Research Papers:

Extra-pancreatic invasion induces lipolytic and fibrotic changes in the adipose microenvironment, with released fatty acids enhancing the invasiveness of pancreatic cancer cells

Takashi Okumura, Kenoki Ohuchida _, Masafumi Sada, Toshiya Abe, Sho Endo, Kazuhiro Koikawa, Chika Iwamoto, Daisuke Miura, Yusuke Mizuuchi, Taiki Moriyama, Kohei Nakata, Yoshihiro Miyasaka, Tatsuya Manabe, Takao Ohtsuka, Eishi Nagai, Kazuhiro Mizumoto, Yoshinao Oda, Makoto Hashizume and Masafumi Nakamura

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Oncotarget. 2017; 8:18280-18295. https://doi.org/10.18632/oncotarget.15430

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Takashi Okumura1, Kenoki Ohuchida1, Masafumi Sada1, Toshiya Abe1, Sho Endo1, Kazuhiro Koikawa1, Chika Iwamoto2, Daisuke Miura3,5, Yusuke Mizuuchi1, Taiki Moriyama1, Kohei Nakata1, Yoshihiro Miyasaka1, Tatsuya Manabe1, Takao Ohtsuka1, Eishi Nagai1, Kazuhiro Mizumoto1, Yoshinao Oda4, Makoto Hashizume2, Masafumi Nakamura1

1Department of Surgery and Oncology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan

2Department of Advanced Medical Initiatives, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan

3Innovation Center for Medical Redox Navigation, Kyushu University, Fukuoka, Japan

4Department of Anatomic Pathology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan

5Kyushu University Hospital Cancer Center, Fukuoka, Japan

Correspondence to:

Kenoki Ohuchida, email: [email protected]

Masafumi Nakamura, email: [email protected]

Keywords: pancreatic cancer, extra-pancreatic invasion, adipose microenvironment, lipolysis, fatty acids

Received: September 20, 2016     Accepted: January 10, 2017     Published: February 17, 2017


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.

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