Systemic inhibition of tumor growth and angiogenesis by thrombospondin-2 using cell-based antiangiogenic gene therapy.
Recent studies indicate that continuous administration improves the antitumoral efficacy of angiogenesis inhibitors, as compared with intermittent dosing, suggesting a potential role of gene therapy in antiangiogenic tumor therapy. We established a tissue-engineered implant system for the continuous in vivo production of thrombospondin-2 (TSP-2), a potent endogenous inhibitor of tumor growth and angiogenesis. Fibroblasts were retrovirally transduced to overexpress TSP-2 and were seeded onto biodegradable polymer scaffolds. After transplantation into the peritoneal cavity of nude mice, bioimplants maintained high levels of TSP-2 secretion over extended time periods, resulting in increased levels of circulating TSP-2. Bioimplant-generated TSP-2 potently inhibited tumor growth and angiogenesis of human squamous cell carcinomas, malignant melanomas, and Lewis lung carcinomas that were implanted at a distant site. These results provide the first proof-of-principle for the feasibility and therapeutic efficiency of systemic, cell-based antiangiogenic gene therapy using biodegradable polymer grafts for the treatment of cancer.
Streit
Michael
M
Cutaneous Biology Research Center and Department of Dermatology, Massachusetts General Hospital and Harvard Medical School, Charlestown 02129, USA.
Stephen
Antonia E
AE
Hawighorst
Thomas
T
Matsuda
Kant
K
Lange-Asschenfeldt
Bernhard
B
Brown
Lawrence F
LF
Vacanti
Joseph P
JP
Detmar
Michael
M
D016475:3T3 Cells / Q000378:metabolism / Q000637:transplantation; D000818:Animals; D002294:Carcinoma, Squamous Cell / Q000098:blood supply* / Q000473:pathology / Q000628:therapy; D002455:Cell Division / Q000235:genetics; D017690:Cell Transplantation / Q000379:methods; D015316:Genetic Therapy / Q000379:methods*; D006801:Humans; D008546:Melanoma, Experimental / Q000098:blood supply* / Q000473:pathology / Q000628:therapy; D051379:Mice; D009389:Neovascularization, Pathologic / Q000628:therapy*; D011108:Polymers; D019736:Prostheses and Implants; D012190:Retroviridae / Q000235:genetics; D019699:Thrombospondins / Q000096:biosynthesis / Q000235:genetics* / Q000378:metabolism; D014162:Transfection; D014407:Tumor Cells, Cultured; D000099262:Thrombospondin 2
D011108:Polymers; D019699:Thrombospondins; D000099262:Thrombospondin 2