Abstract
Exosomes—small membrane vesicles secreted by both normal and malignant cells upon fusion of endosomal multivesicular bodies (MVBs) with the plasma membrane—play an important role in cell-to-cell communication. During the last decade, several reports have highlighted the involvement of these nanovesicles in many aspects of breast cancer development and progression, but the extracellular signals governing their generation in breast cancer cells have not been completely unraveled. Here, we investigated the role of the obesity hormone leptin, a well-known adipokine implicated in mammary tumorigenesis, on the mechanisms regulating exosome biogenesis and release in both estrogen receptor α (ERα)—positive MCF-7 and triple-negative MDA-MB-231 breast cancer cells. We found that leptin treatment enhanced the number of MVBs in the cytoplasm of breast cancer cells and increased the amount of exosomes released in cell conditioned media. At molecular level, leptin increased the protein expression of Tsg101—a key component of the endosomal sorting complex required for transport I (ESCRT-I)—by a post-transcriptional mechanism involving its direct interaction with the chaperone protein Hsp90. Targeting leptin signaling, by a selective leptin receptor antagonist the peptide LDFI (Leu-Asp-Phe-Ile), abrogated leptin effects on Tsg101 expression and on exosome secretion in breast cancer cells. In conclusion, our findings, identifying for the first time leptin/leptin receptor/Hsp90 axis as an important regulator of exosome generation in mammary carcinoma cells, suggest that targeting this signaling pathway might represent a novel therapeutic strategy to impair exosome secretion and interrupt the dangerous cell-to-cell communication in breast cancer.
Highlights
Cell-to-cell communication represents a crucial biological process governing the key events responsible of breast cancer development and progression
To investigate the potential involvement of the obesity hormone leptin on exosome generation in breast cancer cells, we evaluated whether leptin may affect these organelles at the ultrastructural level by transmission electron microscopy (TEM) in both ER-positive MCF-7 and triple-negative MDA-MB-231 breast cancer cells
To determine if this event might result in an increased number of exosomes released by breast cancer cells, we characterized exosomes isolated in conditioned media of breast cancer cells maintained in the presence of exosome-depleted FBS to avoid the collecting of contaminating vesicles from fetal bovine serum
Summary
Cell-to-cell communication represents a crucial biological process governing the key events responsible of breast cancer development and progression. In the last decades, an additional mechanism represented by the release of membrane-derived vesicles, able to transfer bioactive molecules and signals to both neighboring and distant cells, has been described [1]. Exosomes derived by breast cancer cells lead to induction of reactive oxygen species, autophagy and DNA damage repair response in normal human primary mammary epithelial cells, resulting in the creation of a tumor permissive niche [7]. It has been demonstrated that metastasis establishment and resistance to antitumor therapies can be mediated by horizontal transfer of exosome cargo in recipient sensitive cells. Tumor exosomes might help occurrence of chemotherapy resistance by facilitating drug export outside the cells or delivering P-glycoprotein from docetaxel-resistant cells [9], or might contribute to HER2 target therapy failure by directly binding Trastuzumab and interfering with its antitumor activities [10]. Breast cancer-derived exosomes exert a broad array of effects on tumor microenvironment, by inducing mesenchymal stem cell differentiation into cancer-associated fibroblasts (CAFs) [11], by increasing fibroblast proliferation and lifespan [12], destroying vascular endothelial barriers [13], and impairing the immune response [14,15]
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