Pikas survive harsh winters by reducing their metabolism to conserve energy and by eating yak feces.
Image credit: Qingsheng Chi.
Edited by Robert Langer, Massachusetts Institute of Technology, Cambridge, MA, and approved December 13, 2013 (received for review August 29, 2013)
Significance
This paper describes a unique approach to target and kill cancer cells in the bloodstream, in which the extensive surface area of circulating leukocytes is used to display the cancer-specific TNF-related apoptosis inducing ligand (TRAIL) and E-selectin adhesion receptor to the surrounding fluid. The approach is inspired by the cytotoxic activity of natural killer cells and is quite effective at killing cancer cells both in vitro with human blood samples and in mouse blood circulation. The mechanism is surprising and unexpected in that this repurposing of leukocytes in flowing blood is more effective than directly targeting the cancer cells with liposomes or soluble protein.
Abstract
Metastasis through the bloodstream contributes to poor prognosis in many types of cancer. Mounting evidence implicates selectin-based adhesive interactions between cancer cells and the blood vessel wall as facilitating this process, in a manner similar to leukocyte trafficking during inflammation. Here, we describe a unique approach to target and kill colon and prostate cancer cells in the blood that causes circulating leukocytes to present the cancer-specific TNF-related apoptosis inducing ligand (TRAIL) on their surface along with E-selectin adhesion receptor. This approach, demonstrated in vitro with human blood and also in mice, mimics the cytotoxic activity of natural killer cells and increases the surface area available for delivery of the receptor-mediated signal. The resulting “unnatural killer cells” hold promise as an effective means to neutralize circulating tumor cells that enter blood with the potential to form new metastases.
Footnotes
- ↵1To whom correspondence should be addressed. E-mail: mike.king{at}cornell.edu.
Author contributions: M.R.K. conceived of research; M.J.M., E.W., K.R., C.B.S., and M.R.K. designed research; M.J.M., E.W., and K.R. performed research; C.B.S. contributed new reagents/analytic tools; M.J.M., E.W., and K.R. analyzed data; M.J.M., E.W., C.B.S., and M.R.K. wrote the paper.
The authors declare no conflict of interest.
This article is a PNAS Direct Submission.
This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1316312111/-/DCSupplemental.
Freely available online through the PNAS open access option.
TRAIL-coated leukocytes that kill cancer cells
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