Go to The Journal of Clinical Investigation
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Transfers
  • Advertising
  • Job board
  • Contact
  • Current issue
  • Past issues
  • By specialty
    • COVID-19
    • Cardiology
    • Immunology
    • Metabolism
    • Nephrology
    • Oncology
    • Pulmonology
    • All ...
  • Videos
  • Collections
    • Resource and Technical Advances
    • Clinical Medicine
    • Reviews
    • Editorials
    • Perspectives
    • Top read articles
  • JCI This Month
    • Current issue
    • Past issues

  • Current issue
  • Past issues
  • Specialties
  • In-Press Preview
  • Concise Communication
  • Editorials
  • Viewpoint
  • Top read articles
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Transfers
  • Advertising
  • Job board
  • Contact
Resident stroma-secreted chemokine CCL2 governs myeloid-derived suppressor cells in the tumor microenvironment
May Wathone Oo, … , Akira Sasaki, Hitoshi Nagatsuka
May Wathone Oo, … , Akira Sasaki, Hitoshi Nagatsuka
Published December 7, 2021
Citation Information: JCI Insight. ;7(1):e148960. https://doi.org/10.1172/jci.insight.148960.
View: Text | PDF
Research Article Oncology

Resident stroma-secreted chemokine CCL2 governs myeloid-derived suppressor cells in the tumor microenvironment

  • Text
  • PDF
Abstract

Accumulating evidence has shown that cancer stroma and BM-derived cells (BMDCs) in the tumor microenvironment (TME) play vital roles in tumor progression. However, the mechanism by which oral cancer stroma recruits any particular subset of BMDCs remains largely unknown. Here, we sought to identify the subset of BMDCs that is recruited by cancer stroma. We established a sequential transplantation model in BALB/c nude mice, including (a) BM transplantation of GFP-expressing cells and (b) coxenografting of patient-derived stroma (PDS; 2 cases, designated PDS1 and PDS2) with oral cancer cells (HSC-2). As controls, xenografting was performed with HSC-2 alone or in combination with normal human dermal fibroblasts (HDF). PDS1, PDS2, and HDF all promoted BMDC migration in vitro and recruitment in vivo. Multicolor immunofluorescence revealed that the PDS coxenografts recruited Arginase-1+CD11b+GR1+GFP+ cells, which are myeloid-derived suppressor cells (MDSCs), to the TME, whereas the HDF coxenograft did not. Screening using microarrays revealed that PDS1 and PDS2 expressed CCL2 mRNA (encoding C-C motif chemokine ligand 2) at higher levels than did HDF. Indeed, PDS xenografts contained significantly higher proportions of CCL2+ stromal cells and CCR2+Arginase-1+CD11b+GR1+ MDSCs (as receiver cells) than the HDF coxenograft. Consistently, a CCL2 synthesis inhibitor and a CCR2 antagonist significantly inhibited the PDS-driven migration of BM cells in vitro. Furthermore, i.p. injection of the CCR2 antagonist to the PDS xenograft models significantly reduced the CCR2+Arginase-1+CD11b+GR1+ MDSC infiltration to the TME. In conclusion, oral cancer stroma–secreted CCL2 is a key signal for recruiting CCR2+ MDSCs from BM to the TME.

Authors

May Wathone Oo, Hotaka Kawai, Kiyofumi Takabatake, Shuta Tomida, Takanori Eguchi, Kisho Ono, Qiusheng Shan, Toshiaki Ohara, Saori Yoshida, Haruka Omori, Shintaro Sukegawa, Keisuke Nakano, Kuniaki Okamoto, Akira Sasaki, Hitoshi Nagatsuka

×

Figure 5

The inhibition of the CCL2/CCR2 axis significantly lowered stroma-driven BM cell migration.

Options: View larger image (or click on image) Download as PowerPoint
The inhibition of the CCL2/CCR2 axis significantly lowered stroma-driven...
(A) Illustration of Transwell migration assessment of BM cells in the presence of CCL2 inhibitor bindarit (shown as the green bars). CCL2 inhibition with 50 μM (0.1% DMSO), 100 μM (0.2% DMSO), and 300 μM (0.6% DMSO) of bindarit was performed for 4 h before migration. As control 0.6% DMSO was used. (B) Representative images of Transwell migration of BM cells in the presence of bindarit. (C) The number of migrating BM cells among the different tumor/stroma cocultures in the presence of bindarit (300 μM). (D–F) The comparison of BM cell migration in different concentrations of bindarit in +HDF, +PDS1, and +PDS2. (G) Illustration of Transwell migration assessment of BM cells pretreated with CCR2 antagonist RS 102895 (20 μM) for 1 h. (H) Representative images of Transwell migration of BM cells pretreated with RS 102895. (I) The number of BM cells migrating after the treatment with RS 102895 (20 μM) in the different tumor/stroma cocultures. +HDF, HSC-2 + HDF coculture; +PDS1, HSC-2 + PDS1 coculture; +PDS2, HSC-2 + PDS2 coculture (5 fields per group, n = 3). All data are shown as mean ± SD. Statistical analyses were performed using Student’s t test for comparison of 2 groups and 1-way ANOVA followed by Tukey’s multiple-comparison post hoc test for comparison of more than 2 groups; *P < 0.05 **P < 0.01, ***P < 0.001.

Copyright © 2022 American Society for Clinical Investigation
ISSN 2379-3708

Sign up for email alerts