TY - JOUR
T1 - Platelet microparticles infiltrating solid tumors transfer miRNAs that suppress tumor growth
AU - Michael, James V.
AU - Wurtzel, Jeremy G.T.
AU - Mao, Guang Fen
AU - Rao, A. Koneti
AU - Kolpakov, Mikhail A.
AU - Sabri, Abdelkarim
AU - Hoffman, Nicholas E.
AU - Rajan, Sudarsan
AU - Tomar, Dhanendra
AU - Madesh, Muniswamy
AU - Nieman, Marvin T.
AU - Yu, Johnny
AU - Edelstein, Leonard C.
AU - Rowley, Jesse W.
AU - Weyrich, Andrew S.
AU - Goldfinger, Lawrence E.
N1 - Publisher Copyright:
© 2017 by The American Society of Hematology.
PY - 2017/8/3
Y1 - 2017/8/3
N2 - 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 wasa 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 byPMPs.Conversely, Par4-deleted mice, whichhad 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.
AB - 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 wasa 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 byPMPs.Conversely, Par4-deleted mice, whichhad 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.
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UR - http://www.scopus.com/inward/citedby.url?scp=85026750320&partnerID=8YFLogxK
U2 - 10.1182/blood-2016-11-751099
DO - 10.1182/blood-2016-11-751099
M3 - Article
C2 - 28500171
AN - SCOPUS:85026750320
SN - 0006-4971
VL - 130
SP - 567
EP - 580
JO - Blood
JF - Blood
IS - 5
ER -