Inflammation and mitochondrial fatty acid β-oxidation link obesity to early tumor promotion

Abstract

Obesity is associated with increased risk for developing pancreatic cancer, and it is suggested that insulin resistance provides the missing link. Here we demonstrate that under the context of genetic susceptibility, a high fat diet (HFD) predisposes mice with oncogenic K-ras activation to accelerated pancreatic intraepithelial neoplasm (PanIN) development. Tumor promotion is closely associated with increased inflammation and abrogation of TNFR1 signaling significantly blocks this process underlining a central role for TNF␣ in obesity-mediated enhancement of PanIN lesions. Interestingly, however, despite increased TNF␣ levels, mice remain insulin sensitive. We show that, while aggravating tumor promotion, a HFD exerts dramatic changes in energy metabolism through enhancement of pancreatic exocrine insufficiency, metabolic rates, and expression of genes involved in mitochondrial fatty acid (FA) ␤-oxidation that collectively contribute to improved glucose tolerance in these mice. While on one hand these findings provide significant evidence that obesity is linked to tumor promotion in the pancreas, on the other it suggests alterations in inflammatory responses and bioenergetic pathways as the potential underlying cause.energy metabolism ͉ cancer ͉ TNF␣ ͉ mitochondria ͉ pancreas

AZGP1 is a tumor suppressor in pancreatic cancer inducing mesenchymal-to-epithelial transdifferentiation by inhibiting TGF-β-mediated ERK signaling

“…A recent study revealed that high-fat-diet-induced obesity in mice accelerated the development of PanIN in the context of embryonic KRas activation through changes in energy metabolism. These data suggested changes in energy metabolism rather than insulin resistance as key elements in early carcinogenesis of PDAC (Khasawneh et al, 2009). Recent evidence has also established a link between low serum levels of ZAG and obesity in humans; however, whether ZAG serum levels are also related to insulin resistance is still under debate (Marrades et al, 2008).…”

NF-κB and STAT3 signaling pathways collaboratively link inflammation to cancer

“…Recent work has shown that tobacco smoke acts as tumor promoter via triggering chronic inflammation . Similarly, obesity promotes tumorigenesis in the liver and pancreas partially through obesity-induced chronic inflammation (Khasawneh et al, 2009, Park et al, 2010. However, not all of chronic inflammatory diseases increase cancer risk.…”

The zinc-finger protein KCMF1 is overexpressed during pancreatic cancer development and downregulation of KCMF1 inhibits pancreatic cancer development in mice

“…LSL-kRrasG12D mice were crossed to p48-Cre animals to generate mice with pancreas-specific (p48-kRas) and activate oncogenic kRas (Khasawneh et al, 2009). The KCMF1-deficient embryonic stem cell line (XE-080) was obtained from Bay Area Functional Genomics Consortium (BayGenomics, Berkeley, CA, USA), injected into 129SV/NMRI male chimeras and mated to C57BL/6J females following standard procedures.…”