Antiangiogenic cancer therapy with microencapsulated cells.
Inhibition of angiogenesis has led to tumor suppression in several cancer models. Although administering purified recombinant antiangiogenic product is effective, alternative approaches through genetic manipulation may be more cost-effective. We propose to implant nonautologous recombinant cells secreting angiostatin for systemic delivery of angiostatin in cancer treatment. These cells are protected from graft rejection in alginate microcapsules to function as "micro-organs" to deliver angiostatin in vivo. This approach was tested by implanting encapsulated mouse myoblast C2C12 cells genetically modified to secrete angiostatin into mice bearing solid tumor. Angiostatin was detected in sera of the treated mice. Efficacy was demonstrated by suppression of palpable tumor growth and improved survival. At autopsy, angiostatin localized to residual tumors and high levels of angiostatic activity were detected in tumor extracts. Tumor tissues showed increased apoptosis and necrosis compared with those from untreated or mock-treated mice. Immunohistochemical staining against von Willebrand factor, an endothelial cell marker, showed that within tumors from the treated mice, the neovasculature was poorly defined by endothelial cells, many of which were undergoing apoptosis. However, the tumors eventually developed neovasculature independent of endothelial cells. Such vascular mimicry would account for the lack of long-term efficacy despite persistent angiostatin delivery. In conclusion, implantation with nonautologous microencapsulated cells is feasible for systemic delivery of angiostatin, resulting in localization of angiostatin to tumors and targeted apoptosis of the endothelial cells. Clinical efficacy was demonstrated by suppression of tumor growth and extension of life span. Although the potential of this cell-based approach for angiostatin-mediated cancer therapy is confirmed, long-term efficacy must take into account the possible escape by some tumors from angiogenesis inhibition.
Cirone
Pasquale
P
Department of Biology, McMaster University, Hamilton, Ontario L8N 3Z5, Canada.
Bourgeois
Jacqueline M
JM
Chang
Patricia L
PL
D000464:Alginates / Q000737:chemistry; D020533:Angiogenesis Inhibitors; D043168:Angiostatins; D000818:Animals; D017209:Apoptosis; D002460:Cell Line; D017690:Cell Transplantation / Q000379:methods; D004730:Endothelium, Vascular / Q000378:metabolism / Q000473:pathology; D005260:Female; D005818:Genetic Engineering; D006084:Graft Rejection / Q000517:prevention & control; D007150:Immunohistochemistry; D007274:Injections, Intraperitoneal; D051379:Mice; D008810:Mice, Inbred C57BL; D032446:Myoblasts / Q000378:metabolism / Q000637:transplantation; D009374:Neoplasms, Experimental / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D010446:Peptide Fragments / Q000235:genetics*; D010958:Plasminogen / Q000235:genetics*; D011107:Polylysine / Q000031:analogs & derivatives* / Q000737:chemistry; D014407:Tumor Cells, Cultured; D014841:von Willebrand Factor / Q000032:analysis / Q000276:immunology
D000464:Alginates; D020533:Angiogenesis Inhibitors; D010446:Peptide Fragments; C051546:alginate-polylysine-alginate; D014841:von Willebrand Factor; D011107:Polylysine; D043168:Angiostatins; D010958:Plasminogen