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, Masafumi Nakamura

Research output: Contribution to journalArticle

17 Citations (Scopus)

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; LSLKrasG12D; 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.

Original languageEnglish
Pages (from-to)18280-18295
Number of pages16
JournalOncotarget
Volume8
Issue number11
DOIs
Publication statusPublished - Jan 1 2017

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Pancreatic Neoplasms
Fatty Acids
Adipose Tissue
Neoplasms
Fats
Conditioned Culture Medium
gemcitabine
Neoplasm Metastasis
Adipocytes
Oleic Acids
Linoleic Acids
Tumor Microenvironment
High Fat Diet
Stromal Cells
Cell Movement
Extracellular Matrix
Cytoplasm
Fibrosis
Endothelial Cells
Cell Count

All Science Journal Classification (ASJC) codes

  • Oncology

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Extra-pancreatic invasion induces lipolytic and fibrotic changes in the adipose microenvironment, with released fatty acids enhancing the invasiveness of pancreatic cancer cells. / Okumura, Takashi; Ohuchida, Kenoki; Sada, Masafumi; Abe, Toshiya; Endo, Sho; Koikawa, Kazuhiro; Iwamoto, Chika; Miura, Daisuke; Mizuuchi, Yusuke; Moriyama, Taiki; Nakata, Kohei; Miyasaka, Yoshihiro; Manabe, Tatsuya; Ohtsuka, Takao; Nagai, Eishi; Mizumoto, Kazuhiro; Oda, Yoshinao; Hashizume, Makoto; Nakamura, Masafumi.

In: Oncotarget, Vol. 8, No. 11, 01.01.2017, p. 18280-18295.

Research output: Contribution to journalArticle

Okumura, Takashi ; Ohuchida, Kenoki ; Sada, Masafumi ; Abe, Toshiya ; Endo, Sho ; Koikawa, Kazuhiro ; Iwamoto, Chika ; Miura, Daisuke ; Mizuuchi, Yusuke ; Moriyama, Taiki ; Nakata, Kohei ; Miyasaka, Yoshihiro ; Manabe, Tatsuya ; Ohtsuka, Takao ; Nagai, Eishi ; Mizumoto, Kazuhiro ; Oda, Yoshinao ; Hashizume, Makoto ; Nakamura, Masafumi. / Extra-pancreatic invasion induces lipolytic and fibrotic changes in the adipose microenvironment, with released fatty acids enhancing the invasiveness of pancreatic cancer cells. In: Oncotarget. 2017 ; Vol. 8, No. 11. pp. 18280-18295.
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