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Platelet microparticles infiltrating solid tumors transfer miRNAs that suppress tumor growth.

James V. Michael, Jeremy G.T. Wurtzel, Guang Fen Mao, A. Koneti Rao, Mikhail A. Kolpakov, Abdelkarim Sabri, Nicholas E. Hoffman, Sudarsan Rajan, Dhanendra Tomar, Muniswamy Madesh, Marvin T. Nieman, Johnny Yu, Leonard C. Edelstein, Jesse W. Rowley, Andrew S. Weyrich and Lawrence E. Goldfinger

Key points

  • Platelet microparticles infiltrate solid tumors and transfer platelet-derived miRNAs to tumor cells within solid tumors in vivo.

  • Transfer of platelet miRNAs to tumor cells results in downregulation of tumor cell genes and inhibition of solid tumor growth.

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, 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 non-coding small nucleolar RNA. These RNAs were suppressed in PMP-treated tumor cells, resulting in mitochondrial dysfunction and growth inhibition, in a miR-24-dependent manner. Thus, platelet-derived miRNAs transfer in vivo to tumor cells in solid tumors via infiltrating microparticles, regulate tumor cell gene expression, and modulate tumor progression. These findings shed novel insight into mechanisms of horizontal RNA transfer and add multiple layers to the regulatory roles of miRNAs and PMPs in tumor progression. Plasma microparticle-mediated transfer of regulatory RNAs and modulation of gene expression may be a common feature with important outcomes in contexts of enhanced vascular permeability.

  • Submitted November 18, 2016.
  • Accepted May 8, 2017.