Abstract
Tumor-derived exosomes are being recognized as essential mediators of intercellular communication between cancer and immune cells. It is well established that bone marrow-derived macrophages (BMDMs) take up tumor-derived exosomes. However, the functional impact of these exosomes on macrophage phenotypes is controversial and not well studied. Here, we show that breast cancer-derived exosomes alter the phenotype of macrophages through the interleukin-6 (IL-6) receptor beta (glycoprotein 130, gp130)-STAT3 signaling pathway. Addition of breast cancer-derived exosomes to macrophages results in the activation of the IL-6 response pathway, including phosphorylation of the key downstream transcription factor STAT3. Exosomal gp130, which is highly enriched in cancer exosomes, triggers the secretion of IL-6 from BMDMs. Moreover, the exposure of BMDMs to cancer-derived exosomes triggers changes from a conventional toward a polarized phenotype often observed in tumor-associated macrophages. All of these effects can be inhibited through the addition of a gp130 inhibitor to cancer-derived exosomes or by blocking BMDMs exosome uptake. Collectively, this work demonstrates that breast cancer-derived exosomes are capable of inducing IL-6 secretion and a pro-survival phenotype in macrophages, partially via gp130/STAT3 signaling.
Highlights
Breast cancer is the second most frequently diagnosed cancer type for females worldwide, accounting for approximately 1.67 million cases per year [1]
This study reveals that IL-6 receptor gp130 is contained in breast cancer cell-derived exosomes and stimulates STAT3 signaling in bone marrow-derived macrophages (BMDMs)
The role cancer-derived exosomes play on the modulation of bone marrow mesenchymal stromal cells has been previously studied in a neuroblastoma model, and ERK1/2 described to control the level of IL-6 and IL-8/CXCL8 [44]
Summary
Breast cancer is the second most frequently diagnosed cancer type for females worldwide, accounting for approximately 1.67 million cases per year [1]. The primary cause of mortality in breast cancer patients is caused by the spread of tumor cells to other organs such as lung [2], brain [3], and bone [4]. Small vesicles released by cancerous cells, termed as exosomes, were described to be markers, mediators, and inducers of metastasis [5]. Bilipid vesicles that exhibit a size distribution of 30–150 nm, sediments at 100,000 g, and have a specific density of 1.13–1.19 g/mL [6,7,8]. In contrast to other vesicles, exosomes are secreted after fusion of multivesicular bodies with the plasma membrane, resulting in proteins involved in this process to be uniquely associated with exosomes [9]. Exosomes derived from diverse types of cancer
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