Macrophages are primed to transdifferentiate into fibroblasts in malignant ascites and pleural effusions

Mamoru Ito; Michitaka Nakano; Hiroshi Ariyama; Kyoko Yamaguchi; Risa Tanaka; Yuichiro Semba; Takeshi Sugio; Kohta Miyawaki; Yoshikane Kikushige; Shinichi Mizuno; Taichi Isobe; Kenro Tanoue; Ryosuke Taguchi; Shohei Ueno; Takahito Kawano; Masaharu Murata; Eishi Baba; Koichi Akashi

doi:10.1016/j.canlet.2022.215597

Macrophages are primed to transdifferentiate into fibroblasts in malignant ascites and pleural effusions

Mamoru Ito, Michitaka Nakano, Hiroshi Ariyama, Kyoko Yamaguchi, Risa Tanaka, Yuichiro Semba, Takeshi Sugio, Kohta Miyawaki, Yoshikane Kikushige, Shinichi Mizuno, Taichi Isobe, Kenro Tanoue, Ryosuke Taguchi, Shohei Ueno, Takahito Kawano, Masaharu Murata, Eishi Baba, Koichi Akashi

Research output: Contribution to journal › Article › peer-review

1 Citation (Scopus)

Abstract

Cancer-associated fibroblasts (CAFs) play an important role in cancer progression. However, the origin of CAFs remains unclear. This study shows that macrophages in malignant ascites and pleural effusions (cavity fluid-associated macrophages: CAMs) transdifferentiate into fibroblast-like cells. CAMs obtained from gastrointestinal cancer patients were sorted by flow cytometry and cultured in vitro. CD45 +CD14 + CAMs transdifferentiated into CD45 -CD90 + fibroblast-like cells that exhibited spindle shapes. Then, cDNA microarray analysis showed that the CD45 -CD90 + fibroblast-like cells (macrophage-derived CAFs: MDCAFs) had a fibroblast-specific gene expression signature and produced growth factors for epithelial cell proliferation. Human colon cancer cells transplanted into immunodeficient mice with MDCAFs formed larger tumors than cancer cells alone. Gene ontology analyses showed the involvement of TGFβ signaling and cell-matrix adhesion in MDCAFs, and transdifferentiation of CAMs into MDCAFs was canceled by inhibiting TGFβ and cell adhesion. Furthermore, the acquired genetic alterations in hematopoietic stem cells (HSCs) were shared in CAMs and MDCAFs. Taken together, CAMs could be a source of CAFs and might originate from HSCs. We propose the transdifferentiation process of CAMs into MDCAFs as a new therapeutic target for fibrosis associated with gastrointestinal cancer.

Original language	English
Pages (from-to)	215597
Journal	Cancer Letters
Volume	532
DOIs	https://doi.org/10.1016/j.canlet.2022.215597
Publication status	E-pub ahead of print - Feb 10 2022

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.1016/j.canlet.2022.215597

Cite this

Ito, M., Nakano, M., Ariyama, H., Yamaguchi, K., Tanaka, R., Semba, Y., Sugio, T., Miyawaki, K., Kikushige, Y., Mizuno, S., Isobe, T., Tanoue, K., Taguchi, R., Ueno, S., Kawano, T., Murata, M., Baba, E., & Akashi, K. (2022). Macrophages are primed to transdifferentiate into fibroblasts in malignant ascites and pleural effusions. Cancer Letters, 532, 215597. https://doi.org/10.1016/j.canlet.2022.215597

Ito, M, Nakano, M, Ariyama, H , Yamaguchi, K, Tanaka, R, Semba, Y, Sugio, T, Miyawaki, K , Kikushige, Y , Mizuno, S , Isobe, T, Tanoue, K, Taguchi, R, Ueno, S, Kawano, T , Murata, M , Baba, E & Akashi, K 2022, 'Macrophages are primed to transdifferentiate into fibroblasts in malignant ascites and pleural effusions', Cancer Letters, vol. 532, pp. 215597. https://doi.org/10.1016/j.canlet.2022.215597

@article{316aa90f4ce94d70b6159eb9cb8161af,

title = "Macrophages are primed to transdifferentiate into fibroblasts in malignant ascites and pleural effusions",

abstract = "Cancer-associated fibroblasts (CAFs) play an important role in cancer progression. However, the origin of CAFs remains unclear. This study shows that macrophages in malignant ascites and pleural effusions (cavity fluid-associated macrophages: CAMs) transdifferentiate into fibroblast-like cells. CAMs obtained from gastrointestinal cancer patients were sorted by flow cytometry and cultured in vitro. CD45 +CD14 + CAMs transdifferentiated into CD45 -CD90 + fibroblast-like cells that exhibited spindle shapes. Then, cDNA microarray analysis showed that the CD45 -CD90 + fibroblast-like cells (macrophage-derived CAFs: MDCAFs) had a fibroblast-specific gene expression signature and produced growth factors for epithelial cell proliferation. Human colon cancer cells transplanted into immunodeficient mice with MDCAFs formed larger tumors than cancer cells alone. Gene ontology analyses showed the involvement of TGFβ signaling and cell-matrix adhesion in MDCAFs, and transdifferentiation of CAMs into MDCAFs was canceled by inhibiting TGFβ and cell adhesion. Furthermore, the acquired genetic alterations in hematopoietic stem cells (HSCs) were shared in CAMs and MDCAFs. Taken together, CAMs could be a source of CAFs and might originate from HSCs. We propose the transdifferentiation process of CAMs into MDCAFs as a new therapeutic target for fibrosis associated with gastrointestinal cancer. ",

