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.
Highlights
We have shown that in mammary tumors derived from the expression of the Polyomavirus middle T oncogene (PyMT) oncogene in mice and in rats and severe combined immunodeficiency mice injected orthotopically with carcinoma cell lines, a paracrine loop operates involving the interaction of carcinoma cells and macrophages
In response to needles containing either epidermal growth factor (EGF) or colony-stimulating factor 1 (CSF-1), only carcinoma cells and macrophages are collected. This is a true paracrine loop requiring the activity of the EGF and CSF-1 receptors on separate cell types because CSF-1 receptors are expressed only on macrophages and EGF receptors are expressed only on carcinoma cells, and inhibition of collection of both cell types results from inhibition of either receptor type
The use of either CSF-1 or EGF in the collection needle may mimic a process in which CSF-1 secreted by carcinoma cells leads to the activation of macrophages to secrete EGF receptor ligands, leading to stimulation of carcinoma cell movement
Summary
To image and measure migration and chemotaxis at the cellular that chemotaxis by carcinoma cells in the primary tumor is an important step in invasion In this assay, cells are collected by chemotaxis from live primary tumors in rats using microneedles filled with Matrigel and containing growth factors to mimic chemotactic signals that may be present in the primary tumor [23]. Transgenic mice selectively expressing PyMT in the mammary epithelium, under control of the mouse mammary tumor virus (MMTV) promoter, rapidly develop multifocal mammary adenocarcinomas [25] Using this approach, we have identified a paracrine interaction involving reciprocal signaling between carcinoma cells and macrophages involving EGF receptor ligands and the macrophage growth factor colony-stimulating factor 1 (CSF-1). Level within primary metastatic tumors, we have developed animal models that allow direct examination, by intravital imaging, of the behavior of Green Fluorescent Protein (GFP)-expressing carcinoma
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