Induction of monocyte chemoattractant proteins in macrophages via the production of granulocyte/macrophage colony-stimulating factor by breast cancer cells

Teizo Yoshimura, Tomozumi Imamichi, Jonathan M. Weiss, Miwa Sato, Liangzhu Li, Akihiro Matsukawa, Ji Ming Wang

Research output: Contribution to journalArticle

7 Citations (Scopus)

Abstract

Monocyte chemoattractant protein-1 (MCP-1)/CCL2 plays an important role in the initiation and progression of cancer. We previously reported that in 4T1 murine breast cancer, non-tumor stromal cells, including macrophages, were the major source of MCP-1. In the present study, we analyzed the potential mechanisms by which MCP-1 is upregulated in macrophages infiltrating 4T1 tumors. We found that cell-free culture supernatants of 4T1 cells (4T1-sup) markedly upregulated MCP-1 production by peritoneal inflammatory macrophages. 4T1-sup also upregulated other MCPs, such as MCP-3/CCL7 and MCP-5/CCL12, but modestly upregulated neutrophil chemotactic chemokines, such as KC/CXCL1 or MIP-2/CXCL2. Physicochemical analysis indicated that an approximately 2-3 kDa 4T1 cell product was responsible for the capacity of 4T1-sup to upregulate MCP-1 expression by macrophages. A neutralizing antibody against granulocyte/macrophage colony-stimulating factor (GM-CSF), but not macrophage CSF, almost completely abrogated MCP-1-inducing activity of 4T1-sup, and recombinant GM-CSF potently upregulated MCP-1 production by macrophages. The expression levels of GM-CSF in 4T1 tumors in vivo were higher than other tumors, such as Lewis lung carcinoma. Treatment of mice with anti-GM-CSF antibody significantly reduced the growth of 4T1 tumors at the injection sites but did not reduce MCP-1 production or lung metastasis in tumor-bearing mice. These results indicate that 4T1 cells have the capacity to directly upregulate MCP-1 production by macrophages by releasing GM-CSF; however, other mechanisms are also involved in increased MCP-1 levels in the 4T1 tumor microenvironment.

Original languageEnglish
Article number2
JournalFrontiers in Immunology
Volume7
Issue numberJAN
DOIs
Publication statusPublished - 2016

Fingerprint

Monocyte Chemoattractant Proteins
Chemokine CCL2
Granulocyte-Macrophage Colony-Stimulating Factor
Macrophages
Breast Neoplasms
Neoplasms
Up-Regulation
Lewis Lung Carcinoma
Tumor Microenvironment
Peritoneal Macrophages
Stromal Cells
Neutralizing Antibodies
Chemokines

Keywords

  • Breast cancer
  • Chemokines
  • Inflammation
  • Monocytes/macrophages
  • Tumor microenvironment

ASJC Scopus subject areas

  • Immunology
  • Immunology and Allergy

Cite this

Induction of monocyte chemoattractant proteins in macrophages via the production of granulocyte/macrophage colony-stimulating factor by breast cancer cells. / Yoshimura, Teizo; Imamichi, Tomozumi; Weiss, Jonathan M.; Sato, Miwa; Li, Liangzhu; Matsukawa, Akihiro; Wang, Ji Ming.

In: Frontiers in Immunology, Vol. 7, No. JAN, 2, 2016.

Research output: Contribution to journalArticle

@article{0ed5d7cb102f4bca9c1f09c340d54762,
title = "Induction of monocyte chemoattractant proteins in macrophages via the production of granulocyte/macrophage colony-stimulating factor by breast cancer cells",
abstract = "Monocyte chemoattractant protein-1 (MCP-1)/CCL2 plays an important role in the initiation and progression of cancer. We previously reported that in 4T1 murine breast cancer, non-tumor stromal cells, including macrophages, were the major source of MCP-1. In the present study, we analyzed the potential mechanisms by which MCP-1 is upregulated in macrophages infiltrating 4T1 tumors. We found that cell-free culture supernatants of 4T1 cells (4T1-sup) markedly upregulated MCP-1 production by peritoneal inflammatory macrophages. 4T1-sup also upregulated other MCPs, such as MCP-3/CCL7 and MCP-5/CCL12, but modestly upregulated neutrophil chemotactic chemokines, such as KC/CXCL1 or MIP-2/CXCL2. Physicochemical analysis indicated that an approximately 2-3 kDa 4T1 cell product was responsible for the capacity of 4T1-sup to upregulate MCP-1 expression by macrophages. A neutralizing antibody against granulocyte/macrophage colony-stimulating factor (GM-CSF), but not macrophage CSF, almost completely abrogated MCP-1-inducing activity of 4T1-sup, and recombinant GM-CSF potently upregulated MCP-1 production by macrophages. The expression levels of GM-CSF in 4T1 tumors in vivo were higher than other tumors, such as Lewis lung carcinoma. Treatment of mice with anti-GM-CSF antibody significantly reduced the growth of 4T1 tumors at the injection sites but did not reduce MCP-1 production or lung metastasis in tumor-bearing mice. These results indicate that 4T1 cells have the capacity to directly upregulate MCP-1 production by macrophages by releasing GM-CSF; however, other mechanisms are also involved in increased MCP-1 levels in the 4T1 tumor microenvironment.",
keywords = "Breast cancer, Chemokines, Inflammation, Monocytes/macrophages, Tumor microenvironment",
author = "Teizo Yoshimura and Tomozumi Imamichi and Weiss, {Jonathan M.} and Miwa Sato and Liangzhu Li and Akihiro Matsukawa and Wang, {Ji Ming}",
year = "2016",
doi = "10.3389/fimmu.2016.00002",
language = "English",
volume = "7",
journal = "Frontiers in Immunology",
issn = "1664-3224",
publisher = "Frontiers Media S. A.",
number = "JAN",

