Abstract
Although the presence of macrophages in tumors has been correlated with poor prognosis, until now there was no direct observation of how macrophages are involved in hematogenous metastasis. In this study, we use multiphoton microscopy to show, for the first time, that tumor cell intravasation occurs in association with perivascular macrophages in mammary tumors. Furthermore, we show that perivascular macrophages of the mammary tumor are associated with tumor cell intravasation in the absence of local angiogenesis. These results show that the interaction between macrophages and tumor cells lying in close proximity defines a microenvironment that is directly involved in the intravasation of cancer cells in mammary tumors.
Highlights
The tumor microenvironment plays a critical role in tumor growth and metastasis, and the stromal cells of the microenvironment are believed to directly affect the ability of tumor cells to metastasize [1,2,3]
Using an in vivo invasion assay, involving the direct collection of invasive tumor cells into microneedles placed into the primary tumor, and multiphoton imaging, we have described a paracrine interaction between carcinoma cells and macrophages that functions in mammary tumors that is responsible for the migration of invasive tumor cells
Macrophages were visualized using (a) i.v. injected Texas red-dextran, where tumorassociated macrophages are identified by their ability to phagocytose i.v. injected dextrans (Fig. 1A and C; Supplementary Fig. S1; ref. 28); (b) MMTV-PyMT/lys-GFPKi mice, in which the macrophages and neutrophils express green fluorescent protein (GFP) driven by the lys promoter (Fig. 1B, top); and (c) c-fms (CSF-1R) promoter-driven GFP-expressing mice, in which monocytes and macrophages express GFP driven by the c-fms promoter (Fig. 1B, bottom; ref. 16, 17)
Summary
The tumor microenvironment plays a critical role in tumor growth and metastasis, and the stromal cells of the microenvironment are believed to directly affect the ability of tumor cells to metastasize [1,2,3]. For testing the chemotactic response of dextran-loaded macrophages, Texas red-dextran was injected via tail vein 2 h before cell collection in both CAG-CAT-EGFP/MMTV-PyMT and MMTV-PyMT/c-fms-GFP mice.
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