Hypoxic stellate cells of pancreatic cancer stroma regulate extracellular matrix fiber organization and cancer cell motility

Masafumi Sada, Kenoki Ohuchida, Kohei Horioka, Takashi Okumura, Taiki Moriyama, Yoshihiro Miyasaka, Takao Ohtsuka, Kazuhiro Mizumoto, Yoshinao Oda, Masafumi Nakamura

Research output: Contribution to journalArticlepeer-review

33 Citations (Scopus)

Abstract

Desmoplasia and hypoxia in pancreatic cancer mutually affect each other and create a tumor-supportive microenvironment. Here, we show that microenvironment remodeling by hypoxic pancreatic stellate cells (PSCs) promotes cancer cell motility through alteration of extracellular matrix (ECM) fiber architecture. Three-dimensional (3-D) matrices derived from PSCs under hypoxia exhibited highly organized parallel-patterned matrix fibers compared with 3-D matrices derived from PSCs under normoxia, and promoted cancer cell motility by inducing directional migration of cancer cells due to the parallel fiber architecture. Microarray analysis revealed that procollagen-lysine, 2-oxoglutarate 5-dioxygenase 2 (PLOD2) in PSCs was the gene that potentially regulates ECM fiber architecture under hypoxia. Stromal PLOD2 expression in surgical specimens of pancreatic cancer was confirmed by immunohistochemistry. RNA interference-mediated knockdown of PLOD2 in PSCs blocked parallel fiber architecture of 3-D matrices, leading to decreased directional migration of cancer cells within the matrices. In conclusion, these findings indicate that hypoxia-induced PLOD2 expression in PSCs creates a permissive microenvironment for migration of cancer cells through architectural regulation of stromal ECM in pancreatic cancer.

Original languageEnglish
Pages (from-to)210-218
Number of pages9
JournalCancer Letters
Volume372
Issue number2
DOIs
Publication statusPublished - Mar 28 2016

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

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