Platelet-derived nanomedicine targets cancer

In this issue of Blood, Michael et al report that microparticles produced by platelets can infiltrate tumors outside the vasculature. Microparticles transfer their microRNA cargo to tumor cells, which triggers apoptosis and thereby reduces tumor growth.¹  This study highlights a novel role of platelets, via their microparticles, in tumor pathogenesis.

Several studies suggest that platelets can contribute to tumor progression and metastasis.²  Platelet transforming growth factor β, for instance, enhances cancer cell proliferation and plays an important part in metastasis.^3,4  Moreover, platelets in circulation shield tumors from their elimination by the immune system and contribute to arrest in endothelium, a process necessary for formation of secondary lesions.^2,5 

On activation, platelets shed submicron extracellular vesicles from the plasma membrane, known as microparticles (also called microvesicles).⁶  Platelet-derived microparticles account for the majority of the microparticles present in blood and outnumber extracellular vesicles from erythrocytes by approximately twofold.⁶  The platelet microparticle cargo includes microRNA, enzymes, lipid mediators, and transcription factors, and a proportion of platelet microparticles also convey mitochondria.⁶  While the levels of microparticles in blood increase during cancer,⁶  the actual role of platelet microparticles in cancer pathogenesis remained unclear.

Herein, the authors identified 100- to 1000-nm–diameter platelet microparticles in the extravascular tumor environment. Platelet microparticles were found across different grades of tumors and in different subtypes of lung and colon cancer and were associated with tumor cells in an ectopic solid tumor allograft model in mice (see figure). The platelet integrin α_IIb was found broadly distributed at the plasma membrane of tumor cells and inside recycling endosomes, pointing to membrane fusion. No microparticles were detected in tumors of thrombocytopenic mice and mice with a deletion of the protease-activated receptor 4, a known driver of microparticle generation by platelets,⁷  further confirming that microparticles of platelet origin reach tumors in the extravascular space and are associated with tumor cells.

Platelet microparticles can transfer their cargo to endothelial cells, macrophages, and neutrophils.^6,8,9  Using a series of compelling in vitro and in vivo approaches, the authors convincingly demonstrate that tumor cells also internalize platelet-derived microRNA via infiltrating platelet microparticles and that transferred microRNA is distributed in the cytosol in the tumor cell recipient. Although several microRNA species were transferred within tumor cells, miR-24 and miR-27a were selectively transferred to tumor cells in vivo. Intriguingly, targets of miR-24 included noncanonical RNAs, such as a mitochondrial mRNA lacking a 3′ untranslated region and a noncoding small nucleolar RNA. Although the exact role of noncanonical microRNA response elements is still the subject of debate, this study further confirms their biological significance, as shown by their downregulation by miR-24 from platelet microparticles induced mitochondrial depolarization and cleavage of caspase-3 in tumor cells and reduced tumor growth in vivo. Megakaryocytes also generate microparticles and contribute to the load of microparticles present in blood.¹⁰  As the transfusion of microparticles generated by activating platelets in vitro reduced tumor growth, it confirms that platelet-derived microparticles can play a role in cancer pathogenesis.

The findings contained in this study have repercussions in the understanding of cancer pathogenesis and its relationship to platelets. While there is strong evidence that platelets contribute to the promotion of cancer,^2-5  their microparticles appear to counteract platelets by downregulating tumor cell genes and inhibiting tumor growth. The role of platelet microparticles, however, requires internalization by tumor cells and thus strictly implies that microparticles accumulate in the tumor environment. How platelet microparticles play roles beyond the vascular space was not investigated in the present study, but it might implicate leakage of the endothelial barrier, which has been described in different inflammatory contexts and enables microparticle extravasation.⁶  Furthermore, lymph, which contains platelet microparticles and drains tumors, may favor the interaction of tumor cells with microparticles.⁶  Microparticles are thought to contribute to hemostasis and the support of the coagulation cascade. Although it is unknown whether distinct populations of platelet-derived microparticles are delivered to tumors to prevent tumor growth, this important study further confirms the versatility of extracellular vesicles produced by platelets in health and disease.