Abstract
Metastatic spread of a cancer to secondary sites is a coordinated, non-random process. Cancer cell-secreted vesicles, especially exosomes, have recently been implicated in the guidance of metastatic dissemination, with specific surface composition determining some aspects of organ-specific localization. Nevertheless, whether the tumor microenvironment influences exosome biodistribution has yet to be investigated. Here, we show that microenvironmental cytokines, particularly CCL2, decorate cancer exosomes via binding to surface glycosaminoglycan side chains of proteoglycans, causing exosome accumulation in specific cell subsets and organs. Exosome retention results in changes in the immune landscape within these organs, coupled with a higher metastatic burden. Strikingly, CCL2-decorated exosomes are directed to a subset of cells that express the CCL2 receptor CCR2, demonstrating that exosome-bound cytokines are a crucial determinant of exosome-cell interactions. In addition to the finding that cytokine-conjugated exosomes are detected in the blood of cancer patients, we discovered that healthy subjects derived exosomes are also associated with cytokines. Although displaying a different profile from exosomes isolated from cancer patients, it further indicates that specific combinations of cytokines bound to exosomes could likewise affect other physiological and disease settings.
Highlights
Metastatic spread of a cancer to secondary sites is a coordinated, non-random process
Analyzing exosomes isolated from plasma of healthy subjects and breast cancer (BC) patients (Supplementary Fig. 1 and Supplementary Table 1), we identified a number of cytokines and growth factors co-isolating with exosomes, with a greater abundance and variety found on BC patient-derived exosomes (Fig. 1a, b)
To evaluate the behavior of exosomes in such a cytokine milieu, we obtained exosome-depleted tumor interstitial fluid (TIF) from syngeneic, orthotopic EO771 cancer masses, which showed a range of cytokines and growth factors (Fig. 1e, f), including CCL2 and IL-6
Summary
Metastatic spread of a cancer to secondary sites is a coordinated, non-random process. Cancer cell-autonomous mechanisms of metastasis organotropism involve direct receptor/ligand interactions between the tumor cells and the distant organ microenvironment[13], and the preparation of pre-metastatic niches by cancer-derived exosomes in an organ-specific manner, which is partially determined by the integrin composition of the exosomes[14]. We show, using syngeneic mouse models and cancer patient samples, that tumor microenvironmental cytokines bind to cancer-derived exosomes via glycosaminoglycan (GAG) side chains of proteoglycans. These cytokine-bound exosomes are selectively taken up by cytokine-receptor-positive cells in specific tissues, resulting in changes in the immune landscape of these secondary organs, as well as in exosome biodistribution, with a consequent increase in metastasis
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
