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Apoptotic Extracellular Vesicles Ameliorate Multiple Myeloma by Restoring Fas-Mediated Apoptosis
Juan Wang1, Zeyuan Cao1, Panpan Wang1
1South China Center of Craniofacial Stem Cell Research, Hospital of Stomatology, Sun Yat-sen University, Guangdong Provincial Key Laboratory of Stomatology, Guangzhou 510080, China.
Abstract:
Apoptosis is critical for maintaining bodily homeostasis and produces a large number of apoptotic extracellular vesicles (apoEVs). Several types of cancer cells display reduced expression of Fas on the cell surface and are thus capable of escaping Fas ligand-induced apoptosis. However, it is unknown whether normal cell-derived apoEVs can regulate tumor growth. In this study, we show that apoEVs can induce multiple myeloma (MM) cell apoptosis and inhibit MM cell growth. Systemic infusion of mesenchymal stem cell (MSC)-derived apoEVs significantly prolongs the lifespan of MM mice. Mechanistically, apoEVs directly contact MM cells to facilitate Fas trafficking from the cytoplasm to the cell membrane by evoking Ca2+ influx and elevation of cytosolic Ca2+. Subsequently, apoEVs use their Fas ligand to activate the Fas pathway in MM cells, leading to the initiation of apoptosis. This study identifies the role of apoEVs in inducing MM apoptosis and suggests a potential for apoEVs to treat MM.
Insights
Normal cell-derived apoptotic extracellular vesicles (apoEVs) can induce apoptosis and inhibit growth in multiple myeloma (MM) cells. Mesenchymal stem cell (MSC)-derived apoEVs prolong survival in MM mice, offering a potential new MM therapy.
Area of Science:
- Cell Biology
- Immunology
- Oncology
Background:
- Apoptosis is essential for homeostasis and generates apoptotic extracellular vesicles (apoEVs).
- Cancer cells can evade apoptosis by downregulating cell surface Fas.
- The role of normal cell-derived apoEVs in regulating tumor growth is not well understood.
Purpose of the Study:
- To investigate whether normal cell-derived apoEVs can induce apoptosis and inhibit multiple myeloma (MM) cell growth.
- To explore the therapeutic potential of mesenchymal stem cell (MSC)-derived apoEVs in MM.
Main Methods:
- Systemic infusion of MSC-derived apoEVs into MM mice.
- Analysis of apoEV interaction with MM cells, including Fas trafficking and Ca2+ signaling.
- Assessment of MM cell apoptosis and tumor growth inhibition.
Main Results:
- MSC-derived apoEVs significantly prolonged the lifespan of MM mice.
- apoEVs induced apoptosis and inhibited growth of MM cells.
- Mechanistically, apoEVs facilitate Fas trafficking to the cell membrane, activate the Fas pathway, and induce apoptosis in MM cells.
Conclusions:
- Normal cell-derived apoEVs can induce apoptosis and inhibit MM cell growth.
- MSC-derived apoEVs demonstrate therapeutic potential for treating MM.
- apoEVs represent a promising new avenue for MM treatment strategies.
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