Abstract
Crosstalk between breast cancer and macrophages has potential implications for tumor metastasis. This study investigates macrophage polarization induced by triple-negative breast cancer (TNBC) cell-derived exosomes that promote lymph node (LN) metastasis in orthotopic TNBC models. The MDA-MB-231 cancer cell line expressing the exosomal CD63-red fluorescence (RFP) fusion protein was generated to noninvasively visualize exosome transfer into cancer cells and macrophages. Administration of RFP-tagged exosomes enhanced migration of macrophages and induced macrophage polarization in vitro. In orthotopic TNBC models, noninvasive bioluminescent imaging, ultrasound-guided photoacoustic imaging, and histological analysis revealed that intravenous injection of RFP-tagged exosomes promoted primary tumor growth and axillary LN metastasis in which expression of CD206, a marker or alternatively activated type 2 (M2) macrophages, was significantly higher than expression of NOS2, a marker of classically activated type 1 (M1) macrophages. These results suggest breast cancer cell-derived exosomes stimulate macrophage polarization that creates favorable conditions for LN metastatic processes in TNBC.
Highlights
Axillary lymph node (LN) status, one of the first signs of metastatic spread, is an independent prognostic factor for all subtypes of breast cancer [1]
We demonstrate that aggressive triple-negative breast cancer (TNBC) cell (MDAMB-231)–derived exosomes function as intracellular links between cancer cells and macrophages
We demonstrated that TNBC cell–derived exosomes are a factor in www.impactjournals.com/oncotarget the induction of M2-type macrophage polarization to the benefit of breast cancer cells in vitro and in vivo, supporting enhanced tumor growth and axillary LN metastasis in an orthotopic TNBC model
Summary
Axillary lymph node (LN) status, one of the first signs of metastatic spread, is an independent prognostic factor for all subtypes of breast cancer [1]. Evidences from previous clinical studies indicate that axillary LN metastasis develops in 50% of TNBC patients, and 70% to 80% of breast cancer patients with LN metastasis experience recurrence or distant metastasis develops [3, 4]. Exosomes released from cancer cells stimulate cancer cell growth and mobility and the immune cell response in promoting cancer progression and metastasis [7, 8]. The pathological function of cancer-derived exosomes in cancer progression and metastasis includes modifying the immune cell response at both local and distant sites
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