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Platelet microparticles infiltrating solid tumors transfer miRNAs that suppress tumor growth
James V Michael1,2, Jeremy G T Wurtzel1,2, Guang Fen Mao2
1Department of Anatomy & Cell Biology.
Abstract:
Platelet-derived microparticles (PMPs) are associated with enhancement of metastasis and poor cancer outcomes. Circulating PMPs transfer platelet microRNAs (miRNAs) to vascular cells. Solid tumor vasculature is highly permeable, allowing the possibility of PMP-tumor cell interaction. Here, we show that PMPs infiltrate solid tumors in humans and mice and transfer platelet-derived RNA, including miRNAs, to tumor cells in vivo and in vitro, resulting in tumor cell apoptosis. MiR-24 was a major species in this transfer. PMP transfusion inhibited growth of both lung and colon carcinoma ectopic tumors, whereas blockade of miR-24 in tumor cells accelerated tumor growth in vivo, and prevented tumor growth inhibition by PMPs. Conversely, Par4-deleted mice, which had reduced circulating microparticles (MPs), supported accelerated tumor growth which was halted by PMP transfusion. PMP targeting was associated with tumor cell apoptosis in vivo. We identified direct RNA targets of platelet-derived miR-24 in tumor cells, which included mitochondrial mt-Nd2, and Snora75, a noncoding small nucleolar RNA. These RNAs were suppressed in PMP-treated tumor cells, resulting in mitochondrial dysfunction and growth inhibition, in an miR-24-dependent manner. Thus, platelet-derived miRNAs transfer in vivo to tumor cells in solid tumors via infiltrating MPs, regulate tumor cell gene expression, and modulate tumor progression. These findings provide novel insight into mechanisms of horizontal RNA transfer and add multiple layers to the regulatory roles of miRNAs and PMPs in tumor progression. Plasma MP-mediated transfer of regulatory RNAs and modulation of gene expression may be a common feature with important outcomes in contexts of enhanced vascular permeability.
Insights
Platelet-derived microparticles (PMPs) transfer microRNAs to tumor cells, inducing apoptosis and inhibiting tumor growth. This study reveals a novel mechanism of horizontal RNA transfer impacting cancer progression.
Area of Science:
- Oncology
- Molecular Biology
- Cell Biology
Background:
- Platelet-derived microparticles (PMPs) are linked to increased metastasis and poor cancer prognosis.
- PMPs facilitate the transfer of platelet microRNAs (miRNAs) to vascular and potentially tumor cells.
- Solid tumor vasculature's permeability suggests PMP-tumor cell interactions are possible.
Purpose of the Study:
- To investigate the infiltration of PMPs into solid tumors and their RNA transfer to tumor cells.
- To determine the functional impact of platelet-derived miRNAs delivered by PMPs on tumor cell apoptosis and growth.
- To identify specific miRNA targets within tumor cells and elucidate the mechanisms of tumor suppression.
Main Methods:
- In vivo and in vitro experiments using human and mouse models of solid tumors.
- Analysis of PMP infiltration, RNA transfer, and gene expression changes in tumor cells.
- Assessment of tumor growth inhibition following PMP transfusion or miR-24 blockade.
- Identification of direct RNA targets of miR-24 in tumor cells.
Main Results:
- PMPs infiltrate solid tumors and transfer platelet-derived RNA, including miR-24, to tumor cells, inducing apoptosis.
- PMP transfusion inhibited lung and colon carcinoma growth; miR-24 blockade accelerated tumor growth.
- Mice with reduced circulating microparticles showed accelerated tumor growth, which PMP transfusion halted.
- Platelet-derived miR-24 directly targeted and suppressed mitochondrial (mt-Nd2) and noncoding RNA (Snora75) in tumor cells, causing dysfunction and growth inhibition.
Conclusions:
- Platelet-derived miRNAs are transferred to tumor cells within solid tumors via infiltrating PMPs, regulating gene expression and tumor progression.
- This horizontal RNA transfer mechanism offers novel insights into miRNA and PMP roles in cancer.
- Plasma microparticle-mediated regulatory RNA transfer may be a common pathway influencing outcomes in diseases with increased vascular permeability.
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