Abstract
Pancreatic cancer progression involves components of the tumor microenvironment, including stellate cells, immune cells, endothelial cells, and the extracellular matrix. Although peripancreatic fat is the main stromal component involved in extra-pancreatic invasion, its roles in local invasion and metastasis of pancreatic cancer remain unclear. This study investigated the role of adipose tissue in pancreatic cancer progression using genetically engineered mice (Pdx1-Cre; LSL-KrasG12D; Trp53R172H/+) and an in vitro model of organotypic fat invasion. Mice fed a high fat diet had significantly larger primary pancreatic tumors and a significantly higher rate of distant organ metastasis than mice fed a standard diet. In the organotypic fat invasion model, pancreatic cancer cell clusters were smaller and more elongated in shape and showed increased fibrosis. Adipose tissue-derived conditioned medium enhanced pancreatic cancer cell invasiveness and gemcitabine resistance, as well as inducing morphologic changes in cancer cells and increasing the numbers of lipid droplets in their cytoplasm. The concentrations of oleic, palmitoleic, and linoleic acids were higher in adipose tissue-derived conditioned medium than in normal medium, with these fatty acids significantly enhancing the migration of cancer cells. Mature adipocytes were smaller and the concentration of fatty acids in the medium higher when these cells were co-cultured with cancer cells. These findings indicate that lipolytic and fibrotic changes in peripancreatic adipose tissue enhance local invasiveness and metastasis via adipocyte-released fatty acids. Inhibition of fatty acid uptake by cancer cells may be a novel therapy targeting interactions between cancer and stromal cells.
Highlights
Pancreatic cancer (PDAC) is the fourth leading cause of cancer-related deaths worldwide, with a 5-year survival rate of only 6% [1]
Visceral fat induced by a high fat diet enhances primary tumor growth and distant metastasis in KPC mice
This study investigated the effects of visceral fat on the local invasiveness and metastasis of PDACs using a genetically engineered KPC (Pdx1-Cre; LSL-KrasG12D; Trp53R172H/+) mouse model, in which pancreatic epithelial cells express endogenous Kras and Trp53 mutations [24]
Summary
Pancreatic cancer (PDAC) is the fourth leading cause of cancer-related deaths worldwide, with a 5-year survival rate of only 6% [1]. One important pathological feature of www.impactjournals.com/oncotarget pancreatic cancer is the abundance of stromal components, or desmoplasia These components, which include stellate cells, immune cells, endothelial cells and extracellular matrices, have been shown to affect the proliferation and invasiveness of cancer cells and their resistance to therapeutic agents [2, 3]. Several agents targeting these stromal components have been developed [4,5,6,7] and tested in clinical trials [8,9,10,11], but none has been shown effective. It is important to establish appropriate experimental models reflecting human PDAC and focus on the novel biological significance of stromal components
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