}

TY - JOUR

T1 - Induction of monocyte chemoattractant proteins in macrophages via the production of granulocyte/macrophage colony-stimulating factor by breast cancer cells

AU - Yoshimura, Teizo

AU - Imamichi, Tomozumi

AU - Weiss, Jonathan M.

AU - Sato, Miwa

AU - Li, Liangzhu

AU - Matsukawa, Akihiro

AU - Wang, Ji Ming

PY - 2016

Y1 - 2016

N2 - Monocyte chemoattractant protein-1 (MCP-1)/CCL2 plays an important role in the initiation and progression of cancer. We previously reported that in 4T1 murine breast cancer, non-tumor stromal cells, including macrophages, were the major source of MCP-1. In the present study, we analyzed the potential mechanisms by which MCP-1 is upregulated in macrophages infiltrating 4T1 tumors. We found that cell-free culture supernatants of 4T1 cells (4T1-sup) markedly upregulated MCP-1 production by peritoneal inflammatory macrophages. 4T1-sup also upregulated other MCPs, such as MCP-3/CCL7 and MCP-5/CCL12, but modestly upregulated neutrophil chemotactic chemokines, such as KC/CXCL1 or MIP-2/CXCL2. Physicochemical analysis indicated that an approximately 2-3 kDa 4T1 cell product was responsible for the capacity of 4T1-sup to upregulate MCP-1 expression by macrophages. A neutralizing antibody against granulocyte/macrophage colony-stimulating factor (GM-CSF), but not macrophage CSF, almost completely abrogated MCP-1-inducing activity of 4T1-sup, and recombinant GM-CSF potently upregulated MCP-1 production by macrophages. The expression levels of GM-CSF in 4T1 tumors in vivo were higher than other tumors, such as Lewis lung carcinoma. Treatment of mice with anti-GM-CSF antibody significantly reduced the growth of 4T1 tumors at the injection sites but did not reduce MCP-1 production or lung metastasis in tumor-bearing mice. These results indicate that 4T1 cells have the capacity to directly upregulate MCP-1 production by macrophages by releasing GM-CSF; however, other mechanisms are also involved in increased MCP-1 levels in the 4T1 tumor microenvironment.

AB - Monocyte chemoattractant protein-1 (MCP-1)/CCL2 plays an important role in the initiation and progression of cancer. We previously reported that in 4T1 murine breast cancer, non-tumor stromal cells, including macrophages, were the major source of MCP-1. In the present study, we analyzed the potential mechanisms by which MCP-1 is upregulated in macrophages infiltrating 4T1 tumors. We found that cell-free culture supernatants of 4T1 cells (4T1-sup) markedly upregulated MCP-1 production by peritoneal inflammatory macrophages. 4T1-sup also upregulated other MCPs, such as MCP-3/CCL7 and MCP-5/CCL12, but modestly upregulated neutrophil chemotactic chemokines, such as KC/CXCL1 or MIP-2/CXCL2. Physicochemical analysis indicated that an approximately 2-3 kDa 4T1 cell product was responsible for the capacity of 4T1-sup to upregulate MCP-1 expression by macrophages. A neutralizing antibody against granulocyte/macrophage colony-stimulating factor (GM-CSF), but not macrophage CSF, almost completely abrogated MCP-1-inducing activity of 4T1-sup, and recombinant GM-CSF potently upregulated MCP-1 production by macrophages. The expression levels of GM-CSF in 4T1 tumors in vivo were higher than other tumors, such as Lewis lung carcinoma. Treatment of mice with anti-GM-CSF antibody significantly reduced the growth of 4T1 tumors at the injection sites but did not reduce MCP-1 production or lung metastasis in tumor-bearing mice. These results indicate that 4T1 cells have the capacity to directly upregulate MCP-1 production by macrophages by releasing GM-CSF; however, other mechanisms are also involved in increased MCP-1 levels in the 4T1 tumor microenvironment.

KW - Breast cancer

KW - Chemokines

KW - Inflammation

KW - Monocytes/macrophages

KW - Tumor microenvironment

UR - http://www.scopus.com/inward/record.url?scp=84958166353&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84958166353&partnerID=8YFLogxK

U2 - 10.3389/fimmu.2016.00002

DO - 10.3389/fimmu.2016.00002

M3 - Article

C2 - 26834744

AN - SCOPUS:84958166353

VL - 7

JO - Frontiers in Immunology

JF - Frontiers in Immunology

SN - 1664-3224

IS - JAN

M1 - 2

ER -