It remains unclear how obesity worsens treatment outcomes in patients with pancreatic ductal adenocarcinoma (PDAC). In normal pancreas, obesity promotes inflammation and fibrosis. We found in mouse models of PDAC that obesity also promotes desmoplasia associated with accelerated tumor growth and impaired delivery/efficacy of chemotherapeutics through reduced perfusion. Genetic and pharmacological inhibition of angiotensin-II type-1 receptor (AT1) reverses obesity-augmented desmoplasia and tumor growth and improves response to chemotherapy. Augmented activation of pancreatic stellate cells (PSCs) in obesity is induced by tumor-associated neutrophils (TANs) recruited by adipocyte-secreted IL-1β. PSCs further secrete IL-1β, and inactivation of PSCs reduces IL-1β expression and TAN recruitment. Furthermore, depletion of TANs, IL-1β inhibition, or inactivation of PSCs prevents obesity-accelerated tumor growth. In pancreatic cancer patients, we confirmed that obesity is associated with increased desmoplasia and reduced response to chemotherapy. We conclude that crosstalk between adipocytes, TANs, and PSCs exacerbates desmoplasia and promotes tumor progression in obesity.

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Cystic fibrosis (CF) is the most common lethal recessive genetic disease of the Caucasian population. Although reports of cancer frequency in CF have emphasized an elevated observed-to-expected ratio of 6.5 for digestive tract cancers, these studies also show a significantly decreased observed-to-expected ratio for other malignancies including breast cancer. The cystic fibrosis transmembrane conductance regulator (CFTR) functions as an ATP channel. We found that heterozygous and homozygous CFTR knockout mice had elevated blood ATP concentrations. Elevated extracellular ATP is known to inhibit tumor growth in vivo and in vitro. Using double mutant mice created by F2 generation crosses of CFTR knockout and nude mice, we observed reduced breast tumor implantability in CFTR homozygous nude animals. Decreased tumor growth rate was observed in both CFTR heterozygous and homozygous nude animals. Extracellular ATP reduced human breast tumor cell growth rate in vitro, and a breast tumor transfected with human CFTR that had high extracellular ATP concentrations in vitro correspondingly had a slower growth rate in vivo. The results suggest that both CFTR heterozygosity and homozygosity suppress breast cancer growth and that elevated extracellular ATP can account for this phenomenon.

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Endurance-trained sled dogs provide a unique translational model to characterize changes in hematologic and serum biochemical analytes due to the aging process. The primary objective of this study was to determine the effect of age and sex on specific hematologic and serum biochemical parameters in the endurance trained sled dog. Longitudinal and cross-sectional data were analyzed from 9,746 blood and serum samples from 4,804 dogs collected over 7 years as part of the Iditarod Trail Sled Dog Race pre-race examination program. Mixed models analysis was used for statistical analysis and P < 0.01 was considered significant. Dogs ranged from 1-12 years of age and 39% were female. Serum total calcium and phosphorus concentrations and white blood cell count decreased nonlinearly to asymptotic values by 6.6, 3.1, and 6.9 years of age, respectively, equivalent to estimated physiologic ages in human years of 44, 27, and 46 years. Serum glucose concentrations reached their lowest value at 7.8 years of age, equivalent to an estimated human physiologic age of 50 years, after which time the concentration increased. Serum globulin concentrations increased with age, but nonlinearly for females and linearly for males. Most sex-related differences were <5%; however, females had lower serum urea nitrogen (14.7%) and creatinine (7.3%) concentrations, lower serum alanine aminotransferase activity (16.6%), and higher serum total bilirubin concentration (12.8%) and platelet count (6.0%). The endurance-trained sled dog provides an excellent model to separate the physiologic effects of age from those of a sedentary lifestyle on hematologic and serum biochemical analytes.

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The effect of cis-diamminedichloroplatinum(II) (cis-DDP) on the murine fibrosarcoma cells was investigated in vitro and in vivo. For in vitro experiments tumour cell suspensions containing a given amount of cis-DDP were treated in water bath maintained at a desired temperature, and cell survival was determined by the lung colony assay. The D0 or the time to reduce survival from 1.0 to 0.37 on the exponential portion of the survival curve was determined and 1/D0 was plotted as a function of 1/T, where T stands for the absolute temperature. The slope of this Arrhenius plot indicated that the activation energy for chemical reaction of cis-DDP was 44 kcal/M between the temperature range from 37 to 41 degrees C. For in vivo experiments tumours were transplanted into the foot and treated by immersing the animal foot into a water bath when each tumour reached an average diameter of 4 mm (35 mm3). The drug was injected i.p. immediately before hyperthermia. The tumour growth (TG) time or the time required for a tumour to reach 1000 mm3 from the treatment day was determined, and the median TG time was obtained by logit analysis. Dose-response curves between the TG time and drug dose indicated that the cytotoxic effect of cis-DDP was enhanced at elevated temperatures. This enhancement increased with increasing temperature from room temperature to 43.5 degrees C. Because of short plasma half-time of cis-DDP, continuous infusion and pulse injections were attempted.(ABSTRACT TRUNCATED AT 250 WORDS)