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Published on: December 5, 2018
Potential Resistance to Antineoplastic Aminated Fullerenes Mediated by M2-Like Monocyte-Derived Exosomes
Jiawei Huo1,2, Wei Zhou1, Yang Liu1,2
1Beijing National Research Center for Molecular Sciences, Key Laboratory of Molecular Nanostructure and Nanotechnology, Institute of Chemistry, Chinese Academy of Science, Beijing, China.
Abstract:
Exosomes are small extracellular vesicles critical for intercellular signaling via their delivery of cargoes, including proteins, DNA, RNA, lipids, and metabolites. Exosomes play essential roles in remodeling the tumor microenvironment (TME) for tumor growth, metastasis, and drug resistance. Aminated fullerenes (e.g., C70-ethylenediamine [EDA]) exhibit antineoplastic effects by targeting multiple functional proteins. Nanosized C70-EDA with positive surface charges tends to be taken up by monocytes in the bloodstream and monocyte-derived macrophages in the TME. Herein, the alterations of monocytes and monocyte-derived exosomes by C70-EDA have been investigated. C70-EDA reprogramed THP-1 monocyte to an M2-like state and substantially increased the protein content in exosomes secreted by M2-like monocytes. Notably, C70-EDA-induced M2-like monocytes released exosomes that triggered the proliferation of recipient tumor cells, which may alleviate the antineoplastic efficacy of C70-EDA. As revealed by proteomic profiling of exosomes, this outcome is probably a result of Rho GTPase/p21-activated kinase (PAK) pathway activation in recipient tumor cells induced by upregulated exosomal proteins. This work indicates a promising strategy in which aminated fullerenes can be combined with PAK inhibitors for cancer therapy.
Insights
Aminated fullerenes alter monocytes, increasing tumor-promoting exosomes. Combining aminated fullerenes with PAK inhibitors may enhance cancer therapy by blocking this exosome-mediated tumor cell proliferation.
Area of Science:
- Nanomedicine
- Cancer Biology
- Cellular Communication
Background:
- Exosomes mediate intercellular signaling and influence the tumor microenvironment (TME).
- Aminated fullerenes, like C70-ethylenediamine (EDA), show anticancer properties by targeting proteins.
- Positively charged C70-EDA nanoparticles are taken up by monocytes and macrophages.
Purpose of the Study:
- To investigate how C70-EDA affects monocytes and their secreted exosomes.
- To understand the impact of C70-EDA-modified exosomes on tumor cells.
- To identify therapeutic strategies combining aminated fullerenes with other agents.
Main Methods:
- Reprogramming THP-1 monocytes to an M2-like state using C70-EDA.
- Analyzing protein content of exosomes secreted by modified monocytes via proteomic profiling.
- Assessing the effect of C70-EDA-induced exosomes on recipient tumor cell proliferation.
Main Results:
- C70-EDA induced THP-1 monocytes to adopt an M2-like phenotype.
- Exosomes from M2-like monocytes exhibited increased protein cargo.
- These exosomes promoted recipient tumor cell proliferation, potentially via Rho GTPase/p21-activated kinase (PAK) pathway activation.
Conclusions:
- C70-EDA treatment of monocytes generates exosomes that can unexpectedly stimulate tumor cell growth.
- This exosome-mediated effect may counteract the direct anticancer action of aminated fullerenes.
- Combining aminated fullerenes with PAK inhibitors presents a potential strategy to overcome this resistance mechanism in cancer therapy.
