1. Tumor microenvironmental cytokines bound to cancer exosomes determine uptake by cytokine receptor-expressing cells and biodistribution
- Author
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Luize G. Lima, Belinda Yeo, Yeonho Choi, Richard J. Lobb, Sunyoung Ham, Alexandra F. Müller, Hyunku Shin, Suresh Mathivanan, Belinda S. Parker, Erica S. H. Lek, Andreas Möller, and Edna Pei Zhi Chai
- Subjects
0301 basic medicine ,CCR2 ,Receptors, CCR2 ,Science ,T-Lymphocytes ,General Physics and Astronomy ,Breast Neoplasms ,Biology ,Exosomes ,Exosome ,Article ,General Biochemistry, Genetics and Molecular Biology ,Metastasis ,Mice ,03 medical and health sciences ,Breast cancer ,0302 clinical medicine ,Immune system ,Tumor Microenvironment ,medicine ,Animals ,Humans ,Neoplasm Metastasis ,Receptors, Cytokine ,Receptor ,Lung ,Chemokine CCL2 ,Glycosaminoglycans ,Uncategorized ,Tumor microenvironment ,Multidisciplinary ,Macrophages ,Cancer ,General Chemistry ,medicine.disease ,Microvesicles ,Killer Cells, Natural ,Mice, Inbred C57BL ,030104 developmental biology ,Liver ,030220 oncology & carcinogenesis ,Cancer research ,Cytokines ,Female ,Proteoglycans ,Cytokine receptor ,Spleen - 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., Cancer derived exosomes are reported to promote metastatic dissemination. Here the authors show that cytokines in the tumor microenvironment bind to exosomes via glycosaminoglycan side chains of proteoglycans, and these exosomes are preferentially taken up by specific cell lineages and organs to promote metastasis.
- Published
- 2021