Bone marrow-derived macrophages converted into cancer-associated fibroblast-like cells promote pancreatic cancer progression

Chika Iwamoto, Kenoki Ohuchida, Tomohiko Shinkawa, Sho Okuda, Yoshiki Otsubo, Takashi Okumura, Akiko Sagara, Kazuhiro Koikawa, Yohei Ando, Koji Shindo, Naoki Ikenaga, Kohei Nakata, Taiki Moriyama, Yoshihiro Miyasaka, Ohtsuka Takao, Masatoshi Eto, Koichi Akashi, Masafumi Nakamura

Research output: Contribution to journalArticlepeer-review

1 Citation (Scopus)

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is characterized by a desmoplastic reaction caused by cancer-associated fibroblasts (CAFs), which provokes treatment resistance. CAFs are newly proposed to be heterogeneous populations with different functions within the PDAC microenvironment. The most direct sources of CAFs are resident tissue fibroblasts and mesenchymal stem cells, however, the origins and functions of CAF subtypes remain unclear. Here, we established allogeneic bone marrow (BM) transplantation models using spontaneous PDAC mice, and then investigated what subtype cells derived from BM modulate the tumor microenvironment and affect the behavior of pancreatic cancer cells (PCCs). BM-derived multilineage hematopoietic cells were engrafted in recipient pancreas, and accumulated at the invasive front and central lesion of PDAC. We identified BM macrophages-derived CAFs in tumors. BM-derived macrophages treated with PCC-conditioned media expressed CAF markers. BM-derived macrophages led the local invasion of PCCs in vitro and enhanced the tumor invasive growth in vivo. Our data suggest that BM-derived cells are recruited to the pancreas during carcinogenesis and that the specific subpopulation of BM-derived macrophages partially converted into CAF-like cells, acted as leading cells, and facilitated pancreatic cancer progression. The control of the conversion of BM-derived macrophages into CAF-like cells may be a novel therapeutic strategy to suppress tumor growth.

Original languageEnglish
Pages (from-to)15-27
Number of pages13
JournalCancer Letters
Volume512
DOIs
Publication statusPublished - Aug 1 2021

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

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