Engineered Autologous Stromal Cells for the Delivery of Kringle 5, a Potent Endothelial Cell Specific Inhibitor for Anti-Angiogenic Breast Cancer Therapy
Annual summary rept. 10 Jul 2003-9 Jul 2006
SIR MORTIMER B DAVIS JEWISH GENERAL HOSPITAL MONTREAL (QUEBEC)
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The plasminogen kringle 5 K5 domain - which is distinct from angiostatin - possesses potent anti-angiogenic properties on its own which can be exploited in cancer therapy. We have previously shown that K5 suppresses cancer growth in tumor xenograft models, its modulation of inflammation in experimental mice with intact immune systems is unknown. To determine whether K5 possesses immune proinflammatory properties, we investigated the effects of K5 in an immune competent model of breast cancer and observed that tumor rejection is substantially reduced in NOD-SCID and BALBc nude when compared to wild-type BALBc mice, suggesting an important role for T-lymphoid cells in the anti-tumor effect of K5. Tumor explant analysis demonstrates that K5 enhances tumor recruitment of CD3 lymphoid cells, in particular the NKT phenotype. We also observed a significant decrease in tumor-associated microvessel length and density consistent with anti-angiogenic activity. Histological analysis of K5 tumors also revealed a robust neutrophilic infiltrate, which may be explained by the neutrophil chemotactic activity of K5 as well as its ability to promote CD64 upregulation within the CD11b adhesive neutrophil population. In sum, our findings confirm that the K5 protein acts as a potent angiostatic agent and possesses a novel proinflammatory role via its ability to recruit tumor-associated neutrophils and NKT-lymphocytes, leading to a potent anti-tumor response.
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