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Unlabelled: 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 pharmacologic inhibition of angiotensin-II type-1 receptor reverses obesity-augmented desmoplasia and tumor growth and improves response to chemotherapy. Augmented activation of pancreatic stellate cells (PSC) in obesity is induced by tumor-associated neutrophils (TAN) recruited by adipocyte-secreted IL1β. PSCs further secrete IL1β, and inactivation of PSCs reduces IL1β expression and TAN recruitment. Furthermore, depletion of TANs, IL1β inhibition, or inactivation of PSCs prevents obesity-accelerated tumor growth. In patients with pancreatic cancer, we confirmed that obesity is associated with increased desmoplasia and reduced response to chemotherapy. We conclude that cross-talk between adipocytes, TANs, and PSCs exacerbates desmoplasia and promotes tumor progression in obesity., Significance: Considering the current obesity pandemic, unraveling the mechanisms underlying obesity-induced cancer progression is an urgent need. We found that the aggravation of desmoplasia is a key mechanism of obesity-promoted PDAC progression. Importantly, we discovered that clinically available antifibrotic/inflammatory agents can improve the treatment response of PDAC in obese hosts. Cancer Discov; 6(8); 852-69. ©2016 AACR.See related commentary by Bronte and Tortora, p. 821This article is highlighted in the In This Issue feature, p. 803., (©2016 American Association for Cancer Research.)

Obesity remains nowadays one of the main threats to human health, being a problem of worldwide proportions. It is characterized by augmented storage of fatty acids in an enlarged adipose tissue. This process is possible thanks to a rich capillary network, supported by a mechanism that has also a crucial role on cancer: angiogenesis. Given that several studies point obesity as a risk factor for cancer development, angiogenesis may be approached as the missed link between these two pathologies. Understanding the different pathways behind angiogenesis becomes essential to break this link by developing new anti-angiogenic therapies or improving the actual ones. In the first phase, this paper will focus the structural and cellular changes that adipose tissue suffers in obesity. Then, the main pro-angiogenic players will be reviewed, taking into account the pathways that explain their putative role in obesity-cancer link. Finally, the clinical implications of the presented mechanisms will also be regarded, being the main focus on the anti-angiogenic therapies., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Aim: A number of studies have shown an association between obesity and asthma. Controversy remains on the mechanisms supporting this association. In this study we aimed to assess neurogenic inflammation in a model of diet-induced obesity and allergen-challenged mice. Methods: High fat diet-induced (HFD) obese Balb/c mice were sensitized and challenged with ovalbumin (OVA). Glucose, insulin, OVA-specific IgE and substance P (SP), and the main tachykinin involved in neurogenic inflammation, were quantified in sera. Cell counts were performed in bronchoalveolar lavage fluid (BALF). The extent of peribronchial infiltrates was estimated on lung tissue sections and inflammation was score based on inflammatory cell counts surrounding the bronchi. Results: Obesity per se and allergen-sensitization per se increased serum SP ( P = .027, P = .004, respectively). Further increased was observed in obese-sensitized mice ( P = .007). Obese-sensitized mice also showed higher insulin ( P = .0016), OVA-specific IgE ( P = .016), peribronchial inflammatory score ( P = .045), and tendency for higher glycemia. The interaction of obesity and asthma on SP levels was confirmed ( P = .005, R2 = 0.710). SP was positively correlated with metabolic (glycemia, r = 0.539, P = .007) and allergic inflammation parameters (BALF eosinophils, r = 0.445, P = 0.033; BALF mast cells, r = 0.574, P = .004; peribronchial inflammation score, r = 0.661, P < .001; and OVA-specific IgE, r = 0.714, P < .001). Conclusions: Our findings provide support to the neurogenic inflammation link between obesity and asthma in mice. These two conditions independently increased SP and the presence of both pathologies further increased this level. Neurogenic inflammation may be a previously unrecognized mechanism beyond the obese-asthma phenotype. Further studies are need to confirm this role of SP in human obesity-asthma association. [ABSTRACT FROM AUTHOR]