A paracrine loop between tumor cells and macrophages is required for tumor cell migration in mammary tumors.
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.
Wyckoff
Jeffrey
J
Department of Anatomy and Structural Biology, Albert Einstein College of Medicine, Bronx, New York 10461, USA. jwyckoff@aecom.yu.edu
Wang
Weigang
W
Lin
Elaine Y
EY
Wang
Yarong
Y
Pixley
Fiona
F
Stanley
E Richard
ER
Graf
Thomas
T
Pollard
Jeffrey W
JW
Segall
Jeffrey
J
Condeelis
John
J
D000818:Animals; D002633:Chemotaxis / Q000502:physiology*; D004815:Epidermal Growth Factor / Q000378:metabolism / Q000494:pharmacology / Q000502:physiology*; D066246:ErbB Receptors / Q000096:biosynthesis / Q000378:metabolism / Q000502:physiology; D016173:Macrophage Colony-Stimulating Factor / Q000378:metabolism / Q000494:pharmacology / Q000502:physiology*; D008264:Macrophages / Q000378:metabolism / Q000473:pathology*; D008325:Mammary Neoplasms, Experimental / Q000378:metabolism / Q000473:pathology*; D008324:Mammary Tumor Virus, Mouse; D051379:Mice; D008809:Mice, Inbred C3H; D016513:Mice, SCID; D008822:Mice, Transgenic; D015398:Signal Transduction
D004815:Epidermal Growth Factor; D016173:Macrophage Colony-Stimulating Factor; D066246:ErbB Receptors