Adipose tissue-derived stromal cells are sources of cancer-associated fibroblasts and enhance tumor progression by dense collagen matrix

Takashi Okumura, Kenoki Ohuchida, Shin Kibe, Chika Iwamoto, Yohei Ando, Shin Takesue, Hiromichi Nakayama, Toshiya Abe, Sho Endo, Kazuhiro Koikawa, Masafumi Sada, Kohei Horioka, Naoki Mochidome, Makoto Arita, Taiki Moriyama, Kohei Nakata, Yoshihiro Miyasaka, Takao Ohtsuka, Kazuhiro Mizumoto, Yoshinao OdaMakoto Hashizume, Masafumi Nakamura

Research output: Contribution to journalArticle

3 Citations (Scopus)

Abstract

Although recent studies revealed that adipose tissue accelerates pancreatic tumor progression with excessive extracellular matrix, key players for desmoplasia in the adipose microenvironment remains unknown. Here, we investigated the roles of adipose tissue-derived stromal cells (ASCs) in desmoplastic lesions and tumor progression by in vitro and in vivo experiments. In a three-dimensional (3-D) organotypic fat invasion model using visceral fat from CAG-EGFP mice, GFP-positive fibroblastic cells infiltrated toward cancer cells. When tumor cells were inoculated into transplanted visceral fat pads in vivo, tumor weights and stromal components were enhanced compared to subcutaneous and orthotopic tumor cells inoculated without fat pads. Expression of αSMA in established human ASCs was lower compared to cancer associated fibroblasts, and the 3-D collagen matrices produced by ASCs cultured in cancer cell-conditioned medium changed from loose to dense structures that affected the motility of cancer cells. Microarray analyses revealed upregulation of S100A4 in ASCs, while S100A4-positive stromal cells were observed at extrapancreatic invasion sites of human pancreatic cancer. The present findings indicate that ASCs are recruited to extrapancreatic invasion sites and produce dense collagen matrices that lead to enhanced tumor progression. Both inhibition of ASCs recruitment and activation could lead to a novel antistromal therapy.

Original languageEnglish
Pages (from-to)1401-1413
Number of pages13
JournalInternational Journal of Cancer
Volume144
Issue number6
DOIs
Publication statusPublished - Mar 15 2019

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

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