title: Genetic engineering of platelets to neutralize circulating tumor cells.
abstract: Mounting experimental evidence demonstrates that platelets support cancer metastasis. Within the circulatory system, platelets guard circulating tumor cells (CTCs) from immune elimination and promote their arrest at the endothelium, supporting CTC extravasation into secondary sites. Neutralization of CTCs in blood circulation can potentially attenuate metastases to distant organs. Therefore, extensive studies have explored the blockade of platelet-CTC interactions as an anti-metastatic strategy. Such an intervention approach, however, may cause bleeding disorders since the platelet-CTC interactions inherently rely on the blood coagulation cascade including platelet activation. On the other hand, platelets have been genetically engineered to correct inherited bleeding disorders in both animal models and human clinical trials. In this study, inspired by the physical association between platelets and CTCs, platelets were genetically modified to express surface-bound tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), a cytokine known to induce apoptosis specifically in tumor cells. The TRAIL-expressing platelets were demonstrated to kill cancer cells in vitro and significantly reduce metastases in a mouse model of prostate cancer metastasis. Our results suggest that using platelets to produce and deliver cancer-specific therapeutics can provide a Trojan-horse strategy of neutralizing CTCs to attenuate metastasis.
authors.affiliation: Meinig School of Biomedical Engineering, Cornell University, Ithaca, NY 14853, USA.
authors.forename: Jiahe
authors.initials: J
authors.lastname: Li
authors.affiliation: Meinig School of Biomedical Engineering, Cornell University, Ithaca, NY 14853, USA.
authors.forename: Charles C
authors.initials: CC
authors.lastname: Sharkey
authors.affiliation: Meinig School of Biomedical Engineering, Cornell University, Ithaca, NY 14853, USA.
authors.forename: Brittany
authors.initials: B
authors.lastname: Wun
authors.affiliation: Department of Medicine, Hematology/Oncology (SMD), University of Rochester Medical Center, School of Medicine and Dentistry, Rochester, NY 14642, USA.
authors.forename: Jane L
authors.initials: JL
authors.lastname: Liesveld
authors.affiliation: Meinig School of Biomedical Engineering, Cornell University, Ithaca, NY 14853, USA. Electronic address: mike.king@cornell.edu.
authors.forename: Michael R
authors.initials: MR
authors.lastname: King
mesh_terms: D000818:Animals; D001792:Blood Platelets / Q000166:cytology / Q000378:metabolism / Q000473:pathology*; D002454:Cell Differentiation; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D015870:Gene Expression; D005818:Genetic Engineering / Q000379:methods*; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000378:metabolism; D006801:Humans; D008297:Male; D008533:Megakaryocytes / Q000166:cytology / Q000378:metabolism / Q000637:transplantation; D008810:Mice, Inbred C57BL; D009362:Neoplasm Metastasis / Q000235:genetics / Q000473:pathology / Q000628:therapy*; D009360:Neoplastic Cells, Circulating / Q000473:pathology*; D011467:Prostate / Q000473:pathology; D011471:Prostatic Neoplasms / Q000235:genetics / Q000473:pathology / Q000628:therapy*; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000235:genetics*; D014161:Transduction, Genetic / Q000379:methods
chemical_list: D053221:TNF-Related Apoptosis-Inducing Ligand
keywords: Cancer therapy; Circulating tumor cells; Metastasis; Platelet