Delivery of apoptotic signal to rolling cancer cells: a novel biomimetic technique using immobilized TRAIL and E-selectin.
The survival rate for patients with metastases versus localized cancer is dramatically reduced, with most deaths being associated with the formation of secondary tumors. Circulating cancer cells interact with the endothelial lining of the vasculature via a series of adhesive interactions that facilitate tethering and firm adhesion of cancer cells in the initial steps of metastasis. TNF-related apoptosis-inducing ligand (TRAIL) holds promise as a tumor-specific cancer therapeutic, by inducing a death signal by apoptosis via the caspase pathway. In this study, we exploit this phenomenon to deliver a receptor-mediated apoptosis signal to leukemic cells adhesively rolling along a TRAIL and selectin-bearing surface. Results show that cancer cells exhibit selectin-mediated rolling in capillary flow chambers, and that the rolling velocities can be controlled by varying the selectin and selectin surface density and the applied shear stress. It was determined that a 1 h rolling exposure to a functionalized TRAIL and E-selectin surface was sufficient to kill 30% of captured cells compared to static conditions in which 4 h exposure was necessary to kill 30% of the cells. Thus, we conclude that rolling delivery is more effective than static exposure to a TRAIL immobilized surface. We have also verified that there is no significant effect of TRAIL on hematopoietic stem cells and other normal blood cells. This represents the first demonstration of a novel biomimetic method to capture metastatic cells from circulation and deliver an apoptotic signal.
Rana
Kuldeepsinh
K
Department of Biomedical Engineering, Cornell University, Ithaca, New York, USA.
Liesveld
Jane L
JL
King
Michael R
MR
D017209:Apoptosis; D040761:Biomimetic Materials / Q000627:therapeutic use*; D001854:Bone Marrow Cells / Q000166:cytology / Q000378:metabolism; D002448:Cell Adhesion; D045744:Cell Line, Tumor; D003627:Data Interpretation, Statistical; D019040:E-Selectin / Q000627:therapeutic use*; D005434:Flow Cytometry; D018922:HL-60 Cells; D006801:Humans; D055767:Immobilized Proteins; D036904:Leukocyte Rolling; D007963:Leukocytes, Mononuclear / Q000378:metabolism; D009362:Neoplasm Metastasis; D009369:Neoplasms / Q000628:therapy*; D013499:Surface Properties; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000627:therapeutic use*
D019040:E-Selectin; D055767:Immobilized Proteins; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human