Obesity has been implicated as a significant risk factor for development of pancreatic cancer. In the setting of obesity, a systemic chronic inflammatory response is characterized by alterations in the production and secretion of a wide variety of growth factors. Leptin is a hormone whose level increases drastically in the serum of obese patients. High fat diet induced obesity in mice leads to an overall increased body weight, pancreatic weight, serum leptin, and pancreatic tissue leptin levels. Here we report the contribution of obesity and leptin to pancreatic cancer growth utilizing an in vivo orthotopic murine pancreatic cancer model, which resulted in increased tumor proliferation with concomitant increased tumor burden in the diet induced obese mice compared to lean mice. Human and murine pancreatic cancer cell lines were found to express the short as well as the long form of the leptin receptor and functionally responded to leptin induced activation through an increased phosphorylation of AKT473. In vitro, leptin stimulation increased cellular migration which was blocked by addition of a PI3K inhibitor. In vivo, depletion of the leptin receptor through shRNA knockdown partially abrogated increased orthotopic tumor growth in obese mice. These findings suggest that leptin contributes to pancreatic tumor growth through activation of the PI3K/AKT pathway, which promotes pancreatic tumor cell migration.
Respiratory health is negatively impacted by exposure to ozone or to estrogens. Increasingly, individuals have simultaneous environmental exposure to both compounds. Characterizing the cellular responses stimulated by the combination of ozone and estrogens, therefore, is crucial to our complete understanding of the compounds' environmental health impacts. Our work introduces an alveolar cell culture model with defined media that provides evidence of ozone damage and determines sex hormones alter the cells' susceptibility to oxidative damage. Specifically, we investigated the individual and combined effects of environmentally relevant levels of ozone and 17β-estradiol on non-cancerous rat, type-II alveolar cells by examining biomarkers of cellular health and redox balance. The data reveal a complex role for 17β-estradiol in cellular recovery from 1 hr exposure to high ozone levels. At 0.5 hr post-ozone necrosis and inflammation markers show 17β-estradiol augments the detrimental effects of 350 ppb ozone, but after 24 hr of recovery, steroid treatment alters glutathione redox ratio and allows cellular proliferation.
Introduction: Non-alcoholic fatty liver disease (NAFLD), encompassing steatosis and progression to non-alcoholic steatohepatitis (NASH) are liver disorders of increasing clinical significance. Studies in our lab have shown that hepatic steatosis establishes a permissive microenvironment for metastatic tumor seeding and tumor progression in the liver. To understand the molecular factors influencing the initial survival and growth of tumors in the steatotic liver microenvironment, we adopted a candidate approach and performed microarray analysis to compare RNA from normal vs steatotic liver samples in mice. MMP12 (macrophage metalloelastase) was identified as an important proteinase associated with the microenvironments of hepatic steatosis and steatohepatitis. MMP12 can influence immune-mediated injury response by processing latent TNF alpha and regulating neutrophil infiltration, cytokine release as well as macrophage recruitment. We hypothesize that increased MMP12 levels in the steatotic liver contribute to a more permissive microenvironment for primary tumor growth and establishment of metastases by alteration of inflammatory cell populations. Results: Realtime qPCR anlaysis verified a significant increase in MMP12 expression in murine steatotic livers compared to normal control livers. In a splenic injection model, hepatic metastases in steatotic MMP12 deficient livers were significantly reduced as compared to hepatic metastases in steatotic wildtype livers. Flow cytometric analysis demonstrated an alteration in the level of Gr-1 positive inflammatory cell populations in the steatotic livers of both wildtype and MMP12 deficient livers when compared to normal nonsteatotic livers. Although no significant changes were observed in the percentage of F4/80 positive macrophage population, using immunohistochemistry we did observe accumulation of F4/80 positive macrophages into crown-like structures within steatotic MMP12 deficient livers. To determine whether the inflammatory cells in the liver microenvironment were contributing to survival of tumor cells, we performed an in vitro co-culture assay of syngeneic MC38 tumor cells with either CD90.2 cells (pan T cells) or CD11b cells (macrophages/monocytes). Fewer numbers MC38 cells were present 3 days after co-culture with CD11b cells from MMP12 deficient mice, which was corroborated with decreased luciferase measurements from MC38-luc tagged cells. Conclusions: These results suggest a role for MMP12 in mediating the inflammatory response accompanying tumor establishment in the steatotic liver microenvironment. The molecular mechanisms by which MMP12 influences a decrease in metastatic tumor burden in the setting of fatty liver disease are currently being investigated. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 389. doi:1538-7445.AM2012-389
Background: Pancreatic cancer is the fourth leading cause of cancer death with a five year survival rate around 5%, which has not changed in 30 years. Obesity and increased abdominal adipose tissue independently correlate with an increased relative risk for the development of pancreatic cancer. These conditions have been associated with altered levels of adipokines, or adipose secreted cytokines. Circulating serum levels of the adipokine leptin are increasesddramatically in obese patients as well as in high fat diet induced obese mice. Leptin has been shown to induce oncogenic signaling in breast and prostate cancer. We have previously shown an increase in orthotopic pancreatic tumor size in high fat diet induced obese mice compared with regular diet control mice. We hypothesize that leptin signaling mediates pancreatic tumorigenesis. Methods: Leptin receptor status was determined in human as well as murine pancreatic cell lines. Leptin stimulated cell proliferation was determined using a modified BrdU assay. Leptin receptor levels were knocked down in human and murine pancreatic tumor cells using a shRNAmir approach. Leptin receptor shRNA Panc02 knockdown cells were injected orthotopically into the pancreas of C57/Bl6J mice on regular or high fat diet to determine the contribution of leptin to pancreatic tumor growth. Results: We have detected the long form of the leptin receptor in five human and four murine pancreatic cancer cell lines. In vitro administration of leptin stimulated proliferation of Panc1 and CFPAC1 cell lines, which was abrogated with co-incubation of a leptin antagonist. To better understand the mechanism of leptin-mediated signaling, we studied downstream targets and identified a significant increase in phosphorylation of STAT3 in Panc1, BXPC3 and CFPAC1 cell lines after leptin treatment. Orhtotopic injection of leptin receptor shRNA Panc02 cells into normal and obese mice showed a markedly diminished tumor growth in obese mice when compared to the nonsilencing control Panc02 cell growth in obese mice. Conclusion: These results implicate leptin as a mediator of pancreatic tumorigenesis and suggest that leptin activation is mediated in part through STAT3 signaling. Knockdown of the leptin receptor results in inhibition of high fat diet associated tumor growth in vivo. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 299. doi:1538-7445.AM2012-299
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