A Paracrine Loop between Tumor Cells and Macrophages Is Required for Tumor Cell Migration in Mammary Tumors

TLDR

Invasion of breast tumor cells into surrounding tissue and vessels is a key step in metastasis, yet the mechanistic link to macrophage presence remains unclear. Using a chemotaxis‑based in vivo invasion assay and multiphoton intravital imaging, the study shows that macrophage–tumor cell interactions promote carcinoma cell migration within the primary tumor. EGF or CSF‑1 gradients recruit tumor cells and macrophages to microneedles, and inhibition of either pathway reduces their migration, providing the first direct evidence of a synergistic macrophage–tumor cell interaction that may drive metastasis.

Abstract

Abstract Invasion of tumor cells into the surrounding connective tissue and blood vessels is a key step in the metastatic spread of breast tumors. Although the presence of macrophages in primary tumors is associated with increased metastatic potential, the mechanistic basis for this observation is unknown. Using a chemotaxis-based in vivo invasion assay and multiphoton-based intravital imaging, we show that the interaction between macrophages and tumor cells facilitates the migration of carcinoma cells in the primary tumor. Gradients of either epidermal growth factor (EGF) or colony-stimulating factor 1 (CSF-1) stimulate collection into microneedles of tumor cells and macrophages even though tumor cells express only EGF receptor and macrophages express only CSF-1 receptor. Intravital imaging shows that macrophages and tumor cells migrate toward microneedles containing either EGF or CSF-1. Inhibition of either CSF-1– or EGF-stimulated signaling reduces the migration of both cell types. This work provides the first direct evidence for a synergistic interaction between macrophages and tumor cells during cell migration in vivo and indicates a mechanism for how macrophages may contribute to metastasis.