author = "Mamoru Ito and Michitaka Nakano and Hiroshi Ariyama and Kyoko Yamaguchi and Risa Tanaka and Yuichiro Semba and Takeshi Sugio and Kohta Miyawaki and Yoshikane Kikushige and Shinichi Mizuno and Taichi Isobe and Kenro Tanoue and Ryosuke Taguchi and Shohei Ueno and Takahito Kawano and Masaharu Murata and Eishi Baba and Koichi Akashi",

note = "Copyright {\textcopyright} 2022. Published by Elsevier B.V.",

year = "2022",

month = feb,

day = "10",

doi = "10.1016/j.canlet.2022.215597",

language = "English",

volume = "532",

pages = "215597",

journal = "Cancer Letters",

issn = "0304-3835",

publisher = "Elsevier Ireland Ltd",

}

TY - JOUR

T1 - Macrophages are primed to transdifferentiate into fibroblasts in malignant ascites and pleural effusions

AU - Ito, Mamoru

AU - Nakano, Michitaka

AU - Ariyama, Hiroshi

AU - Yamaguchi, Kyoko

AU - Tanaka, Risa

AU - Semba, Yuichiro

AU - Sugio, Takeshi

AU - Miyawaki, Kohta

AU - Kikushige, Yoshikane

AU - Mizuno, Shinichi

AU - Isobe, Taichi

AU - Tanoue, Kenro

AU - Taguchi, Ryosuke

AU - Ueno, Shohei

AU - Kawano, Takahito

AU - Murata, Masaharu

AU - Baba, Eishi

AU - Akashi, Koichi

PY - 2022/2/10

Y1 - 2022/2/10

N2 - Cancer-associated fibroblasts (CAFs) play an important role in cancer progression. However, the origin of CAFs remains unclear. This study shows that macrophages in malignant ascites and pleural effusions (cavity fluid-associated macrophages: CAMs) transdifferentiate into fibroblast-like cells. CAMs obtained from gastrointestinal cancer patients were sorted by flow cytometry and cultured in vitro. CD45 +CD14 + CAMs transdifferentiated into CD45 -CD90 + fibroblast-like cells that exhibited spindle shapes. Then, cDNA microarray analysis showed that the CD45 -CD90 + fibroblast-like cells (macrophage-derived CAFs: MDCAFs) had a fibroblast-specific gene expression signature and produced growth factors for epithelial cell proliferation. Human colon cancer cells transplanted into immunodeficient mice with MDCAFs formed larger tumors than cancer cells alone. Gene ontology analyses showed the involvement of TGFβ signaling and cell-matrix adhesion in MDCAFs, and transdifferentiation of CAMs into MDCAFs was canceled by inhibiting TGFβ and cell adhesion. Furthermore, the acquired genetic alterations in hematopoietic stem cells (HSCs) were shared in CAMs and MDCAFs. Taken together, CAMs could be a source of CAFs and might originate from HSCs. We propose the transdifferentiation process of CAMs into MDCAFs as a new therapeutic target for fibrosis associated with gastrointestinal cancer.

AB - Cancer-associated fibroblasts (CAFs) play an important role in cancer progression. However, the origin of CAFs remains unclear. This study shows that macrophages in malignant ascites and pleural effusions (cavity fluid-associated macrophages: CAMs) transdifferentiate into fibroblast-like cells. CAMs obtained from gastrointestinal cancer patients were sorted by flow cytometry and cultured in vitro. CD45 +CD14 + CAMs transdifferentiated into CD45 -CD90 + fibroblast-like cells that exhibited spindle shapes. Then, cDNA microarray analysis showed that the CD45 -CD90 + fibroblast-like cells (macrophage-derived CAFs: MDCAFs) had a fibroblast-specific gene expression signature and produced growth factors for epithelial cell proliferation. Human colon cancer cells transplanted into immunodeficient mice with MDCAFs formed larger tumors than cancer cells alone. Gene ontology analyses showed the involvement of TGFβ signaling and cell-matrix adhesion in MDCAFs, and transdifferentiation of CAMs into MDCAFs was canceled by inhibiting TGFβ and cell adhesion. Furthermore, the acquired genetic alterations in hematopoietic stem cells (HSCs) were shared in CAMs and MDCAFs. Taken together, CAMs could be a source of CAFs and might originate from HSCs. We propose the transdifferentiation process of CAMs into MDCAFs as a new therapeutic target for fibrosis associated with gastrointestinal cancer.

U2 - 10.1016/j.canlet.2022.215597

DO - 10.1016/j.canlet.2022.215597

M3 - Article

C2 - 35150810

SN - 0304-3835

VL - 532

SP - 215597

JO - Cancer Letters

JF - Cancer Letters

ER -

Macrophages are primed to transdifferentiate into fibroblasts in malignant ascites and pleural effusions

Abstract

UN SDGs

Access to Document

Fingerprint

Cite this