Unnatural killer cells to prevent bloodborne metastasis: inspiration from biology and engineering

Abstract

Metastasis contributes to over 90% of cancer-related deaths. Many types of cancer metastasize via the bloodstream, where circulating tumor cells (CTCs) originating from the primary tumor can undergo selectin-mediated adhesion with the blood vessel wall and subsequently transmigrate to anatomically distant organs. In an effort to neutralize CTCs with the potential to form metastases, a new therapeutic approach has been developed in which circulating leukocytes are functionalized to target and kill cancer cells in the bloodstream. This approach mimics the cytotoxic activity of natural killer cells and the chemical engineering concept of a fluidized bed reactor, which increases the surface area for surface-catalyzed reactions. The resulting 'unnatural killer cells', proven effective in vitro with human blood and also in the living mouse, holds promise in neutralizing CTCs to interrupt the metastasis process.

Keywords: E-selectin; TRAIL; circulating tumor cells; leukocyte.

Figure 1. Schematic of the two-step mechanism utilizing UnKs to target and induce circulating tumor cell apoptosis in the bloodstream

(A) Upon injection into the bloodstream, leukocytes possessing E-selectin ligands adhesively interact with ES/TRAIL liposomes to form UnKs. (B) UnKs then contact CTC and activate death receptors via TRAIL, to induce CTC apoptosis. ES: E-selectin; TRAIL: TNF-related apoptosis-inducing ligand; UnKs: Unnatural killer cells. Adapted from [13].