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Research Articles: Therapeutics, Targets, and Development

Plasminogen Kringle 5 blocks tumor progression by antiangiogenic and proinflammatory pathways

¹ Division of Experimental Medicine, Lady Davis Institute for Medical Research, McGill University; ² Department of Pathology and Microbiology, Université de Montréal; ³ Lady Davis Institute for Medical Research; ⁴ Animal Cell Technology, Biotechnology Research Institute; and ⁵ Division of Hematology/Oncology, Department of Medicine, Jewish General Hospital, Montreal, Quebec, Canada

Requests for reprints: Jacques Galipeau, Lady Davis Institute for Medical Research, 3755 Cote-Ste-Catherine Road, Montreal, Quebec, Canada H3T 1E2. Phone: 514-340-8214; Fax: 514-340-8281. E-mail: jacques.galipeau{at}mcgill.ca

Abstract

Proteolytic processing of human plasminogen generates potent antiangiogenic peptides such as angiostatin. The plasminogen kringle 5 (K5) domain, which is distinct from angiostatin, possesses potent antiangiogenic properties on its own, which can be exploited in cancer therapy. It has been recently observed that antiangiogenic agents promote leukocyte-vessel wall interaction as part of their antitumor effect. Although 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 nonobese diabetic/severe combined immunodeficient and BALB/c nude when compared with wild-type BALB/c mice, suggesting an important role for T-lymphoid cells in the antitumor effect of K5. Tumor explant analysis shows 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 antiangiogenic activity. Histologic 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 up-regulation 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 antitumor response. [Mol Cancer Ther 2007;6(2):441–9]

Grant support: CIHR operating grant MOP-15017.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Note: S.R. Perri is a recipient of the U.S. Army Medical Research and Materiel Command Breast Cancer Research Predoctoral Traineeship Award DAMD17-03-1-0545. J. Galipeau is a recipient of the CIHR Clinician-Scientist Award.

Received 7/25/06; revised 10/ 2/06; accepted 12/21/06.

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