BACKGROUND Ethanol exposure prior to traumatic injury, such as a burn, elevates systemic and local inflammatory responses and increases morbidity and mortality. Adipose is a large tissue mass that is often inflamed during obesity or other stresses which disturbs metabolic homeostasis. To date, there has been little investigation into the inflammatory response of adipose tissue after combined ethanol exposure and burn injury. METHODS Two ethanol exposure regimens were utilized to examine the role of inflammation in adipose tissue after ethanol and burn injury. Mice were either given a single or episodic binge exposure to ethanol or saline followed by scald (burn) or sham injury 30 minutes later. Twenty-four hours post injury, serum and adipose tissue were collected for assessment of inflammatory mediators. RESULTS Single binge ethanol alone induced no inflammation in adipose when compared with sham vehicle treated mice. However, single binge ethanol followed by burn injury induced significant elevations in mRNA and protein concentrations of pro-inflammatory mediators interleukin-6 (IL-6), KC, and monocyte chemoattractant protein 1 (MCP-1) compared to either insult alone or sham vehicle group. Additionally, ethanol exposure and burn injury significantly blunted inducible nitric oxide synthase (iNOS), indicating a complex inflammatory response. Episodic binge ethanol exposure followed by burn injury exacerbated the post-burn adipose inflammatory response. The magnitude of the episodic binge-induced inflammatory parameters post-burn were 2- to 5- fold greater than the response detected after a single exposure of ethanol, indicating ethanol-induced potentiation of burn-induced inflammatory response. Finally, inflammatory loci and crown-like structures in adipose were significantly increased by episodic binge ethanol and burn injury. CONCLUSIONS This is the first report of binge and burn-induced crown-like structure formation. Evidence presented herein suggests an important role for alcohol and burn as an additional mediator of adipose inflammation in post-burn injury, a common complication in burn patients.
Obesity is associated with basal-like breast cancer (BBC), an aggressive breast cancer subtype. The objective of this study was to determine whether high fat diet-induced obesity promotes BBC onset in adulthood and to evaluate the role of stromal-epithelial interactions in obesity-associated tumorigenesis. Specifically, we hypothesized that hepatocyte growth factor (HGF) plays a promoting role in BBC, which tends to express the HGF receptor, c-Met. In C3(1)-Tag mice, a murine model of BBC, we demonstrate that obesity leads to a significant increase in HGF secretion and an associated decrease in tumor latency. By immunohistochemical analysis, normal mammary tissue exhibit obesity-induced hepatocyte growth factor (HGF) in stroma and corresponding epithelial expression of c-Met. HGF secretion was also increased in primary mammary fibroblasts isolated from normal mammary and tumors of obese mice compared to lean. These results show that diet-induced elevation of HGF expression is a stable phenotype, maintained after several passages and after removal of dietary stimulation. In cocultures, neutralization of HGF blunted tumor cell migration; further linking diet-mediated HGF-dependent effects in tumor aggressiveness. In sum, these results suggest that HGF plays an important role in obesity-associated carcinogenesis and raise the hypothesis that diet may affect lasting changes in stroma, potentially through epigenetic means. Understanding the effects of obesity on risk and progression is important given epidemiologic studies that imply half of BBC could be eliminated by reducing obesity. Our findings suggest the possibility that reducing obesity may be useful in preventing obesity-associated breast cancer mediated by the HGF/c-Met pathway. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P6-02-09.
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