal complexes, including cellular and nuclear atypia, crowding of cells, and loss of normal tissue architecture. The amount of fibroinflammatory stroma increased considerably; numerous small vessels were evident. A number of immunocytes from both the myeloid and lymphoid lineages were identified in transgenic pancreata. Neutrophils were the earliest to infiltrate, followed shortly by macrophages and mast cells. B and T cells generally began to appear by 8–12 weeks, and organized aggregates of lymphoid cells were often found in advanced lesions. ^ We tested the efficacy of several chemopreventive agents in this model, including celecoxib, a COX-2 selective inhibitor, pentoxifylline, a cytokine inhibitor, curcumin, a polyphenol with antioxidant and anti-inflammatory properties, and GW2974, a dual EGFR/ErbB2 inhibitor. Effects on lesion development were modest in the GW2974 and pentoxifylline treated groups, but significant prevention effects were observed with curcumin and celecoxib. ^

ASSOCIATIONS AND INTERRELATIONSHIPS OF SOCIOECONOMIC STATUS, BEHAVIORAL FACTORS AND BIOLOGICAL FACTORS WITH BIRTH WEIGHT

Although the influences of socioeconomic, behavioral and biological factors on birth weight have been extensively studied, most studies have been limited to clinical populations. This study examines such relationships in a national probability sample, the National Health and Nutrition Examination Survey of 1971-1974. The study sample consisted of 2161 white children and 812 black children, aged 1 to 5 years. Analyses were performed on a subsample consisting of 753 white and 138 black children whose mothers were also selected into the survey. Detailed analyses examined interrelationships among socio-economic, behavioral and biological factors by means of multiple regression and partial correlation procedures in the white population. These analyses were not carried out among blacks because of an observed clustering bias introduced in the black subsample that hampered generalization to the US population.^ The results among the whites indicated that the biological factors of maternal height, maternal weight, maternal size (weight/height('2)), maternal age and sex of child were independently related to birth weight and were also interrelated with socioeconomic factors such as family income, education of the mother and education of the head of the household. The joint effect was significantly associated with birth weight.^ Mothers' dietary practices represented the behavioral factors. Selected nutrients from the mothers' 24-hour dietary recall were used to develop indices of dietary quality. Dietary quality was significantly interrelated with socioeconomic status, biological factors and birth weight.^ The findings of this study suggest that smaller, younger mothers of lower socioeconomic status and female children were significantly associated with lower birth weight. The findings also suggest that dietary quality is a mediating factor among socioeconomic status and biological factors in that mothers with more financial and educational resources have better dietary practices. Such mothers may also practice other health behaviors that would prevent having a low birthweight baby. This dissertation contributes primarily to the further conceptualization and empirical testing of the interrelationships among socioeconomic, behavioral and biological factors with respect to birth weight. ^