title: Human umbilical cord mesenchymal stem cells delivering sTRAIL home to lung cancer mediated by MCP-1/CCR2 axis and exhibit antitumor effects.
abstract: Mesenchymal stem cells (MSCs) are believed to be a potential vehicle delivering antitumor agents for their tumor-homing capacity, while the underlying mechanism is yet to be explored. The apoptotic ligand TNF-related apoptosis-inducing ligand (TRAIL) has been suggested as a promising candidate for cancer gene therapy owing to its advantage of selectively inducing apoptosis in cancer cells while sparing normal cells. An isoleucine zipper (ISZ) added to the N-terminal of secretable soluble TRAIL (sTRAIL) can generate the trimeric form of TRAIL (ISZ-sTRAIL) and increase its antitumor potential. However, the inefficient delivery and toxicity are still obstacles for its use. In this study, the migration of human umbilical cord mesenchymal stem cells (HUMSCs) to lung cancer was observed through transwell migration assay and animal bioluminescent imaging both in vitro and in vivo. We found that the homing ability of HUMSCs was suppressed after either knocking down the expression of monocyte chemoattractant protein-1(MCP-1) in lung cancer cells or blocking CCR2 expressed on the surface of HUMSCs, indicating the important role of MCP-1/CCR2 axis in the tropism of HUMSCs to lung cancer. Furthermore, we genetically modified HUMSCs to deliver ISZ-sTRAIL to tumor sites specifically. This targeted therapeutic system exhibited promising apoptotic induction and antitumor potential in a xenograft mouse model without obvious side effects. In conclusion, HUMSCs expressing ISZ-sTRAIL might be an efficient therapeutic approach against lung cancer and MCP-1/CCR2 axis is essential for the tumor tropism of HUMSCs.
authors.affiliation: Department of Immunology, Tianjin Medical University Cancer Institute and Hospital; National Clinical Research Center of Cancer; Key Laboratory of Cancer Immunology and Biotherapy, Tianjin, 300060, China.
authors.forename: Cihui
authors.initials: C
authors.lastname: Yan
authors.affiliation: Department of Immunology, Tianjin Medical University Cancer Institute and Hospital; National Clinical Research Center of Cancer; Key Laboratory of Cancer Immunology and Biotherapy, Tianjin, 300060, China.
authors.forename: Xinmiao
authors.initials: X
authors.lastname: Song
authors.affiliation: Department of Immunology, Tianjin Medical University Cancer Institute and Hospital; National Clinical Research Center of Cancer; Key Laboratory of Cancer Immunology and Biotherapy, Tianjin, 300060, China.
authors.forename: Wenwen
authors.initials: W
authors.lastname: Yu
authors.affiliation: Department of Immunology, Tianjin Medical University Cancer Institute and Hospital; National Clinical Research Center of Cancer; Key Laboratory of Cancer Immunology and Biotherapy, Tianjin, 300060, China.
authors.forename: Feng
authors.initials: F
authors.lastname: Wei
authors.affiliation: Department of Immunology, Tianjin Medical University Cancer Institute and Hospital; National Clinical Research Center of Cancer; Key Laboratory of Cancer Immunology and Biotherapy, Tianjin, 300060, China.
authors.forename: Hui
authors.initials: H
authors.lastname: Li
authors.affiliation: Department of Immunology, Tianjin Medical University Cancer Institute and Hospital; National Clinical Research Center of Cancer; Key Laboratory of Cancer Immunology and Biotherapy, Tianjin, 300060, China.
authors.forename: Mengguo
authors.initials: M
authors.lastname: Lv
authors.affiliation: Department of Immunology, Tianjin Medical University Cancer Institute and Hospital; National Clinical Research Center of Cancer; Key Laboratory of Cancer Immunology and Biotherapy, Tianjin, 300060, China. zhangxinwei@tjmuch.com.|Department of Biotherapy, Tianjin Medical University Cancer Institute and Hospital, Tianjin, 300060, China. zhangxinwei@tjmuch.com.
authors.forename: Xinwei
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Department of Immunology, Tianjin Medical University Cancer Institute and Hospital; National Clinical Research Center of Cancer; Key Laboratory of Cancer Immunology and Biotherapy, Tianjin, 300060, China. renxiubao@tjmuch.com.|Department of Biotherapy, Tianjin Medical University Cancer Institute and Hospital, Tianjin, 300060, China. renxiubao@tjmuch.com.
authors.forename: Xiubao
authors.initials: X
authors.lastname: Ren
mesh_terms: D000818:Animals; D015153:Blotting, Western; D045744:Cell Line, Tumor; D054443:Cell Migration Assays; D002465:Cell Movement / Q000502:physiology; D018932:Chemokine CCL2 / Q000235:genetics* / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D059630:Mesenchymal Stem Cells / Q000378:metabolism*; D051379:Mice; D058990:Molecular Targeted Therapy; D060888:Real-Time Polymerase Chain Reaction; D054390:Receptors, CCR2 / Q000235:genetics* / Q000378:metabolism; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000494:pharmacology*; D014470:Umbilical Cord / Q000166:cytology
chemical_list: C111835:CCL2 protein, human; C515334:CCR2 protein, human; D018932:Chemokine CCL2; D054390:Receptors, CCR2; D053221:TNF-Related Apoptosis-Inducing Ligand
keywords: CCR2; Lung cancer; MCP-1; Mesenchymal stem cell; TRAIL