Crosstalk between Cancer Cells and Fibroblasts for the Production of Monocyte Chemoattractant Protein-1 in the Murine 4T1 Breast Cancer.

Masayoshi Fujisawa,Tiantian Li,Chunning Li,Naofumi Mukaida,Teizo Yoshimura,Mayu Imamura,Akihiro Matsukawa

doi:10.3390/cimb43030122

Masayoshi Fujisawa, Tiantian Li

Open Access

https://doi.org/10.3390/cimb43030122

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Abstract

The chemokine monocyte chemoattractant protein-1 (MCP-1/CCL2) is shown to promote the progression of breast cancer. We previously identified cancer cell-derived granulocyte-macrophage colony-stimulating factor (GM-CSF) as a potential regulator of MCP-1 production in the murine 4T1 breast cancer, but it played a minimum role in overall MCP-1 production. Here, we evaluated the crosstalk between 4T1 cells and fibroblasts. When fibroblasts were co-cultured with 4T1 cells or stimulated with the culture supernatants of 4T1 cells (4T1-sup), MCP-1 production by fibroblasts markedly increased. 4T1 cells expressed mRNA for platelet-derived growth factor (PDGF)-a, b and c, and the PDGF receptor inhibitor crenolanib almost completely inhibited 4T1-sup-induced MCP-1 production by fibroblasts. However, PDGF receptor antagonists failed to reduce MCP-1 production in tumor-bearing mice. Histologically, 4T1 tumors contained a small number of αSMA-positive fibroblasts, and Mcp-1 mRNA was mainly associated with macrophages, especially those surrounding necrotic lesions on day 14, by in situ hybridization. Thus, although cancer cells have the capacity to crosstalk with fibroblasts via PDGFs, this crosstalk does not play a major role in MCP-1 production or cancer progression in this model. Unraveling complex crosstalk between cancer cells and stromal cells will help us identify new targets to help treat breast cancer patients.

Highlights

Breast cancer is the most common cancer in women, and the majority of breast cancer-related deaths are caused by metastasis [1]
To examine the presence of crosstalk between 4T1 cells and fibroblasts that may contribute to the production of monocyte chemoattractant protein-1 (MCP-1) in 4T1 tumors, we cultured 4T1 cells and NIH/3T3 fibroblasts separately or together for 4 days in tissue culture plates and measured the concentration of MCP-1 in the supernatants. 3T3 cells constitutively released a basal level of MCP-1, and approximately 2.1 ng/mL of MCP-1 was detected in the 3T3 cell supernatant
We aimed to identify whether fibroblasts crosstalk with 4T1 breast cancer cells to produce MCP-1 in the tumor microenvironments (TMEs) [12]

Summary

Introduction

Breast cancer is the most common cancer in women, and the majority of breast cancer-related deaths are caused by metastasis [1]. A better understanding of the mechanisms that drive breast cancer metastasis is crucial to identifying novel biomarkers and therapeutic targets for breast cancer [1]. The murine 4T1 breast cancer is a triple-negative (TN) subtype of breast cancer and a subclone of the original mammary tumor that arose in a BALB/c mouse foster-nursed by a C3H female mouse [2,3]. Unlike other transplantable cancer models, 4T1 cells consist of heterogenous clonal subpopulations with different morphology, behaviors and gene expression profiles [5]. These unique features of 4T1 cells make them a terrific model to analyze the complex mechanisms involved in the lung metastasis of breast cancer cells

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