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.

EMT: Present and future in clinical oncology

“…These CTC clusters may represent collective migration of cells, some of which retain epithelial characteristics endowing phenotypic advantage to rapidly grow macrometastasis at target organs (Diepenbruck and Christofori, ). Alternatively, CTC clusters can correspond to the association of individually seeded CTCs together with blood platelets that are indeed emerging as key regulators of EMT and tumor cell survival during their blood dissemination (Labelle et al ., ; Leblanc and Peyruchaud, ; Takemoto et al ., ) in addition to potential therapeutic targets (Li et al ., ,b; Roop et al ., ).…”

The Promise of Circulating Tumor Cells for Precision Cancer Therapy

“…TNF-related apoptosis-inducing ligand (TRAIL) is a cytokine known to induce apoptosis specifically in tumor cells. Using synthetic silica particles functionalized with activated platelet membrane with surface conjugation of TRAIL or platelets genetically modified to express surface-bound TRAIL, Li and colleagues demonstrated selective killing of cancer cells in vitro and a significant metastatic reduction in mouse models of prostate and breast cancer metastasis [158,159]. This is the first demonstration of a Trojan-horse approach to neutralize CTCs and attenuate future science group…”

The Role of Circulating Tumor Cells in the Metastatic Cascade: Biology, Technical Challenges, and Clinical Relevance

“…Disrupting CTC-platelet interaction by blocking platelet function using drug-loaded liposomes conjugated to a tumor-homing pentapeptide (CREKA) could inhibit tumor metastasis formation [196]. However, this approach could also impair platelet normal hemostatic function [197]. Alternatively, TRAIL-expressing platelets could be engineered to kill DR-expressing CTCs and reduce metastasis formation [197].…”

“…However, this approach could also impair platelet normal hemostatic function [197]. Alternatively, TRAIL-expressing platelets could be engineered to kill DR-expressing CTCs and reduce metastasis formation [197].…”